WO2022193806A1 - Method for asymmetric catalytic synthesis of nicotine - Google Patents

Method for asymmetric catalytic synthesis of nicotine Download PDF

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WO2022193806A1
WO2022193806A1 PCT/CN2022/071759 CN2022071759W WO2022193806A1 WO 2022193806 A1 WO2022193806 A1 WO 2022193806A1 CN 2022071759 W CN2022071759 W CN 2022071759W WO 2022193806 A1 WO2022193806 A1 WO 2022193806A1
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reaction
compound
nicotine
chiral
catalyst
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PCT/CN2022/071759
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French (fr)
Chinese (zh)
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稂琪伟
高爽
丁小兵
苏伟
肖阳
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凯特立斯（深圳）科技有限公司
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    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
    • B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
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    • B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
    • B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
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Definitions

  • the invention belongs to the technical field of chemical synthesis and preparation, and relates to asymmetric catalysis of compounds, in particular to a method for asymmetric catalytic synthesis of nicotine.
  • Asymmetric hydrogenation to prepare a chiral alcohol intermediate with high optical activity is a key step in the invention.
  • Nicotine widely exists in tobacco plants and various Solanaceae plants. It is a chiral amine alkaloid containing pyridine and tetrahydropyrrole rings, and has unique physiological activities due to its special structure.
  • nicotinic compounds are widely used insecticides; on the other hand, in the field of medicine, clinical studies have shown that nicotinic action on acetylcholine receptors is expected to be a promising candidate for the treatment of Alzheimer's disease, PA.
  • Effective drugs for other central nervous system disorders such as Kinson's disease, schizophrenia and depression.
  • nicotine can also be used as a chiral ionic liquid to participate in various asymmetric chemical reactions.
  • the chemical synthesis of nicotine has always been the focus of scientists. Natural nicotine was first isolated from tobacco by German chemists Posselt and Reimann in 1828, and was first synthesized in the laboratory by A. Pictet and Crepieux in 1904. After more than 100 years of development, there have been many research reports on chemical preparation of nicotine.
  • the existing chemical synthesis methods of nicotine are mainly divided into two categories. The first category is to synthesize racemic nicotine first, and then obtain nicotine through the method of chiral separation. This method has simple synthesis steps, but requires a large amount of manual work. Separation and purification operations are complicated and costly.
  • the second type is to obtain nicotine directly through asymmetric synthesis, without additional chiral separation reagents, and optically active nicotine can be directly obtained, but these methods are very expensive for large-scale preparation of nicotine, and there is no commercial synthetic route.
  • Journal of Organic Chemisry, 1982, 47, 1069-1073; Chavdarian et al. first reported the work of asymmetric synthesis of nicotine (reaction formula 1). They used L-Proline as the initial raw material to obtain the module of chiral amino alcohol, and then obtained the target product (S)-nicotine through five-step reaction, but its ee value was only 24%.
  • Patent: CN 104341390A This work uses a kind of iridium-phosphine oxazoline chiral catalyst to catalyze the cyclic imine containing pyridine group, obtains key chiral intermediate with very high ee value, then obtains ( S)-nicotine, its ee value is as high as 98% (reaction 4).
  • the existing asymmetric nicotine synthesis method not only uses expensive reagents, but also requires low-temperature reaction, many reaction steps, complicated separation and purification operations, increased production cost and equipment cost, and is difficult to be used in industrial production.
  • the present invention discloses an asymmetric catalytic synthesis method for nicotine, which prepares a highly optically active chiral alcohol through asymmetric catalytic hydrogenation reaction, forms a tetrahydropyrrole ring through intramolecular ring closure, and then undergoes asymmetric catalytic hydrogenation to prepare a chiral alcohol with high optical activity.
  • the target product nicotine can be obtained by methylation. It is a green and pollution-free synthetic route with high atomic economy, which can greatly reduce the amount of three wastes and is conducive to industrial scale-up production.
  • the invention provides a kind of asymmetric catalytic synthesis method of nicotine, which is realized by the following technical solutions:
  • the intermediate (2) is charged with hydrogen to react to obtain a hydrogenated product (3), wherein the catalyst can be a ruthenium bisphosphine bisamine catalytic system, and the general structural formula is:
  • Ar group can be phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, Methyl-p-isopropylphenyl, etc.
  • the R group can be an H atom, or an aliphatic hydrocarbon of 1 to 6 carbon atoms or an aromatic group of 6 to 12 carbon atoms;
  • the above-mentioned catalyst can also be obtained by in-situ complexation of a metal compound and a chiral ligand, the catalyst metal salt is selected from common permetal compounds such as ruthenium, rhodium, iridium, and palladium, and the chiral ligand is selected from:
  • the Cat.A is selected from Cat.4-10:
  • the homogeneous catalytic hydrogenation reaction is carried out in a mixed solvent containing one or any ratio of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane and toluene, more preferably alcohols solvent.
  • the base used in the homogeneous catalytic hydrogenation reaction is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, carbonic acid
  • the base is the potassium salt.
  • the temperature of the homogeneous catalytic hydrogenation reaction is 25-80 degrees Celsius
  • the hydrogen pressure is 2-8 Mpa
  • the homogeneous catalytic hydrogenation reaction time is 8-60 hours.
  • the transition metal catalyst is preferably obtained by complexing [Ir(COD)Cl] 2 with a chiral ligand, and the chiral ligand is preferably:
  • the present invention further provides novel intermediate compounds selected from compound (2) or (3), wherein the structure of compound (2) is as follows:
  • the present invention further provides a method for preparing nicotine.
  • the synthesis route is as follows, wherein the intermediate formula (3) is prepared by the aforementioned method.
  • the asymmetric hydrogenated precursor 2 was obtained by reacting with N-Boc-2-pyrrolidone, and the precursor 2 was obtained with high enantioselectivity under the induction of transition metal catalysts.
  • the chiral intermediate 3 is obtained, the chiral alcohol is derivatized to obtain the intermediate 4, and finally the amino protecting group is removed and the tetrahydropyrrole 5 is obtained by intramolecular ring closure under basic conditions, and finally N-methylation can be obtained. nicotine.
  • the intermediate (2) is dissolved in a suitable solvent, a chiral catalyst and a suitable base are added, the mol ratio of the intermediate (2) and the catalyst is 2mmol: 0.01-1nmol, and the gas in the reactor is replaced with hydrogen three times. , and finally filled with 2-8Mpa hydrogen, reacted at 20-80°C for 8-60 hours, slowly released the gas in the reaction kettle, spin-dried, and purified by silica gel column chromatography to obtain a chiral hydrogenation product (3);
  • the chiral alcohol product (3) is activated to form a suitable leaving group, such as halogen, sulfonate, etc.,
  • the intermediate (4) is reacted with a suitable reagent to remove the amino protecting group, then under alkaline conditions, an intramolecular nucleophilic ring-closing reaction occurs, and after the reaction is completed, it is extracted with ethyl acetate, The organic phase was collected and concentrated to obtain the chiral tetrahydropyrrole compound (5);
  • the intermediate (5) was added with formic acid and paraformaldehyde solution to react for 5 hours, cooled to room temperature, added potassium carbonate until the reaction solution was alkaline, extracted with ethyl acetate, and distilled under reduced pressure to obtain nicotine product.
  • the leaving group LG in the compound (4) is preferably halogen, sulfonate, more preferably chlorine, methanesulfonate (OMs), p-toluenesulfonate (OTs).
  • the reagent for removing the amino protecting group of compound (4) is preferably hydrochloric acid or trifluoroacetic acid.
  • the present invention successfully develops a method for preparing nicotine, which can efficiently construct a chiral alcohol intermediate by catalyzing the asymmetric hydrogenation of pyridyl alkyl ketone.
  • the reaction is highly stable and reactive, achieves excellent steric control, and can yield chiral alcohol intermediates with greater than 99% enantioselectivity.
  • the present invention is stable in operation, low in cost, environmentally friendly, and has extremely high industrial value.
  • Figure 1 is a schematic diagram of the asymmetric synthesis process of nicotine.
