CN113527367A - 一种含四（3,5-二三氟甲基苯基）硼阴离子的手性双膦配体铑络合物和制备方法及应用 - Google Patents
一种含四（3,5-二三氟甲基苯基）硼阴离子的手性双膦配体铑络合物和制备方法及应用 Download PDFInfo
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- diphosphine ligand
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- 239000010948 rhodium Substances 0.000 title claims abstract description 35
- 229910052703 rhodium Inorganic materials 0.000 title claims abstract description 33
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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Abstract
本发明涉及一种含四(3,5‑二三氟甲基苯基)硼阴离子的手性双膦配体铑络合物和制备方法及应用。具体来说是将手性双膦配体与铑盐进行络合，再与NaBArF进行阴离子交换，即可得到含有BArF‑阴离子的高稳定性手性双膦配体铑络合物。该络合物能够高效催化β‑脱氢氨基酸酯的不对称催化氢化反应，制备高光学纯度的β‑氨基酸酯衍生物，从而为光学纯β‑氨基酸及β‑氨基醇提供了一种适合工业化的合成方法，具有良好的应用前景。
Description
技术领域
本发明涉及一种含四(3,5-二三氟甲基苯基)硼阴离子的手性双膦配体铑络合物和制备方法及应用。具体来说是将手性双膦配体与铑盐进行络合，再与NaBArF进行阴离子交换，即可得到含有BArF-阴离子的高稳定性手性双膦配体铑络合物。该络合物能够高效催化β-脱氢氨基酸酯的不对称催化氢化反应，制备高光学纯度的β-氨基酸酯衍生物，从而为光学纯β-氨基酸及β-氨基醇提供了一种适合工业化的合成方法，具有良好的应用前景。
背景技术
手性β-氨基酸及其衍生物具有重要的生物活性[Drey,C.N.C.In Chemistry andBiochemistry oftheAmino Acids,Ed.:Barrett,G.C.,Chapman and Hall,New York,1985,Chapter3.]，同时也是合成β-内酰胺类抗生素、紫杉醇(抗肿瘤药物)、度鲁特韦(Dolutegravir,抗HIV药物)等重要药物的基础原料[(1)Juaristi,E.；Quintana,D.；Escalante,J.AldrichimicaActa 1994,27,3.(2)Nicolaou,K.C.；Dai,W.M.；Guy,R.K.Angew.Chem.Int.Ed.Engl.1994,33,15.(3)Hughes,D.L.Org.Process Res.Dev.2019,23,716]，因此其高效不对称合成受到了广泛关注[Cardillo,G.；Tomasini,C.Chem.Soc.Rev.1996,25,117.]。
β-脱氢氨基酸酯的不对称催化氢化是制备光学活性β-氨基酸酯衍生物的有效方法，经后续的水解、还原还可以制备β-氨基酸及β-氨基醇，由此路线可以高效获得抗HIV药物度鲁特韦的关键中间体(R)-3-氨基丁醇。该方法具有原料廉价易得，操作简单，原子利用度高，工艺清洁等优点，工业化应用前景好，而这条路线走向实用的关键是发展出高效及高选择性的手性催化剂。
迄今为止，虽然文献中对β-脱氢氨基酸酯的不对称催化氢化已经做过大量研究，也发展出多种手性单膦或手性双膦配体与过渡金属钌、铑、镍等金属前体搭配作为催化剂促进该反应，但是这些手性催化剂存在反应活性差(催化剂用量大多大于1mol％)，对映选择性不高(对映选择性大多小于95％ee)，配体结构复杂、合成困难、稳定性差，使用非绿色溶剂等问题，远达不到工业生产的要求[(1)Tang,W.；Zhang,X.Chem.Rev.2003,103,3029.(2)Xie,J.-H.Zhu,S.-F.；Zhou,Q.-L.Chem.Rev.2011,111,1713.Ager,D.J.；deVries.A.H.M.；de Vries.J.G.Chem.Soc.Rev.2012,41,3340.]。
