CN115536708A - 一种二茂铁骨架的手性双膦配体及其制备方法和应用 - Google Patents
一种二茂铁骨架的手性双膦配体及其制备方法和应用 Download PDFInfo
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- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 239000003446 ligand Substances 0.000 title claims abstract description 51
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 title claims abstract description 24
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims abstract description 7
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000012300 argon atmosphere Substances 0.000 description 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 3
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- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- XGRJZXREYAXTGV-UHFFFAOYSA-N chlorodiphenylphosphine Chemical compound C=1C=CC=CC=1P(Cl)C1=CC=CC=C1 XGRJZXREYAXTGV-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- SSGGNFYQMRDXFH-UHFFFAOYSA-N sulfanylurea Chemical compound NC(=O)NS SSGGNFYQMRDXFH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- FCEBDAANWYNQMO-UHFFFAOYSA-N chloro-bis(3,5-dimethylphenyl)phosphane Chemical compound CC1=CC(C)=CC(P(Cl)C=2C=C(C)C=C(C)C=2)=C1 FCEBDAANWYNQMO-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000002888 effect on disease Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F17/00—Metallocenes
- C07F17/02—Metallocenes of metals of Groups 8, 9 or 10 of the Periodic Table
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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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2419—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member
- B01J31/2428—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member with more than one complexing phosphine-P atom
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- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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Abstract
本发明公开了一种二茂铁骨架的手性双膦配体及其制备方法和应用,所述手性双膦配体的制备过程为:氮气保护下,将如式(II)所示的双膦取代的二茂铁‑α‑乙胺衍生物和如式(III)所示的芳甲酰基异氰酸酯或芳甲酰基异硫氰酸酯加入有机溶剂中,于0~40℃下反应1~24小时,TLC跟踪至反应完全,减压浓缩回收溶剂,残留物经柱层析分离,得到如式(I)所示的二茂铁骨架的手性双膦配体。
Description
技术领域
本发明属于不对称催化技术领域,具体涉及一种二茂铁骨架的手性双膦配体及其制备方法和应用。
背景技术
特别是在药物的临床应用中,含手性的药物往往能够对疾病有独特的疗效。获取手性化合物的方法主要有手性拆分法、手性源合成法、不对称合成法等,而在不对称合成法中,不对称氢化以其原子经济性好,选择性高以及绿色清洁的工艺特点,成为了目前工业生产中较为成熟的手性催化技术。不对称氢化中使用的催化剂主要为过渡金属与手性配体的络合物,而配体是决定催化剂催化效率和选择性的核心与关键。因此,设计合成结构新颖的手性配体一直都是不对称合成研究的热点。
在不对称催化领域中,小分子(硫)脲结构单元是常见的形成分子(内)间氢键的官能团,二茂铁骨架是手性配体中的优势骨架,而将(硫)脲结构单元和二茂铁骨架连接到同一配体结构中的报道并不多见(Org.Biomol.Chem.,2014,12,2423–2426;Catal.Commun.,2019,121,78–83;Org.Lett.,2013,15,4014-4017)。迄今为止所报道的手性配体数不胜数,许多也表现出了很高的立体选择性,但由于合成复杂,修饰困难,价格昂贵等原因限制了其工业化应用。本发明提供了一类合成简单,对水和空气稳定、易于大规模制备的二茂铁骨架的手性双膦配体,该配体在不对称氢化α,β-不饱和内酰胺中表现出高活性和高选择性,具有潜在的工业化应用前景。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种二茂铁骨架的手性双膦配体及其制备方法和应用,本发明提供的配体具有合成简单,对水和空气稳定、与贵金属前体组成的催化剂,在催化α,β-不饱和酰胺的不对称氢化反应中具有高活性和高选择性等特点。
所述的一种二茂铁骨架的手性双膦配体,其结构通式如式(I)所示:
式(I)中:R1、R2各自独立地选自C1~C6烷基、C1~C6烷氧基、芳基、芳氧基或氢原子,R1、R2可任选地成环或不成环;R3为氢或甲基;X为S或O;R4为芳基、含有至少一个S、O或N原子的五元或六元杂环芳基或C1~C6烷基。
进一步地,所述R1、R2中,芳基为苯基或取代苯基,取代苯基的苯环上取代基数量为1~3个,选自C1~C4烷基;所述R4中,芳基为苯基或取代苯基,取代苯基的苯环上取代基数量为1~3个,选自C1~C4烷基或C1~C4卤代烷基。