  • 3-bromopyridine (3.16g, 20mmol) was added to the three-necked round-bottomed flask and dissolved in 50mL of anhydrous tetrahydrofuran, stirred and cooled to -78°C in a low temperature tank, and then 4.8mL of n-butyllithium (4.8mL) was slowly added dropwise.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 50 mL of methylene chloride was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10 g of a red oily liquid, i.e. hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
  • the reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours.
  • the gas in the autoclave was slowly released, 500 mL of methylene chloride was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 101 g of a red oily liquid, i.e. hydrogenation product 3a, with a yield of 99%, The ee value was found to be 99% by HPLC analysis.
  • reaction yield was 95%.

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  • Inorganic Chemistry (AREA)
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Abstract

The present invention relates to a method for asymmetric catalytic synthesis of nicotine, specifically to a method for preparing nicotine by five-step reaction by using 3-bromopyridine as a starting material, specifically comprising: 1) carrying out a nucleophilic reaction of 3-bromopyridine and N-Boc-2-pyrrolidone under suitable conditions to obtain a hydrogenated precursor compound (2); 2) obtaining a chiral alcohol intermediate compound (3) having high optical activity by means of asymmetric catalysis of a chiral catalyst; 3) carrying out activation to cause a chiral alcohol to become a leaving group to obtain a compound (4); 4) under suitable conditions, removing protecting groups on nitrogen and causing intramolecular ring closure to obtain a compound (5); and 5) finally, carrying out an N-methylation reaction to purify the product to obtain nicotine. The preparation of the chiral alcohol intermediate compound (3) having high optical activity by asymmetric catalytic reduction is the key step of the method. The present method is easy to operate, low in cost, and applicable to industrial preparation.

Description

一种不对称催化合成尼古丁的方法A kind of method for asymmetric catalytic synthesis of nicotine 技术领域technical field
本发明属于化学合成制备技术领域，涉及化合物的不对称催化，具体涉及一种尼古丁的不对称催化合成方法，不对称氢化制备高光学活性的手性醇中间体为该发明中的关键步骤。The invention belongs to the technical field of chemical synthesis and preparation, and relates to asymmetric catalysis of compounds, in particular to a method for asymmetric catalytic synthesis of nicotine. Asymmetric hydrogenation to prepare a chiral alcohol intermediate with high optical activity is a key step in the invention.
背景技术Background technique
尼古丁广泛存在于烟草植株和各种茄科植物中，是一种含吡啶和四氢吡咯环的手性胺类生物碱，由于其特殊的结构而具有独特的生理活性。一方面在农业生产中，烟碱类化合物是一种广泛使用的杀虫剂；另一方面在医药领域，已有临床研究表明，烟碱能作用于乙酰胆碱受体有望成为治疗老年痴呆症、帕金森症、精神分裂症和抑郁症等其他的中枢神经系统疾病的有效药物。除此之外，在化学合成领域中，有研究报道，尼古丁还可以作为一种手性离子液体参与各种不对称化学反应。Nicotine widely exists in tobacco plants and various Solanaceae plants. It is a chiral amine alkaloid containing pyridine and tetrahydropyrrole rings, and has unique physiological activities due to its special structure. On the one hand, in agricultural production, nicotinic compounds are widely used insecticides; on the other hand, in the field of medicine, clinical studies have shown that nicotinic action on acetylcholine receptors is expected to be a promising candidate for the treatment of Alzheimer's disease, PA. Effective drugs for other central nervous system disorders such as Kinson's disease, schizophrenia and depression. In addition, in the field of chemical synthesis, it has been reported that nicotine can also be used as a chiral ionic liquid to participate in various asymmetric chemical reactions.
经科学研究证实，尼古丁对乙酰胆碱受体的亲和力是右旋烟碱的10-100倍，在市场上其应用也更为广泛。而目前市场上所用的尼古丁主要来源于植物提取，其来源受到了原材料、气候以及周期等诸多方面因素的影响，仅仅依靠从植物中提取尼古丁已经不能满足市场的需要。因此，借助化学合成制备技术去实现尼古丁的大规模生产具有重要的意义。It has been confirmed by scientific research that the affinity of nicotine for acetylcholine receptors is 10-100 times that of d-nicotine, and its application in the market is also more extensive. At present, the nicotine used in the market mainly comes from plant extraction, and its source is affected by many factors such as raw materials, climate, and cycle. It is no longer enough to rely on nicotine extraction from plants to meet the needs of the market. Therefore, it is of great significance to realize the large-scale production of nicotine by means of chemical synthesis preparation technology.
Figure PCTCN2022071759-appb-000001
Figure PCTCN2022071759-appb-000001
烟碱的化学合成研究一直是科学家们所关注的焦点。天然烟碱在1828年首次由德国化学家Posselt和Reimann从烟草中分离出来，并于1904年由A.Pictet和Crepieux首次在实验室中用合成的方式得到。经过了一百多年的发展，出现了很多化学制备尼古丁的研究工作报道。现有的尼古丁的化学合成方法主要分为两大类，第一类是先合成消旋烟碱，再通过手性拆分的方法得到尼古丁，这种方法合成步骤简单，但是需要使用大量的手性拆分试剂使分离纯化操作变得复杂， 而且成本较高。参见例如：文献Journal ofOrganic Chemistry,1990,55,1736-1744；文献Journal ofthe Chemical Society,Perkin Transactions I,2002(2),143-154；文献Synlett,2009(15),2497-2499；文献Journal of Heterocyclic Chemistry,2009,46(6),1252-1258；专利CN 102617547A；专利CN 107406411A等。The chemical synthesis of nicotine has always been the focus of scientists. Natural nicotine was first isolated from tobacco by German chemists Posselt and Reimann in 1828, and was first synthesized in the laboratory by A. Pictet and Crepieux in 1904. After more than 100 years of development, there have been many research reports on chemical preparation of nicotine. The existing chemical synthesis methods of nicotine are mainly divided into two categories. The first category is to synthesize racemic nicotine first, and then obtain nicotine through the method of chiral separation. This method has simple synthesis steps, but requires a large amount of manual work. Separation and purification operations are complicated and costly. See for example: Journal of Organic Chemistry, 1990, 55, 1736-1744; Journal of the Chemical Society, Perkin Transactions I, 2002(2), 143-154; Synlett, 2009(15), 2497-2499; Journal of Heterocyclic Chemistry, 2009, 46(6), 1252-1258; Patent CN 102617547A; Patent CN 107406411A, etc.
第二类是直接通过不对称合成的方法得到尼古丁，不需要额外的手性拆分试剂，可以直接获得光学活性的烟碱，但这些方法用于大规模制备尼古丁是非常昂贵的，尚未出现商业化的合成路线。例如：文献JournalofOrganic Chemisry,1982,47,1069-1073；Chavdarian等首次报道了尼古丁的不对称合成工作(反应式1)。他们以L-Proline为初始原料制得手性氨基醇的模块，再通过五步反应得到了目标产物(S)-nicotine，然而其ee值仅有24％。The second type is to obtain nicotine directly through asymmetric synthesis, without additional chiral separation reagents, and optically active nicotine can be directly obtained, but these methods are very expensive for large-scale preparation of nicotine, and there is no commercial synthetic route. For example: Journal of Organic Chemisry, 1982, 47, 1069-1073; Chavdarian et al. first reported the work of asymmetric synthesis of nicotine (reaction formula 1). They used L-Proline as the initial raw material to obtain the module of chiral amino alcohol, and then obtained the target product (S)-nicotine through five-step reaction, but its ee value was only 24%.
反应式1：Reaction 1:
Figure PCTCN2022071759-appb-000002
Figure PCTCN2022071759-appb-000002
文献：Organic&Biomolecular Chemistry,2005,3,3266-3268；Helmchen等通过金属铱催化烯丙基还原胺化的策略完成了(S)-nicotine的不对称合成，其ee值高达99％(反应式2)。Literature: Organic & Biomolecular Chemistry, 2005, 3, 3266-3268; Helmchen et al. completed the asymmetric synthesis of (S)-nicotine through the strategy of metal iridium-catalyzed reductive amination of allyl groups, and its ee value was as high as 99% (reaction formula 2) .