本发明目的在于发展出结构新颖明确的手性催化剂，实现β-脱氢氨基酸酯的高效、高选择性氢化，进而提供一条原料廉价易得、操作简单、收率高、废料少、环境友好、产物化学纯度和光学纯度高、易于工业化生产的β-氨基酸酯及其衍生物的合成路线。
发明内容
本发明的目的在于提供一种含四(3,5-二三氟甲基苯基)硼阴离子的手性双膦配体铑络合物和制备方法及应用，以改善或克服已有技术的不足。
本发明所述的含有四(3,5-二三氟甲基苯基)硼阴离子的手性双膦配体铑络合物(I)，其具有如下的结构式：
其中BArF-的结构式为：
所述的手性双膦配体铑络合物(I)包括左旋体、右旋体及消旋体。
所述的手性双膦配体铑络合物(I)的制备方法，它是经过如下步骤制备：在有机溶剂中，0-100℃下，手性双膦配体1、相应铑盐及NaBArF络合1-72小时，制备得到含有BArF-阴离子的手性双膦配体铑络合物，其反应式为：
其中COD为1,5-环辛二烯，OTf为对甲基苯磺酸根离子。
所述的有机溶剂为甲醇、乙醇、异丙醇、叔丁醇、乙腈、丙酮、乙酸乙酯、乙醚、甲基叔丁基醚、四氢呋喃、二氯甲烷、甲苯的一种或两种以上的混合物，优选乙醇。
所述手性双膦配体1、相应铑盐、NaBArF的比例为1:1:1.2。
反应温度优选25℃。反应时间优选2小时。
所述的手性双膦配体铑络合物(I)的应用，在于它作为催化剂用于Z-3-乙酰氨基丁烯酸乙酯的不对称催化氢化反应，其反应方程式为：
上述手性双膦配体铑络合物(I)的应用，在氩气氛围下，将反应物、催化剂、脱气溶剂依次加入氢化内管中，然后于氢气氛围下，室温搅拌至反应结束。
上述手性双膦配体铑络合物(I)的应用，所述的不对称催化氢化反应条件是：所用溶剂是甲醇、乙醇、异丙醇、甲苯、四氢呋喃中的一种或几种有机溶剂；催化剂用量为0.1-1mol％；氢气压力为1atm-30atm；底物浓度为0.001-10.0M；反应温度为0-100℃；反应时间为1-72小时。
本发明的优点和有益效果：
总而言之，将合成的手性双膦配体与铑盐进行络合，再经过阴离子交换，可以制备新型的含有BArF-阴离子的手性双膦配体铑络合物。此催化剂合成简单、易于放大、稳定性好。该新型催化剂能够完成β-脱氢氨基酸酯的高活性、高对映选择性氢化，进而提供一条原料廉价易得、操作简单、收率高、废料少、环境友好、产物化学纯度和光学纯度高、易于工业化生产β-氨基酸酯衍生物的合成路线。本发明所提供的新型含有BArF-阴离子的手性双膦配体铑络合物催化剂克服了已有技术的缺点，是目前β-脱氢氨基酸酯不对称氢化最为稳定且高效的铑催化剂之一，具有良好的应用前景。
附图说明
图1为手性双膦配体铑络合物(I)的核磁共振氢谱；
图2为手性双膦配体铑络合物(I)的核磁共振碳谱；
图3为手性双膦配体铑络合物(I)的核磁共振磷谱。
具体实施方式
通过下述实施实例将有助于进一步理解本发明，但不应将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容所实现的技术均属于本发明的范围。
一般说明：
以下实例中使用了缩写，其含义如下：
Me是甲基，Et是乙基，iPr是异丙基，tBu是叔丁基，Ph是苯基，Bn是苄基，COD是1,5-环辛二烯，OTf是三氟甲磺酸根，MeOH是甲醇，EtOH是乙醇，TFE是三氟乙醇，HFIP是六氟异丙醇，THF是四氢呋喃，DCM是二氯甲烷，PE是石油醚，EA是乙酸乙酯，toluene是甲苯，Ar是氩气，PTSA是对甲苯磺酸。
equiv是当量，rt代表室温，S/C是底物与催化剂的物质的量之比，ND代表未检测到，TLC是薄层色谱，NMR是核磁共振，HRMS是高分辨质谱。
所用溶剂在使用前用标准操作提纯，脱气，干燥；所用试剂均为市售或按照已有文献方法合成得到，并在使用前提纯。
制备实施例1：含有BArF-阴离子的手性双膦配体铑络合物(I)的制备
