CN115073251A - 一种不对称催化合成尼古丁的方法 - Google Patents

一种不对称催化合成尼古丁的方法 Download PDF

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CN115073251A
CN115073251A CN202110276922.5A CN202110276922A CN115073251A CN 115073251 A CN115073251 A CN 115073251A CN 202110276922 A CN202110276922 A CN 202110276922A CN 115073251 A CN115073251 A CN 115073251A
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nicotine
chiral
catalyst
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稂琪伟
高爽
丁小兵
苏伟
肖阳
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Shenzhen Green Kate Pharmaceutical Technology Co ltd
Shenzhen Catalys Technology Co Ltd
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Abstract

本发明涉及一种尼古丁的不对称催化合成方法，具体地说是一种以3‑溴吡啶为起始原料经过五步反应制备尼古丁的方法。具体包括：1)3‑溴吡啶和N‑Boc‑2‑吡咯烷酮在合适的条件下发生亲核反应，得到氢化前体化合物(2)；2)经手性催化剂的不对称催化得到高光学活性的手性醇中间体化合物(3)；3)手性醇经活化后变成离去基团，得到化合物(4)；4)在合适的条件下脱除氮上保护基，并发生分子内关环得到化合物(5)；5)最后经过N‑甲基化反应，提纯产物得到尼古丁。其中，不对称催化还原制备高光学活性的手性醇中间体化合物(3)是该方法的关键步骤。本发明操作简便，成本低廉，并且适用于工业化制备。

Description

一种不对称催化合成尼古丁的方法
技术领域
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。
背景技术
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。
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。
Figure BDA0002977014730000011
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 of OrganicChemistry,1990,55,1736-1744；文献Journal of the Chemical Society,PerkinTransactions I,2002(2),143-154；文献Synlett,2009(15),2497-2499；文献Journal ofHeterocyclic Chemistry,2009,46(6),1252-1258；专利CN 102617547A；专利CN107406411A等。
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Journalof Organic 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％。
反应式1：
Figure BDA0002977014730000021
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)。
反应式2：
Figure BDA0002977014730000022
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)。
反应式3：
Figure BDA0002977014730000031
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)。
反应式4：
Figure BDA0002977014730000032
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。
发明内容
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。
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：
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：
Figure BDA0002977014730000041
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：
Figure BDA0002977014730000042
式(1)所示化合物，X,Y各自独立为卤素或醋酸根或氢；
Figure BDA0002977014730000043
表示双膦配体，
Figure BDA0002977014730000044
表示二胺结构；
具体地举例如下：
Figure BDA0002977014730000045
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；
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：
Figure BDA0002977014730000051
化合物3中所述*表示有R或者S两种构型。
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；
所述Cat.A选自Cat.4-10：
Figure BDA0002977014730000052
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。
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。
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。
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：
Figure BDA0002977014730000061
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：
Figure BDA0002977014730000062
所述化合物(3)结构如下式：
Figure BDA0002977014730000063
其中，所述化合物式(3)中“*”包括R和S两种构型。
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。
Figure BDA0002977014730000064
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。
进一步地，通过以下技术方案来实现，包括以下步骤：
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)；
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)；
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，
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)；
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。
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)。
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。
本发明相对于现有技术具有以下有益效果：
(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。
(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。
(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。
附图发明
图1，尼古丁不对称合成工艺示意图。
图2，化合物2的1H NMR谱图。
图3，化合物2的13C NMR谱图。
图4，化合物3a的1H NMR谱图。
图5，化合物3a的13C NMR谱图。
图6，消旋化合物3的HPLC谱图。
图7，手性化合物3的HPLC谱图。
具体实施方式
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。
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。
实施例1中间体2的合成
Figure BDA0002977014730000081
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。
1H NMR(400MHz,CDCl3)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,CDCl3)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(NaOtBu，S/C＝10000)
Figure BDA0002977014730000091
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,CHCl3)，1HNMR(400MHz,CDCl3)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,CDCl3)δ156.16,147.96,147.23,140.66,133.78,123.40,71.02,40.05,35.90,29.51,28.26,26.16.
实施例3手性醇中间体化合物(3a)的制备(NaOH，S/C＝10000)
Figure BDA0002977014730000092
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％。
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)
Figure BDA0002977014730000101
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,CHCl3)。
实施例5手性醇中间体化合物(3a)的制备(KOtBu，S/C＝10000)
Figure BDA0002977014730000102
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％。
实施例6手性醇中间体化合物(3a)的制备(KOH，S/C＝10000)
Figure BDA0002977014730000111
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％。
实施例7手性醇中间体化合物(3a)的制备(KOH，S/C＝50000)
Figure BDA0002977014730000112
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％。
实施例8手性醇中间体化合物(3a)的制备(KOH，S/C＝200000)
Figure BDA0002977014730000121
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％。
实施例9手性醇中间体化合物(3a)的制备(百克级规模)
Figure BDA0002977014730000122
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％。
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)
Figure BDA0002977014730000131
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。
表1.
Figure BDA0002977014730000141
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)
Figure BDA0002977014730000142
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。
表2.
Figure BDA0002977014730000143
Figure BDA0002977014730000151
实施例12
中间体4a的合成，离去基团LG为甲磺酰基(OMs)
Figure BDA0002977014730000152
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％。
实施例13
中间体5的合成，离去基团LG为甲磺酰基(OMs)
Figure BDA0002977014730000153
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％。
[α]D 25＝-30.6(c＝0.25,MeOH)，1H NMR(400MHz,CDCl3)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).13CNMR(101MHz,CDCl3)δ:148.5,148.1,140.0,134.0,123.2,59.9,46.8,34.2,25.4.
实施例14
中间体4b的合成，离去基团LG为对甲苯磺酰基(OTs)
Figure BDA0002977014730000161
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％。
实施例15
中间体5的合成，离去基团LG为对甲苯磺酰基(OTs)
Figure BDA0002977014730000162
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％。
[α]D 25＝-30.6(c＝0.25,MeOH)，1H NMR(400MHz,CDCl3)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).13CNMR(101MHz,CDCl3)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
Figure BDA0002977014730000171
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,CHCl3)，1H NMR(400MHz,CDCl3):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,CDCl3):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。

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：
Figure FDA0002977014720000011
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：
Figure FDA0002977014720000012
式(1)所示化合物，X,Y各自独立为卤素或醋酸根或氢；
Figure FDA0002977014720000013
表示双膦配体，
Figure FDA0002977014720000014
表示二胺结构；
具体地举例如下：
Figure FDA0002977014720000015
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；
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：
Figure FDA0002977014720000021
化合物(3)中所述*表示有R或者S两种构型。
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；
所述Cat.A选自Cat.4-10：
Figure FDA0002977014720000022
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。
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。
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。
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。
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：
Figure FDA0002977014720000031
所述化合物(3)结构如下式：
Figure FDA0002977014720000032
其中，所述化合物式(3)中“*”包括R和S两种构型。
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：
Figure FDA0002977014720000033
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。
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：
Figure FDA0002977014720000041
包括以下步骤：
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)；
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)；
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；
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)；
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。
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)。
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