反应式2：Reaction 2:
Figure PCTCN2022071759-appb-000003
Figure PCTCN2022071759-appb-000003
文献：Journalof Organic Chemistry,2011,76(15),5936-5953；O’Brien等通过锂化、转金属、金属钯催化的Negishi偶联反应，从简单易得的原料N-Boc-四氢吡咯出发，完成了(S)-nicotine的不对称合成，其ee值高达84％(反应式3)。Literature: Journal of Organic Chemistry, 2011, 76(15), 5936-5953; O'Brien et al. obtained N-Boc-tetrahydropyrrole from the simple and readily available raw material N-Boc-tetrahydropyrrole through lithiation, metal transfer, and palladium-catalyzed Negishi coupling reaction. The asymmetric synthesis of (S)-nicotine was completed, and its ee value was as high as 84% (reaction 3).
反应式3：Reaction 3:
Figure PCTCN2022071759-appb-000004
Figure PCTCN2022071759-appb-000004
专利：CN 104341390A；该工作用一种铱-膦噁唑啉手性催化剂催化含吡啶基团的环状亚胺，以很高的ee值得到关键手性中间体，再通过两步反应得到(S)-nicotine，其ee值高达98％(反应式4)。Patent: CN 104341390A; This work uses a kind of iridium-phosphine oxazoline chiral catalyst to catalyze the cyclic imine containing pyridine group, obtains key chiral intermediate with very high ee value, then obtains ( S)-nicotine, its ee value is as high as 98% (reaction 4).
反应式4：Reaction 4:
Figure PCTCN2022071759-appb-000005
Figure PCTCN2022071759-appb-000005
总之，现有的不对称合成尼古丁方法，不但所用试剂价格昂贵，而且需要采用低温反应，反应步骤多，分离纯化操作复杂，增加了生产成本和设备成本，很难用于工业化生产。In a word, the existing asymmetric nicotine synthesis method not only uses expensive reagents, but also requires low-temperature reaction, many reaction steps, complicated separation and purification operations, increased production cost and equipment cost, and is difficult to be used in industrial production.
发明内容SUMMARY OF THE INVENTION
鉴于目前合成尼古丁的方法存在诸多不足，本发明公开一种尼古丁的不对称催化合成方法，通过不对称催化氢化反应制备高光学活性手性醇，经分子内关环形成四氢吡咯环，再经甲基化就可以得到目标产物尼古丁(nicotine)。它是一 条原子经济性高，绿色无污染的合成路线，能够大大降低三废量，利于工业放大生产。In view of the shortcomings of the current methods for synthesizing nicotine, the present invention discloses an asymmetric catalytic synthesis method for nicotine, which prepares a highly optically active chiral alcohol through asymmetric catalytic hydrogenation reaction, forms a tetrahydropyrrole ring through intramolecular ring closure, and then undergoes asymmetric catalytic hydrogenation to prepare a chiral alcohol with high optical activity. The target product nicotine can be obtained by methylation. It is a green and pollution-free synthetic route with high atomic economy, which can greatly reduce the amount of three wastes and is conducive to industrial scale-up production.
本发明提供一种尼古丁的不对称催化合成方法，通过以下技术方案来实现：The invention provides a kind of asymmetric catalytic synthesis method of nicotine, which is realized by the following technical solutions:
一种尼古丁中间体下式(3)的不对称催化合成方法，其反应路线为：An asymmetric catalytic synthesis method of the following formula (3) of a nicotine intermediate, the reaction route of which is:
Figure PCTCN2022071759-appb-000006
Figure PCTCN2022071759-appb-000006
中间体(2)在手性催化剂存在情况下，充入氢气反应得到氢化产物(3)，其中，所述催化剂可以为钌双膦双胺催化体系，结构通式为：In the presence of a chiral catalyst, the intermediate (2) is charged with hydrogen to react to obtain a hydrogenated product (3), wherein the catalyst can be a ruthenium bisphosphine bisamine catalytic system, and the general structural formula is:
Figure PCTCN2022071759-appb-000007
Figure PCTCN2022071759-appb-000007
式(1)所示化合物，X,Y各自独立为卤素或醋酸根或氢；Compound represented by formula (1), X, Y are each independently halogen or acetate or hydrogen;
Figure PCTCN2022071759-appb-000008
表示双膦配体，
Figure PCTCN2022071759-appb-000009
表示二胺结构；
Figure PCTCN2022071759-appb-000008
represents a bisphosphine ligand,
Figure PCTCN2022071759-appb-000009
Represents the diamine structure;
具体地举例如下：Specific examples are as follows:
Figure PCTCN2022071759-appb-000010
Figure PCTCN2022071759-appb-000010
其中，式Cat.A、Cat.1-4中，Ar基团可以为苯基、4-甲基苯基，3,5-二甲基苯基、3,5-二叔丁基苯基、甲基对异丙基苯基等，R基团可以为H原子，或1～6个碳原子的脂肪烃或6～12个碳原子的芳香性基团；Wherein, in formula Cat.A, Cat.1-4, Ar group can be phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, Methyl-p-isopropylphenyl, etc., the R group can be an H atom, or an aliphatic hydrocarbon of 1 to 6 carbon atoms or an aromatic group of 6 to 12 carbon atoms;
以上所述催化剂也可以为由金属化合物和手性配体原位络合得到，催化剂金属盐选自钌、铑、铱、钯等常见过金属化合物，手性配体选自：The above-mentioned catalyst can also be obtained by in-situ complexation of a metal compound and a chiral ligand, the catalyst metal salt is selected from common permetal compounds such as ruthenium, rhodium, iridium, and palladium, and the chiral ligand is selected from:
Figure PCTCN2022071759-appb-000011
Figure PCTCN2022071759-appb-000011
化合物3中所述*表示有R或者S两种构型。The * in compound 3 indicates that there are two configurations of R or S.
作为本发明的一种优选方案，所述Cat.1中Ar＝Ph；Cat.2中Ar＝Xyl；Cat.3中Ar＝Ph；As a preferred solution of the present invention, Ar=Ph in Cat.1; Ar=Xyl in Cat.2; Ar=Ph in Cat.3;
所述Cat.A选自Cat.4-10：The Cat.A is selected from Cat.4-10:
Figure PCTCN2022071759-appb-000012
Figure PCTCN2022071759-appb-000012
作为本发明的一种优选方案，所述均相催化氢化反应在含有甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、甲苯的一种或任意比例的混合溶剂中进行，更优选为醇类溶剂。As a preferred solution of the present invention, the homogeneous catalytic hydrogenation reaction is carried out in a mixed solvent containing one or any ratio of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane and toluene, more preferably alcohols solvent.
作为本发明的一种优选方案，所述均相催化氢化反应所用的碱为叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钾、氢氧化钠、碳酸钠、碳酸钾、碳酸铯的一种或任意比例的混合物，更优选碱为钾盐。As a preferred version of the present invention, the base used in the homogeneous catalytic hydrogenation reaction is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, carbonic acid One or a mixture of cesium in any ratio, more preferably the base is the potassium salt.
作为本发明的一种优选方案，所述均相催化氢化反应的温度为25-80摄氏度，氢气压力为2-8Mpa，所述均相催化氢化反应时间为8-60小时。As a preferred solution of the present invention, the temperature of the homogeneous catalytic hydrogenation reaction is 25-80 degrees Celsius, the hydrogen pressure is 2-8 Mpa, and the homogeneous catalytic hydrogenation reaction time is 8-60 hours.
作为本发明的一种优选方案，过渡金属催化剂优选为[Ir(COD)Cl] 2和手性配体络合得到，手性配体优选为： As a preferred solution of the present invention, the transition metal catalyst is preferably obtained by complexing [Ir(COD)Cl] 2 with a chiral ligand, and the chiral ligand is preferably:
Figure PCTCN2022071759-appb-000013
Figure PCTCN2022071759-appb-000013
本发明进一步提供了新颖的中间体化合物，所述化合物选自化合物(2)或者(3)，其中化合物(2)结构如下式：The present invention further provides novel intermediate compounds selected from compound (2) or (3), wherein the structure of compound (2) is as follows:
Figure PCTCN2022071759-appb-000014
Figure PCTCN2022071759-appb-000014
所述化合物(3)结构如下式：The structure of the compound (3) is as follows:
Figure PCTCN2022071759-appb-000015
Figure PCTCN2022071759-appb-000015
其中，所述化合物式(3)中“*”包括R和S两种构型。Wherein, "*" in the compound formula (3) includes two configurations of R and S.