在手套箱中，向10mL Schlenk管中依次称入配体1(55mg,0.1mmol)、[Rh(COD)2]OTf(52mg,0.11mmol)、NaBArF(109mg,0.12mmol)，然后将其封好带出手套箱，并使体系一直处于氩气氛围，随后用注射器加入现蒸并已脱气的EtOH(2mL)，于室温下搅拌络合2h，1HNMR或TLC确定反应完全，停止反应。反应液真空脱溶后通过硅胶柱层析(DCM/PE＝1:2至2:1进行梯度洗脱)提纯目标产物，得到含有BArF-阴离子的手性双膦配体铑络合物(I)122mg，为棕黄色固体，收率：78％，熔点：72.2-74.8℃。1H NMR(400MHz,CDCl3)δ7.90-7.85(m,2H),7.72-7.71(m,8H),7.52-7.36(m,16H),7.31-7.23(m,4H),7.18-7.14(m,1H),7.05-7.00(m,2H),6.90-6.85(m,1H),6.40-6.35(m,2H),5.89-5.83(m,1H),5.48(t,J＝5.5Hz,1H),4.40-4.34(m,1H),3.98(t,J＝4.0Hz,1H),3.86-3.80(m,1H),2.86-2.75(m,1H),2.86-2.75(m,1H),2.48-2.46(m,1H),2.43(d,J＝8.0Hz,1H),2.28-1.99(m,6H),1.35(d,J＝8.0Hz,3H)；13CNMR(101MHz,CDCl3)δ161.41,160.92,160.42,159.93,142.50,134.87,134.74,133.76,131.82,131.78,130.86,130.82,130.80,130.75,130.58,130.56,130.18,130.16,130.07,130.02,130.00,129.91,129.88,129.81,129.71,129.35,129.20,129.08,128.97,128.37,128.29,128.23,128.18,128.13,128.03,127.99,127.94,127.80,127.74,127.70,127.67,127.65,127.56,127.37,127.27,126.66,126.59,124.85,124.09,124.02,122.14,119.44,116.46,116.42,116.38,108.43,108.36,96.67,96.53,95.23,92.36,56.88,33.14,33.10,31.87,31.83,29.81,29.75,27.16,25.85,14.54,14.44；31PNMR(162MHz,CDCl3)δ88.61(dd,J＝153.2,32.9Hz),16.90(dd,J＝148.4,33.1Hz)；[α]D 27＝88.4(c 0.50,CHCl3)；HRMS(ESI)calcd for[positive ion,C41H43NP2Rh]+:714.1926,found 714.1931.
应用实施例1：Z-3-乙酰氨基丁烯酸乙酯不对称氢化的初步尝试
在手套箱中，将Z-3-乙酰氨基丁烯酸乙酯(40mg,0.23mmol)、催化剂(I)(3.6mg,2.3μmol,1.0mol％)依次称入氢化内管中，用封口膜封好带出手套箱，并放入氢化釜中，快速加入现蒸脱气乙醇(1mL)，搅拌均匀后拧紧氢化釜，迅速置换氢气3次，充入氢气(25atm)，室温下搅拌反应12h。反应结束后，将反应液转移至圆底烧瓶，旋蒸脱去溶剂，加入二溴甲烷作内标，以核磁确定转化率及产率。剩余粗品过短硅胶柱(淋洗液EA)后经HPLC测定ee值(AD-3，正己烷/异丙醇＝92:8；1.0ml/min，210nm)。在当前反应条件下，原料能够完全转化，目标产物具有95％的收率，93％的ee值。初步尝试结果表明该催化剂在β-脱氢氨基酸酯不对称氢化反应中具有良好的催化性能。
应用实施例2：催化剂用量对Z-3-乙酰氨基丁烯酸乙酯的不对称氢化的影响
在手套箱中，将Z-3-乙酰氨基丁烯酸乙酯(40mg,0.23mmol)、相应量的催化剂(I)依次称入氢化内管中，用封口膜封好带出手套箱，并放入氢化釜中，快速加入现蒸脱气乙醇(1mL)，搅拌均匀后拧紧氢化釜，迅速置换氢气3次，充入氢气(25atm)，室温下搅拌反应12h。反应结束后，将反应液转移至圆底烧瓶，旋蒸脱去溶剂，加入二溴甲烷作内标，以核磁确定转化率及产率。剩余粗品过短硅胶柱(淋洗液EA)后经HPLC测定ee值。实验结果表明，转化数(产物与催化剂的物质的量之比)最高可达350，此时ee值为92％。而文献中同类型催化剂报道的最高转化数为100。(Zhou,X.-M.；Huang,J.-D.；Luo,L.-B.；Zhang,C.-L.；Zheng,Z.；Hu,X.-P.Tetrahedron:Asymmetry 2010,21,420.)
表2：催化剂用量用于Z-3-乙酰氨基丁烯酸乙酯不对称氢化的实验结果
a1HNMR定量(内标CH2Br2)
bHPLC:手性柱AD-3,正己烷/异丙醇＝92:8,1.0ml/min,210nm.
应用实施例3：溶剂对Z-3-乙酰氨基丁烯酸乙酯不对称氢化影响
在手套箱中，将Z-3-乙酰氨基丁烯酸乙酯(40mg,0.23mmol)、催化剂(I)(0.7mg,0.46μmol)依次称入氢化内管中，用封口膜封好带出手套箱，并放入氢化釜中，快速加入现蒸脱气溶剂(1mL)，搅拌均匀后拧紧氢化釜，迅速置换氢气3次，充入氢气(25atm)，室温下搅拌反应12h。反应结束后，将反应液转移至圆底烧瓶，旋蒸脱去溶剂，加入二溴甲烷作内标，通过核磁确定转化率及产率。剩余粗品过短硅胶柱(淋洗液EA)后经HPLC测定ee值。由下表可知：表现较好的溶剂有MeOH(序号1、11)、EtOH(序号2、12)、THF(序号8、13)，但从工业应用角度考虑，EtOH更适合作为反应溶剂，因此选定EtOH做最优溶剂。
表3：不同溶剂下Z-3-乙酰氨基丁烯酸乙酯不对称氢化的实验结果
a1HNMR定量(内标CH2Br2)
bHPLC:手性柱AD-3，正己烷/异丙醇＝92:8,1.0ml/min,210nm.
c催化剂用量:S/C＝1000.
应用实施例4：添加剂对Z-3-乙酰氨基丁烯酸乙酯不对称氢化的影响
首先在手套箱中将Z-3-乙酰氨基丁烯酸乙酯(40mg,0.23mmol)称入氢化内管中，用封口膜封好带出手套箱并放入氢化釜中；之后在手套箱中将催化剂(I)称入Schlenk管中，用橡胶塞封好后带出手套箱，并用氩气保护体系，随之向此Schlenk管中迅速加入适量现蒸脱气乙醇，搅拌至溶解配制成催化剂(I)的乙醇溶液。随后取出适量催化剂(I)的乙醇溶液注入氢化釜，再迅速补加现蒸脱气乙醇至溶剂总量为1mL，加入相应的添加剂，搅拌均匀后拧紧氢化釜；迅速置换氢气3次，充入氢气(25atm)，室温下搅拌反应12h。反应结束后，将反应液转移至圆底烧瓶，旋蒸脱去溶剂，加入二溴甲烷作内标，通过核磁确定转化率及产率。剩余粗品过短硅胶柱(淋洗液EA)后经HPLC测定ee值。结果如下表(表4)所示，在尝试的各类添加剂中，Et3N(序号15、16)表现出促进性结果。
表4：不同添加剂下Z-3-乙酰氨基丁烯酸乙酯不对称氢化的实验结果
a1HNMR定量(内标CH2Br2)
bHPLC:手性柱AD-3,正己烷/异丙醇＝92:8,1.0ml/min,210nm.
c催化剂用量:S/C＝500.
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (10)
1.一种含有四(3,5-二三氟甲基苯基)硼阴离子的手性双膦配体铑络合物(I)，其具有如下的结构式：
其中BArF-的结构式为：
2.权利要求1所述的手性双膦配体铑络合物(I)，其特征在于：包括左旋体、右旋体及消旋体。
3.一种权利要求1所述的手性双膦配体铑络合物(I)的制备方法，其特征在于：在有机溶剂中，0-100℃下，手性双膦配体1、相应铑盐及NaBArF络合1-72小时，制备得到含有BArF-阴离子的手性双膦配体铑络合物，其反应式为：
其中COD为1,5-环辛二烯，OTf为对甲基苯磺酸根离子。
4.一种权利要求1所述的手性双膦配体铑络合物(I)的应用，其特征在于：它作为催化剂用于Z-3-乙酰氨基丁烯酸乙酯的不对称催化氢化反应，其反应式为：
5.根据权利要求4所述的手性双膦配体铑络合物(I)的应用，其特征在于：在氩气氛围下，将反应物、催化剂、脱气溶剂依次加入氢化内管中，然后于氢气氛围下，室温搅拌至反应结束。
6.根据权利要求5所述的手性双膦配体铑络合物(I)的应用，其特征在于：所述脱气溶剂是甲醇、乙醇、异丙醇、甲苯、四氢呋喃中的一种或几种的混合物。
7.根据权利要求5所述的手性双膦配体铑络合物(I)的应用，其特征在于：所述催化剂用量为原料的0.1-1mol％。
8.根据权利要求5所述的手性双膦配体铑络合物(I)的应用，其特征在于：所述氢气压力为1atm-30atm。
9.根据权利要求5所述的手性双膦配体铑络合物(I)的应用，其特征在于：所述反应物浓度为0.001-10.0M。
10.根据权利要求5所述的手性双膦配体铑络合物(I)的应用，其特征在于：所述反应温度为0-100℃，反应时间为1-72小时。
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| CN114426560A (zh) * | 2022-01-24 | 2022-05-03 | 南开沧州渤海新区绿色化工研究有限公司 | 一种手性双膦配体及其铑配合物和制备方法及其应用 |
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