本发明进一步提供了一种尼古丁的制备方法，合成路线如下，其中，所述中间体式(3)通过前述的方法制备得到。The present invention further provides a method for preparing nicotine. The synthesis route is as follows, wherein the intermediate formula (3) is prepared by the aforementioned method.
Figure PCTCN2022071759-appb-000016
Figure PCTCN2022071759-appb-000016
从廉价易得的3-溴吡啶1为起始原料，经与N-Boc-2-吡咯烷酮反应得到不对称氢化的前体2，并在过渡金属催化剂的诱导下以高对映选择性得到重要的手性中间体3，手性醇经衍生化得到中间体4，最后脱去氨基保护基在碱性条件下经分子内关环得到四氢吡咯5，最后经N-甲基化后可以得到尼古丁。Starting from cheap and readily available 3-bromopyridine 1, the asymmetric hydrogenated precursor 2 was obtained by reacting with N-Boc-2-pyrrolidone, and the precursor 2 was obtained with high enantioselectivity under the induction of transition metal catalysts. The chiral intermediate 3 is obtained, the chiral alcohol is derivatized to obtain the intermediate 4, and finally the amino protecting group is removed and the tetrahydropyrrole 5 is obtained by intramolecular ring closure under basic conditions, and finally N-methylation can be obtained. nicotine.
进一步地，通过以下技术方案来实现，包括以下步骤：Further, it is realized by the following technical solutions, including the following steps:
1)氩气保护下，3-溴吡啶的四氢呋喃溶液在-40℃下与n-BuLi的正己烷溶液或异丙基氯化镁溶液混合，然后与N-Boc-2-吡咯烷酮混合反应；室温下用稀盐酸溶液淬灭反应，乙酸乙酯萃取，粗产物干燥，旋干，打浆纯化得到中间体(2)；1) Under the protection of argon, the tetrahydrofuran solution of 3-bromopyridine is mixed with n-BuLi's n-hexane solution or isopropyl magnesium chloride solution at -40°C, and then mixed with N-Boc-2-pyrrolidone; The reaction was quenched with dilute hydrochloric acid solution, extracted with ethyl acetate, the crude product was dried, spin-dried, and purified by beating to obtain intermediate (2);
2)将中间体(2)溶于合适的溶剂中，加入手性催化剂和合适的碱，所述中间体(2)与催化剂的摩尔比为2mmol：0.01-1nmol，用氢气置换反应釜气体三次，最后充入2-8Mpa氢气，20-80℃下反应8-60小时，缓慢释放反应釜中的气体，旋干，用硅胶柱层析纯化，得到手性氢化产物(3)；2) the intermediate (2) is dissolved in a suitable solvent, a chiral catalyst and a suitable base are added, the mol ratio of the intermediate (2) and the catalyst is 2mmol: 0.01-1nmol, and the gas in the reactor is replaced with hydrogen three times. , and finally filled with 2-8Mpa hydrogen, reacted at 20-80°C for 8-60 hours, slowly released the gas in the reaction kettle, spin-dried, and purified by silica gel column chromatography to obtain a chiral hydrogenation product (3);
3)手性醇产物(3)经过活化形成合适的离去基团，如卤素，磺酸酯等，3) The chiral alcohol product (3) is activated to form a suitable leaving group, such as halogen, sulfonate, etc.,
4)在合适的条件下，中间体(4)与合适的试剂反应脱去氨基保护基，然后在碱性条件下，发生分子内的亲核关环反应，反应完后用乙酸乙酯萃取，收集有机相浓缩得手性四氢吡咯化合物(5)；4) Under suitable conditions, the intermediate (4) is reacted with a suitable reagent to remove the amino protecting group, then under alkaline conditions, an intramolecular nucleophilic ring-closing reaction occurs, and after the reaction is completed, it is extracted with ethyl acetate, The organic phase was collected and concentrated to obtain the chiral tetrahydropyrrole compound (5);
5)在80℃下，中间体(5)加入甲酸和多聚甲醛溶液反应5小时，冷至室温，加碳酸钾直到反应液呈碱性，乙酸乙酯萃取，减压蒸馏得到尼古丁产品。5) At 80°C, the intermediate (5) was added with formic acid and paraformaldehyde solution to react for 5 hours, cooled to room temperature, added potassium carbonate until the reaction solution was alkaline, extracted with ethyl acetate, and distilled under reduced pressure to obtain nicotine product.
作为本发明的一种优选技术方案，所述化合物(4)中离去基团LG优选为卤素，磺酸酯，更优选为氯，甲磺酸酯(OMs)，对甲苯基磺酸酯(OTs)。As a preferred technical solution of the present invention, the leaving group LG in the compound (4) is preferably halogen, sulfonate, more preferably chlorine, methanesulfonate (OMs), p-toluenesulfonate ( OTs).
作为本发明的一种优选方案，化合物(4)脱去氨基保护基的试剂优选为盐酸，三氟乙酸。As a preferred solution of the present invention, the reagent for removing the amino protecting group of compound (4) is preferably hydrochloric acid or trifluoroacetic acid.
本发明相对于现有技术具有以下有益效果：The present invention has the following beneficial effects with respect to the prior art:
(1)本发明成功发展了一种尼古丁的制备方法，通过催化吡啶烷基酮的不对称氢化反应，可以高效构建手性醇中间体。反应具有高度的稳定性和反应活性，实现了优异的立体控制，可以得到大于99％的对映选择性的手性醇中间体。(1) The present invention successfully develops a method for preparing nicotine, which can efficiently construct a chiral alcohol intermediate by catalyzing the asymmetric hydrogenation of pyridyl alkyl ketone. The reaction is highly stable and reactive, achieves excellent steric control, and can yield chiral alcohol intermediates with greater than 99% enantioselectivity.
(2)通过大量的实验研究发现，使用优选的催化剂体系Ir/f-amphox，不对称氢化反应具有非常高的反应活性，催化剂转化数(TON，turnover number)高达200000。(2) Through a large number of experimental studies, it is found that using the preferred catalyst system Ir/f-amphox, the asymmetric hydrogenation reaction has very high reactivity, and the catalyst turnover number (TON, turnover number) is as high as 200,000.
(3)本发明操作稳定、成本低廉、环境友好，具有极高的工业化价值。(3) The present invention is stable in operation, low in cost, environmentally friendly, and has extremely high industrial value.
附图发明Invention of drawings
图1，尼古丁不对称合成工艺示意图。Figure 1 is a schematic diagram of the asymmetric synthesis process of nicotine.
图2，化合物2的 1HNMR谱图。 Figure 2, 1 HNMR spectrum of compound 2.
图3，化合物2的 13C NMR谱图。 Figure 3,13C NMR spectrum of compound 2.
图4，化合物3a的 1HNMR谱图。 Figure 4, 1 HNMR spectrum of compound 3a.
图5，化合物3a的 13C NMR谱图。 Figure 5,13C NMR spectrum of compound 3a.
图6，消旋化合物3的HPLC谱图。Figure 6, HPLC spectrum of racemic compound 3.
图7，手性化合物3的HPLC谱图。Figure 7, HPLC spectrum of chiral compound 3.
具体实施方式Detailed ways
下面结合具体实施例对本发明做进一步的说明，但本发明不局限于此。The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.
实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件；所用材料、试剂等，如无特殊说明，均可从商业途径得到。The experimental methods for which specific conditions are not specified in the examples are usually in accordance with the conventional conditions and the conditions described in the manual, or in accordance with the conditions suggested by the manufacturer; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels. .
实施例1 中间体2的合成Example 1 Synthesis of Intermediate 2
Figure PCTCN2022071759-appb-000017
Figure PCTCN2022071759-appb-000017
氩气保护下，向三口圆底烧瓶中加入3-溴吡啶(3.16g，20mmol)并用50mL无水四氢呋喃溶解，低温槽中搅拌冷却至-78℃，然后缓慢滴加4.8mL正丁基锂(2.4M)的正己烷溶液，滴加过程中保持-78℃，滴加完后继续保持-78℃搅拌30min，将N-Boc-2-吡咯烷酮(3.70g，20mmol)用30mL四氢呋喃溶解，随后滴加至反应混合液中，继续保持-78℃搅拌3小时，然后缓慢升至室温反应24h，用20mL稀盐酸(2M)淬灭反应，乙酸乙酯萃取，有机相用饱和碳酸氢钠和饱和食盐水洗涤，无水硫酸钠干燥，旋干，得粗产品并用乙醚重结晶得4.1g白色固体，即中间体2，78％yield。Under the protection of argon, 3-bromopyridine (3.16g, 20mmol) was added to the three-necked round-bottomed flask and dissolved in 50mL of anhydrous tetrahydrofuran, stirred and cooled to -78°C in a low temperature tank, and then 4.8mL of n-butyllithium (4.8mL) was slowly added dropwise. 2.4M) n-hexane solution, kept at -78 °C during the dropwise addition, and continued to stir at -78 °C for 30 min after the dropwise addition, N-Boc-2-pyrrolidone (3.70 g, 20 mmol) was dissolved in 30 mL of tetrahydrofuran, and then added dropwise. Add to the reaction mixture, keep stirring at -78 °C for 3 hours, then slowly warm to room temperature for 24 hours, quench the reaction with 20 mL of dilute hydrochloric acid (2M), extract with ethyl acetate, and use saturated sodium bicarbonate and saturated common salt for the organic phase. Washed with water, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product, which was recrystallized with ether to obtain 4.1 g of a white solid, namely Intermediate 2, 78% yield.
1H NMR(400MHz,CDCl 3)δ9.13(dt,J＝2.4,1.1Hz,1H),8.74(dt,J＝4.9,1.5Hz,1H),8.19(dt,J＝8.0,1.9Hz,1H),7.46–7.32(m,1H),4.76(s,1H),3.21(q,J＝6.7Hz,2H),3.02(t,J＝7.0Hz,2H),1.97–1.90(m,2H),1.38(s,9H). 13C NMR(101MHz,CDCl 3)δ198.5,156.0,153.4,149.5,135.3,132.0,123.6,39.9,35.9,29.6,28.3,24.2. 1 H NMR (400 MHz, CDCl 3 ) δ 9.13 (dt, J=2.4, 1.1 Hz, 1H), 8.74 (dt, J=4.9, 1.5 Hz, 1H), 8.19 (dt, J=8.0, 1.9 Hz, 1H), 7.46–7.32 (m, 1H), 4.76 (s, 1H), 3.21 (q, J=6.7Hz, 2H), 3.02 (t, J=7.0Hz, 2H), 1.97–1.90 (m, 2H) ), 1.38(s, 9H). 13 C NMR (101MHz, CDCl 3 )δ198.5, 156.0, 153.4, 149.5, 135.3, 132.0, 123.6, 39.9, 35.9, 29.6, 28.3, 24.2.
实施例2 手性醇中间体化合物(3a)的制备(NaO tBu，S/C＝10000) Example 2 Preparation of chiral alcohol intermediate compound (3a) (NaO t Bu, S/C=10000)
Figure PCTCN2022071759-appb-000018
Figure PCTCN2022071759-appb-000018
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和叔丁醇钠(3.6mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。[α] D 25＝+262(c＝1.0,CHCl 3)， 1HNMR(400MHz,CDCl 3)δ8.38–8.35(m,1H),8.31–8.28(m,1H),7.65–7.62(m,1H),7.19–7.16(m,1H),4.95(s,2H),4.66–4.62(m,1H),3.09–3.04(m,2H),1.76–1.59(m,1H),1.57–1.42(m,1H),1.35(s,9H). 13C NMR(101MHz,CDCl 3)δ156.16,147.96,147.23,140.66,133.78,123.40,71.02,40.05,35.90,29.51,28.26,26.16. Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and sodium tert-butoxide (3.6 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis. [α] D 25 =+262 (c=1.0, CHCl 3 ), 1 H NMR (400 MHz, CDCl 3 ) δ 8.38–8.35 (m, 1H), 8.31–8.28 (m, 1H), 7.65–7.62 (m ,1H),7.19–7.16(m,1H),4.95(s,2H),4.66–4.62(m,1H),3.09–3.04(m,2H),1.76–1.59(m,1H),1.57–1.42 (m, 1H), 1.35 (s, 9H). 13 C NMR (101 MHz, CDCl 3 ) δ 156.16, 147.96, 147.23, 140.66, 133.78, 123.40, 71.02, 40.05, 35.90, 29.51, 28.26, 26.16.
实施例3 手性醇中间体化合物(3a)的制备(NaOH，S/C＝10000)Example 3 Preparation of chiral alcohol intermediate compound (3a) (NaOH, S/C=10000)
Figure PCTCN2022071759-appb-000019
Figure PCTCN2022071759-appb-000019
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和氢氧化钠(1.5mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and sodium hydroxide (1.5 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
实施例4 相反构型手性醇中间体化合物(3b)的制备(NaOH，S/C＝10000)Example 4 Preparation of reverse configuration chiral alcohol intermediate compound (3b) (NaOH, S/C=10000)
Figure PCTCN2022071759-appb-000020
Figure PCTCN2022071759-appb-000020
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和应用实例2相反构型的手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和氢氧化钠(1.5mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3b，产率为98％，经HPLC分析，测得ee值为99％。[α] D 25＝-260(c＝1.0,CHCl 3)。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and the chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) with the opposite configuration of Application Example 2 were dissolved Stir in 4 mL of isopropanol at room temperature for 3 hours to give a clear orange solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and sodium hydroxide (1.5 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3b, with a yield of 98%, The ee value was found to be 99% by HPLC analysis. [α] D 25 =-260 (c=1.0, CHCl 3 ).
实施例5 手性醇中间体化合物(3a)的制备(KO tBu，S/C＝10000) Example 5 Preparation of chiral alcohol intermediate compound (3a) (KO t Bu, S/C=10000)
Figure PCTCN2022071759-appb-000021
Figure PCTCN2022071759-appb-000021
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和叔丁醇钾(4.3mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and potassium tert-butoxide (4.3 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
实施例6 手性醇中间体化合物(3a)的制备(KOH，S/C＝10000)Example 6 Preparation of chiral alcohol intermediate compound (3a) (KOH, S/C=10000)
Figure PCTCN2022071759-appb-000022
Figure PCTCN2022071759-appb-000022
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和氢氧化钾(2mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and potassium hydroxide (2 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
实施例7 手性醇中间体化合物(3a)的制备(KOH，S/C＝50000)Example 7 Preparation of chiral alcohol intermediate compound (3a) (KOH, S/C=50000)
Figure PCTCN2022071759-appb-000023
Figure PCTCN2022071759-appb-000023
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液30uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和氢氧化钾(2mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 30 uL of the orange solution was taken with a micro syringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and potassium hydroxide (2 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, namely the hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
实施例8 手性醇中间体化合物(3a)的制备(KOH，S/C＝200000)Example 8 Preparation of chiral alcohol intermediate compound (3a) (KOH, S/C=200000)
Figure PCTCN2022071759-appb-000024
Figure PCTCN2022071759-appb-000024
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液76uL，加入到中间体2(10g，38mmol)、异丙醇(20mL)和氢氧化钾(20mg,0.38mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体10g，即氢化产物3a，产率为98％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 76 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (10 g, 38 mmol), isopropanol (20 mL) and potassium hydroxide (20 mg, 0.38 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of methylene chloride was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 10 g of a red oily liquid, i.e. hydrogenated product 3a, with a yield of 98%, The ee value was found to be 99% by HPLC analysis.
实施例9 手性醇中间体化合物(3a)的制备(百克级规模)Example 9 Preparation of chiral alcohol intermediate compound (3a) (hundred grams scale)
Figure PCTCN2022071759-appb-000025
Figure PCTCN2022071759-appb-000025
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体f-amphox- tBu-L3(5.8mg，0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液3mL，加入到中间体2(100g，380mmol)、异丙醇(200mL)和氢氧化钾(213mg,3.8mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入500mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体101g，即氢化产物3a，产率为99％，经HPLC分析，测得ee值为99％。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand f-amphox- t Bu-L3 (5.8 mg, 0.0105 mmol) were dissolved in 4 mL of isopropanol, Stir at room temperature for 3 hours to give a clear orange solution. 3 mL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (100 g, 380 mmol), isopropanol (200 mL) and potassium hydroxide (213 mg, 3.8 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 500 mL of methylene chloride was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 101 g of a red oily liquid, i.e. hydrogenation product 3a, with a yield of 99%, The ee value was found to be 99% by HPLC analysis.
实施例10 手性醇中间体化合物(3a)的制备(其他三齿配体催化剂考察)Example 10 Preparation of chiral alcohol intermediate compound (3a) (investigation of other tridentate ligand catalysts)
Figure PCTCN2022071759-appb-000026
Figure PCTCN2022071759-appb-000026
在氩气氛围下，将[Ir(COD)Cl] 2(3.4mg，0.005mol)和手性配体(0.0105mmol)溶于4mL异丙醇中，在室温条件下搅拌3小时，得到橙色澄清溶液。用微量注射器取该橙色溶液150uL，加入到中间体2(1g，3.8mmol)、异丙醇(2mL)和叔丁醇钾(4.3mg,0.038mmol)的混合体系中。将反应体系置于高压釜中，用氢气置换高压釜中的气体三次，最后充入40atm氢气，在60℃下反应24小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，HPLC测得转化率和ee值，结果如下表1所示。 Under argon atmosphere, [Ir(COD)Cl] 2 (3.4 mg, 0.005 mol) and chiral ligand (0.0105 mmol) were dissolved in 4 mL of isopropanol and stirred at room temperature for 3 hours to obtain an orange clear solution. 150 uL of the orange solution was taken with a microsyringe and added to a mixed system of Intermediate 2 (1 g, 3.8 mmol), isopropanol (2 mL) and potassium tert-butoxide (4.3 mg, 0.038 mmol). The reaction system was placed in an autoclave, the gas in the autoclave was replaced with hydrogen three times, and finally 40 atm of hydrogen was charged, and the reaction was carried out at 60° C. for 24 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, i.e. hydrogenated product 3a, and HPLC measured the conversion rate and ee value, the results are shown in Table 1 below.
表1.Table 1.
Figure PCTCN2022071759-appb-000027
Figure PCTCN2022071759-appb-000027
实施例11 手性醇中间体化合物(3a)的制备(钌双膦双胺类型催化剂考察)Example 11 Preparation of chiral alcohol intermediate compound (3a) (investigation of ruthenium bisphosphine bisamine type catalyst)
Figure PCTCN2022071759-appb-000028
Figure PCTCN2022071759-appb-000028
在氩气氛围下，在50mL反应釜中加入1g中间体2(3.8mmol)、2mL异丙醇和4.3mg叔丁醇钾(0.038mmol)，最后加入0.0001mmol催化剂。用氢气置换高压釜中的气体三次，最后充入50atm氢气，在25℃下反应16小时。反应结束后，缓慢释放高压釜中的气体，加入50mL二氯甲烷，水洗，饱和食盐水洗，无水硫酸钠干燥，减压浓缩得到红色油状液体1g，即氢化产物3a，HPLC测得转化率和ee值，结果如下表2所示。Under an argon atmosphere, 1 g of intermediate 2 (3.8 mmol), 2 mL of isopropanol and 4.3 mg of potassium tert-butoxide (0.038 mmol) were added to a 50 mL reaction kettle, and finally 0.0001 mmol of catalyst was added. The gas in the autoclave was replaced with hydrogen three times, and finally 50 atm of hydrogen was charged, and the reaction was carried out at 25° C. for 16 hours. After the reaction, the gas in the autoclave was slowly released, 50 mL of dichloromethane was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1 g of a red oily liquid, i.e. hydrogenated product 3a, and HPLC measured the conversion rate and ee value, the results are shown in Table 2 below.
表2.Table 2.
Figure PCTCN2022071759-appb-000029
Figure PCTCN2022071759-appb-000029
Figure PCTCN2022071759-appb-000030
Figure PCTCN2022071759-appb-000030
实施例12Example 12
中间体4a的合成，离去基团LG为甲磺酰基(OMs)Synthesis of intermediate 4a, leaving group LG is methanesulfonyl (OMs)
Figure PCTCN2022071759-appb-000031
Figure PCTCN2022071759-appb-000031
称取化合物3(5.3g，20mmol)，加入50mL二氯甲烷溶解，再滴加5.6mL三乙胺(40mmol)，将反应体系置于0℃低温冷浴中，边搅拌边缓慢滴加1.7mL甲磺酰氯(22mmol)，滴加完继续在0℃反应30min，反应结束后，用饱和碳酸钠洗涤，60mL二氯甲烷分三次萃取，硅胶柱纯化，得黄色油状液体6.7g。中间体4a，黄色油状液体，收率为98％。Weigh compound 3 (5.3 g, 20 mmol), add 50 mL of dichloromethane to dissolve, then add 5.6 mL of triethylamine (40 mmol) dropwise, place the reaction system in a low-temperature cooling bath at 0 °C, and slowly add 1.7 mL dropwise while stirring Methanesulfonyl chloride (22 mmol) was added dropwise and continued to react at 0°C for 30 min. After the reaction, washed with saturated sodium carbonate, extracted three times with 60 mL of dichloromethane, and purified by silica gel column to obtain 6.7 g of a yellow oily liquid. Intermediate 4a, yellow oily liquid, yield 98%.
实施例13Example 13
中间体5的合成，离去基团LG为甲磺酰基(OMs)Synthesis of intermediate 5, leaving group LG is methylsulfonyl (OMs)
Figure PCTCN2022071759-appb-000032
Figure PCTCN2022071759-appb-000032
称取化合物4a(6.9g，20mmol)，加入50mL二氯甲烷和50mL三氟乙酸溶解，在室温下搅拌2小时。反应结束后减压除去溶剂，随后滴加至60mL氢氧化钠溶液(1M，3equiv)和140mL甲醇的混合溶液中，室温搅拌2小时。反应结束后，减压除去溶剂，反应残渣加入稀盐酸中和，用乙酸乙酯萃取，保留有机相，无水硫酸钠干燥后浓缩，经硅胶柱纯化后得到2.9g淡黄色油状液体，即中间体5，反应收率为95％。Compound 4a (6.9 g, 20 mmol) was weighed, dissolved in 50 mL of dichloromethane and 50 mL of trifluoroacetic acid, and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then it was added dropwise to a mixed solution of 60 mL of sodium hydroxide solution (1 M, 3 equiv) and 140 mL of methanol, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was removed under reduced pressure, the reaction residue was neutralized by adding dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was retained, dried over anhydrous sodium sulfate, and concentrated, and purified by silica gel column to obtain 2.9 g of a light yellow oily liquid, namely the middle For body 5, the reaction yield was 95%.
[α] D 25＝-30.6(c＝0.25,MeOH)， 1H NMR(400MHz,CDCl 3)δ:8.60(d,J＝2.0Hz,1H),8.49(dd,J＝1.6,4.8Hz 1H),7.71-7.73(m,1H),7.25-7.28(m,1H),4.19(t,J＝7.6Hz，1H),3.21-3.22(m,1H),3.07-3.11(m,1H),2.30-2.40(m,2H),1.87-2.04(m,2H),1.66(m,1H). 13C NMR(101MHz,CDCl 3)δ:148.5,148.1,140.0,134.0,123.2,59.9,46.8,34.2,25.4. [α] D 25 =-30.6 (c=0.25, MeOH), 1 H NMR (400 MHz, CDCl 3 ) δ: 8.60 (d, J=2.0 Hz, 1H), 8.49 (dd, J=1.6, 4.8 Hz 1H ),7.71-7.73(m,1H),7.25-7.28(m,1H),4.19(t,J=7.6Hz,1H),3.21-3.22(m,1H),3.07-3.11(m,1H), 2.30-2.40 (m, 2H), 1.87-2.04 (m, 2H), 1.66 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ: 148.5, 148.1, 140.0, 134.0, 123.2, 59.9, 46.8, 34.2, 25.4.
实施例14Example 14
中间体4b的合成，离去基团LG为对甲苯磺酰基(OTs)Synthesis of intermediate 4b, leaving group LG is p-toluenesulfonyl (OTs)
Figure PCTCN2022071759-appb-000033
Figure PCTCN2022071759-appb-000033
称取化合物3(5.3g，20mmol)，加入30mL二氯甲烷溶解，再滴加5.6mL三乙胺(40mmol)，将反应体系置于0℃低温冷浴中。将对甲苯磺酰氯(4.18g，22mmol)溶于20mL二氯甲烷溶液中，缓慢滴加至反应体系，滴加完继续在0℃反应30min，反应结束后，用饱和碳酸钠洗涤，60mL二氯甲烷分三次萃取，硅胶柱纯化，得黄色油状液体8.0g，即中间体4b，反应收率为95％。Compound 3 (5.3 g, 20 mmol) was weighed, 30 mL of dichloromethane was added to dissolve, 5.6 mL of triethylamine (40 mmol) was added dropwise, and the reaction system was placed in a low temperature cooling bath at 0°C. p-Toluenesulfonyl chloride (4.18 g, 22 mmol) was dissolved in 20 mL of dichloromethane solution, slowly added dropwise to the reaction system, and the reaction was continued at 0 °C for 30 min after the dropwise addition. Methane was extracted three times and purified by silica gel column to obtain 8.0 g of yellow oily liquid, namely intermediate 4b, and the reaction yield was 95%.
实施例15Example 15
中间体5的合成，离去基团LG为对甲苯磺酰基(OTs)Synthesis of intermediate 5, leaving group LG is p-toluenesulfonyl (OTs)
Figure PCTCN2022071759-appb-000034
Figure PCTCN2022071759-appb-000034
称取化合物4b(8.4g，20mmol)，加入50mL二氯甲烷和50mL三氟乙酸溶解，在室温下搅拌2小时。反应结束后减压除去溶剂，随后滴加至60mL氢氧化钠溶液(1M，3equiv)和140mL甲醇的混合溶液中，室温搅拌2小时。反应结束后，减压除去溶剂，反应残渣加入稀盐酸中和，用乙酸乙酯萃取，保留有机相，无水硫酸钠干燥后浓缩，经硅胶柱纯化后得到2.6g淡黄色油状液体，即中间体5，反应收率为90％。Compound 4b (8.4 g, 20 mmol) was weighed, dissolved in 50 mL of dichloromethane and 50 mL of trifluoroacetic acid, and stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and then it was added dropwise to a mixed solution of 60 mL of sodium hydroxide solution (1 M, 3 equiv) and 140 mL of methanol, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, the reaction residue was neutralized by adding dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was retained, dried over anhydrous sodium sulfate, and then concentrated. For body 5, the reaction yield was 90%.
[α] D 25＝-30.6(c＝0.25,MeOH)， 1H NMR(400MHz,CDCl 3)δ:8.60(d,J＝2.0Hz,1H),8.49(dd,J＝1.6,4.8Hz 1H),7.71-7.73(m,1H),7.25-7.28(m,1H),4.19(t,J＝7.6Hz，1H),3.21-3.22(m,1H),3.07-3.11(m,1H),2.30-2.40(m,2H),1.87-2.04(m,2H),1.66(m,1H). 13C NMR(101MHz,CDCl 3)δ:148.5,148.1,140.0,134.0,123.2,59.9,46.8,34.2,25.4. [α] D 25 =-30.6 (c=0.25, MeOH), 1 H NMR (400 MHz, CDCl 3 ) δ: 8.60 (d, J=2.0 Hz, 1H), 8.49 (dd, J=1.6, 4.8 Hz 1H ),7.71-7.73(m,1H),7.25-7.28(m,1H),4.19(t,J=7.6Hz,1H),3.21-3.22(m,1H),3.07-3.11(m,1H), 2.30-2.40 (m, 2H), 1.87-2.04 (m, 2H), 1.66 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ: 148.5, 148.1, 140.0, 134.0, 123.2, 59.9, 46.8, 34.2, 25.4.
实例16 尼古丁的合成Example 16 Synthesis of Nicotine
Figure PCTCN2022071759-appb-000035
Figure PCTCN2022071759-appb-000035
中间体5(1.48g，10mmol)加入18mL 88％甲酸和9.2mL 37％甲醛的混合溶液。混合物在80℃下反应5h，然后冷却至室温，加入固体碳酸钾直至反应液为碱性(pH＝10-11)，用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，旋干，减压蒸馏得1.3g目标产物尼古丁。尼古丁，无色油状液体，82％yield，98％ee，[α] 25 D＝-98.2(c＝1,CHCl 3)， 1H NMR(400MHz,CDCl 3):δ8.56-8.47(m,2H),7.75-7.67(m,1H),7.27-7.23(m,1H),3.32-3.21(m,1H),3.10(t,J＝8.3Hz,1H),2.39-2.28(m,1H),2.28-2.19(m,1H),2.17(s,3H),2.04-1.91(m,1H),1.89-1.79(m,1H),1.78-1.66(m,1H). 13C NMR(101MHz,CDCl 3):δ149.5,148.6,138.6,134.9,123.6,68.9,57.0,40.3,35.1,22.6. Intermediate 5 (1.48 g, 10 mmol) was added with a mixed solution of 18 mL of 88% formic acid and 9.2 mL of 37% formaldehyde. The mixture was reacted at 80°C for 5 h, then cooled to room temperature, solid potassium carbonate was added until the reaction solution was alkaline (pH=10-11), extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Under reduced pressure distillation, 1.3 g of the target product nicotine was obtained. Nicotine, colorless oily liquid, 82% yield, 98% ee, [α] 25 D =-98.2 (c=1, CHCl 3 ), 1 H NMR (400MHz, CDCl 3 ): δ8.56-8.47 (m, 2H), 7.75-7.67(m, 1H), 7.27-7.23(m, 1H), 3.32-3.21(m, 1H), 3.10(t, J=8.3Hz, 1H), 2.39-2.28(m, 1H) , 2.28-2.19(m, 1H), 2.17(s, 3H), 2.04-1.91(m, 1H), 1.89-1.79(m, 1H), 1.78-1.66(m, 1H). 13 C NMR(101MHz, CDCl 3 ): δ149.5, 148.6, 138.6, 134.9, 123.6, 68.9, 57.0, 40.3, 35.1, 22.6.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (10)

  1. 一种尼古丁中间体下式(3)的不对称催化合成方法，其特征在于，其反应路线为：An asymmetric catalytic synthesis method of the following formula (3) of a nicotine intermediate, characterized in that its reaction scheme is:
    Figure PCTCN2022071759-appb-100001
    Figure PCTCN2022071759-appb-100001
    中间体(2)在手性催化剂存在情况下，充入氢气反应得到氢化产物(3)，其中，所述催化剂可以为钌双膦双胺催化体系，结构通式为：In the presence of a chiral catalyst, the intermediate (2) is charged with hydrogen to react to obtain a hydrogenated product (3), wherein the catalyst can be a ruthenium bisphosphine bisamine catalytic system, and the general structural formula is:
    Figure PCTCN2022071759-appb-100002
    Figure PCTCN2022071759-appb-100002
    式(1)所示化合物，X,Y各自独立为卤素或醋酸根或氢；Compound represented by formula (1), X, Y are each independently halogen or acetate or hydrogen;
    Figure PCTCN2022071759-appb-100003
    表示双膦配体，
    Figure PCTCN2022071759-appb-100004
    表示二胺结构；
    Figure PCTCN2022071759-appb-100003
    represents a bisphosphine ligand,
    Figure PCTCN2022071759-appb-100004
    Represents the diamine structure;
    具体地举例如下：Specific examples are as follows:
    Figure PCTCN2022071759-appb-100005
    Figure PCTCN2022071759-appb-100005
    其中，式Cat.A、Cat.1-4中，Ar基团可以为苯基、4-甲基苯基，3,5-二甲基苯基、3,5-二叔丁基苯基、甲基对异丙基苯基等，R基团可以为H原子，或1～6个碳原子的脂肪烃或6～12个碳原子的芳香性基团；Wherein, in formula Cat.A, Cat.1-4, Ar group can be phenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3,5-di-tert-butylphenyl, Methyl-p-isopropylphenyl, etc., the R group can be an H atom, or an aliphatic hydrocarbon of 1 to 6 carbon atoms or an aromatic group of 6 to 12 carbon atoms;
    以上所述催化剂也可以为由金属化合物和手性配体原位络合得到，催化剂金属盐选自钌、铑、铱、钯等常见过金属化合物，手性配体选自：The above-mentioned catalyst can also be obtained by in-situ complexation of a metal compound and a chiral ligand, the catalyst metal salt is selected from common permetal compounds such as ruthenium, rhodium, iridium, and palladium, and the chiral ligand is selected from:
    Figure PCTCN2022071759-appb-100006
    Figure PCTCN2022071759-appb-100006
    化合物(3)中所述*表示有R或者S两种构型。* in compound (3) indicates that there are two configurations of R or S.
  2. 根据权利要求1的方法，其特征在于，所述Cat.1中Ar＝Ph；Cat.2中Ar＝Xyl；Cat.3中Ar＝Ph；The method according to claim 1, wherein Ar=Ph in said Cat.1; Ar=Xyl in Cat.2; Ar=Ph in Cat.3;
    所述Cat.A选自Cat.4-10：The Cat.A is selected from Cat.4-10:
    Figure PCTCN2022071759-appb-100007
    Figure PCTCN2022071759-appb-100007
  3. 根据权利要求1所述的方法，其特征在于，所述均相催化氢化反应在含有甲醇、乙醇、异丙醇、四氢呋喃、二氯甲烷、甲苯的一种或任意比例的混合溶剂中进行；所用的碱为叔丁醇钾、叔丁醇钠、叔丁醇锂、氢氧化钾、氢氧化钠、碳酸钠、碳酸钾、碳酸铯的一种或任意比例的混合物。The method according to claim 1, wherein the homogeneous catalytic hydrogenation reaction is carried out in a mixed solvent containing one or any ratio of methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, and toluene; The base is potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or a mixture in any proportion.
  4. 根据权利要求1所述的合成方法，其特征在于，所述反应的温度为20-80摄氏度；所述反应的氢气压力为2-8Mpa。The synthesis method according to claim 1, wherein the temperature of the reaction is 20-80 degrees Celsius; the hydrogen pressure of the reaction is 2-8Mpa.
  5. 根据权利要求1所述的合成方法，其特征在于，所述反应时间为8-60小时。synthetic method according to claim 1, is characterized in that, described reaction time is 8-60 hours.
  6. 根据权利要求1所述的合成方法，其特征在于，所述中间体(2)与催化剂的摩尔比为2mmol：0.01-1nmol。The synthesis method according to claim 1, wherein the molar ratio of the intermediate (2) to the catalyst is 2 mmol: 0.01-1 nmol.
  7. 化合物，其特征在于，所述化合物选自化合物(2)或者(3)，其中，化合物(2)结构如下式：A compound, characterized in that the compound is selected from compound (2) or (3), wherein the structure of compound (2) is as follows:
    Figure PCTCN2022071759-appb-100008
    Figure PCTCN2022071759-appb-100008
    所述化合物(3)结构如下式：The structure of the compound (3) is as follows:
    Figure PCTCN2022071759-appb-100009
    Figure PCTCN2022071759-appb-100009
    其中，所述化合物式(3)中“*”包括R和S两种构型。Wherein, "*" in the compound formula (3) includes two configurations of R and S.
  8. 一种尼古丁的不对称催化合成方法，其特征在于，合成路线如下：A kind of asymmetric catalytic synthesis method of nicotine, is characterized in that, synthesis route is as follows:
    Figure PCTCN2022071759-appb-100010
    Figure PCTCN2022071759-appb-100010
    其中，所述中间体(3)通过权利要求1-6中任一权利要求所述的合成方法制备得到。Wherein, the intermediate (3) is prepared by the synthesis method described in any one of claims 1-6.
  9. 根据权利要求8所述的一种尼古丁的不对称催化合成方法，其特征在于，合成路线如下：The asymmetric catalytic synthesis method of a kind of nicotine according to claim 8, is characterized in that, synthetic route is as follows:
    Figure PCTCN2022071759-appb-100011
    Figure PCTCN2022071759-appb-100011
    包括以下步骤：Include the following steps:
    1)氩气保护下，3-溴吡啶的四氢呋喃溶液在-40℃下与n-BuLi的正己烷溶液或异丙基氯化镁溶液混合，然后与N-Boc-2-吡咯烷酮混合反应；室温下用稀盐酸溶液淬灭反应，乙酸乙酯萃取，粗产物干燥，旋干，打浆纯化得到中间体(2)；1) Under the protection of argon, the tetrahydrofuran solution of 3-bromopyridine is mixed with n-BuLi's n-hexane solution or isopropyl magnesium chloride solution at -40°C, and then mixed with N-Boc-2-pyrrolidone; The reaction was quenched with dilute hydrochloric acid solution, extracted with ethyl acetate, the crude product was dried, spin-dried, and purified by beating to obtain intermediate (2);
    2)将中间体(2)溶于合适的溶剂中，加入手性催化剂和合适的碱，所述中间体(2)与催化剂的摩尔比为2mmol：0.01-1nmol，用氢气置换反应釜内气体三次，最后充入2-8Mpa氢气，20-80℃下反应8-60小时，缓慢释放反应釜中的气体，旋干，用硅胶柱层析纯化，得到手性氢化产物(3)；2) the intermediate (2) is dissolved in a suitable solvent, a chiral catalyst and a suitable base are added, and the mol ratio of the intermediate (2) to the catalyst is 2mmol: 0.01-1nmol, and the gas in the reaction kettle is replaced with hydrogen. Three times, finally fill with 2-8Mpa hydrogen, react at 20-80°C for 8-60 hours, slowly release the gas in the reaction kettle, spin dry, and purify by silica gel column chromatography to obtain a chiral hydrogenation product (3);
    3)手性醇产物(3)经过活化形成合适的离去基团LG，如卤素，磺酸酯等；3) The chiral alcohol product (3) is activated to form a suitable leaving group LG, such as halogen, sulfonate, etc.;
    4)在合适的条件下，中间体(4)与合适的试剂反应脱去氨基保护基，然后在碱性条件下，发生分子内的亲核关环反应，反应完后用乙酸乙酯萃取，收集有机相浓缩得手性四氢吡咯化合物(5)；4) Under suitable conditions, the intermediate (4) is reacted with a suitable reagent to remove the amino protecting group, then under alkaline conditions, an intramolecular nucleophilic ring-closing reaction occurs, and after the reaction is completed, it is extracted with ethyl acetate, The organic phase was collected and concentrated to obtain the chiral tetrahydropyrrole compound (5);
    5)在80℃下，中间体(5)加入甲酸和多聚甲醛溶液反应5小时，反应冷至室温，加碳酸钾直到反应液呈碱性，乙酸乙酯萃取，减压蒸馏得到尼古丁产品。5) At 80°C, the intermediate (5) was added with formic acid and paraformaldehyde solution to react for 5 hours, the reaction was cooled to room temperature, potassium carbonate was added until the reaction solution was alkaline, extracted with ethyl acetate, and distilled under reduced pressure to obtain the nicotine product.
  10. 根据权利要求8所述的方法，其特征在于，所述化合物(4)中离去基团LG优选为卤素，磺酸酯，更优选为氯，甲磺酸酯(OMs)，对甲苯基磺酸酯(OTs)。The method according to claim 8, wherein the leaving group LG in the compound (4) is preferably halogen, sulfonate, more preferably chlorine, methanesulfonate (OMs), p-toluenesulfonate acid esters (OTs).
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