进一步地,本申请提供的一种二茂铁骨架的手性双膦配体,包括10种配体中的一种,每种配体对应两种异构体,10种配体的结构式如下:
所述的一种二茂铁骨架的手性双膦配体的制备方法,包括以下步骤:氮气保护下,将如式(II)所示的双膦取代的二茂铁-α-乙胺衍生物和如式(III)所示的芳甲酰基异氰酸酯或芳甲酰基异硫氰酸酯加入至有机溶剂中,于0~40℃下搅拌反应1~24小时,TLC跟踪至反应完全,减压浓缩回收溶剂,残留物经柱层析分离(洗脱液为石油醚:乙酸乙酯=5~20:1,体积比),得到如式(I)所示的二茂铁骨架的手性双膦配体;
式(II)中的R1、R2、R3与式(I)中相同,式(III)中R4与式(I)中相同。
进一步地,所述的如式(II)所示的双膦取代的二茂铁-α-乙胺衍生物、式(III)所示的芳甲酰基异氰酸酯或芳甲酰基异硫氰酸酯的物质的量之比为1:1.0~2.0;反应温度为20~30℃,反应时间为1~5小时。
进一步地,所述的有机溶剂为二氯甲烷、丙酮或乙腈,如式(II)所示的双膦取代的二茂铁-α-乙胺衍生物在有机溶剂中的浓度为0.02~0.1mol/L,优选为0.05~0.07mol/L。
一种贵金属催化剂,是由本发明提供的二茂铁骨架的手性双膦配体与过渡金属前体络合所得的配合物,所述过渡金属为Ru、Rh、Ir或Pd中任意的一种。
具体的过渡金属前体选自:Pd(COD)Cl2、Pd(PPh3)4、PdCl2(PPh3)2、Pd(dba)2、Pd(OAc)2、[Rh(NBD)2]BF4、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(acac)(CO)]2、Rh(ethylene)2(acac)、Rh(ethylene)2Cl2、RhCl(PPh3)3、Rh(CO)2Cl2、RuCl2(COD)、[Ru(COD)2]Cl、[Ir(NBD)2Cl]2、Ir(NBD)2)BF4、[Ir(COD)Cl]2或[Ir(COD)2]BF4中的任意一种。
进一步地,二茂铁骨架的手性双膦配体与过渡金属前体的摩尔比为1:0.8~1.2。
所述的贵金属催化剂可应用于不对称氢化反应中,具体应用于布瓦西坦的不对称合成中,反应通式如下:
通过采用上述技术,本发明提供的一种新型二茂铁骨架的手性双膦配体,具有合成简单、对水和空气稳定、高活性和高选择性、易于实现工业化生产等特点,而且该配体可以通过简单的基团改变来调控配体的位阻和电性,适合大规模制备,具有较好的工业化应用前景,可应用于药物布瓦西坦的不对称氢化合成中。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
实施例1:配体L2的合成
(1)将(R)-Ugi胺1(5.14g,20mmol)溶于50mL乙醚中,氮气保护和0℃下,向反应瓶中滴加正丁基锂(10mL,2.5mol/L),滴加完毕后保温反应3小时。继续向反应瓶中缓慢滴加正丁基锂(12mL,2.5mol/L)及N,N,N,N-四甲基乙二胺(TMEDA)(3.95g,30mmol),滴加完毕后保温搅拌反应5小时。然后滴加氯代二苯基膦(17.65g,80mmol),滴完后缓慢升至室温,搅拌反应12小时。用饱和氯化铵溶液淬灭反应,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯:三乙胺=2:1:0.01,体积比)得化合物2a(6.3g,收率52%)。
(2)将化合物2a(6.3g,10mmol)与15mL醋酐混合,100℃下反应3小时,减压浓缩除去过量的醋酐和低沸点物质;往残留物中加入50mL 40%的甲氨水溶液中,置换氮气后,100℃反应12h。反应完毕后冷却反应液,二氯甲烷萃取,无水硫酸钠干燥,浓缩,柱层析(石油醚:乙酸乙酯:三乙胺=1:1:0.01,体积比)纯化得化合物IIa(3.2g,收率53%)。
(3)在50mL反应瓶中加入化合物IIa(611.5mg,1mmol)和化合物IIIb(310mg,1.5mmol)以及二氯甲烷15mL,25℃下反应2小时。反应完毕,二氯甲烷萃取,无水硫酸钠干燥,柱层析(石油醚:乙酸乙酯=10:1,体积比)分离得黄色配体L2(0.52g,收率63.6%)。
1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),7.54(t,J=7.8Hz,2H),7.25(m,,20H),6.83(q,J=7.6Hz,1H),4.51(s,2H),4.23(d,J=3.3Hz,2H),4.02(s,1H),3.74(s,1H),3.38(s,1H),2.27(s,3H),2.18(s,6H),1.92(s,3H),1.53(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ180.51,175.51,140.21(d,J=10.1Hz),139.80(d,J=10.1Hz),139.51(d,J=10.1Hz),137.14(d,J=9.1Hz),135.62(d,J=21.1Hz),134.13(d,J=20.1),133.75(d,J=19.1Hz),133.02(d,J=19.1Hz),132.78,131.89,131.56,130.34,129.91,129.52,129.37,128.75(d,J=6Hz),128.51(d,J=6Hz),128.41,128.12,127.51,93.11(d,J=24.5Hz),77.86(d,J=16.4Hz),77.62(d,J=14.5Hz),75.61(d,J=18.9Hz),74.54(d,J=4.6Hz),74.11(d,J=10.4Hz),73.81(d,J=2.1Hz),73.54(d,J=9.9Hz),72.15(d,J=2.1Hz),71.61(d,J=2.1Hz),68.61(d,J=9.1Hz),35.80,21.37,20.54,18.61.31P NMR(162MHz,DMSO-d6)δ-17.72,-25.43.HRMS(ESI):[M+H+]Calc.C48H47FeN2OP2S 817.2235,found817.2243。
实施例2:配体L3的合成
在50mL反应瓶中加入化合物IIa(611.5mg,1mmol)和化合物IIIc(412.5mg,1.5mmol)以及二氯甲烷15mL,25℃下反应2小时。反应完毕,二氯甲烷萃取,无水硫酸钠干燥,柱层析(石油醚:乙酸乙酯=10:1,体积比)得黄色配体L3(0.49g,收率54.8%)。
1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),7.45–7.17(m,23H),6.45(q,J=7.6Hz,1H),4.47(s,2H),4.15(d,J=3.3Hz,2H),3.89(s,1H),3.54(s,1H),3.38(s,1H),1.88(s,3H),1.43(d,J=6.8Hz,3H),1.32(s,18H).13C NMR(100MHz,DMSO-d6)δ182.51,173.67,141.22,138.42(d,J=9.9Hz),137.26(d,J=5.4Hz),137.03(d,J=9.7Hz),136.73,135.42(d,J=21.1Hz),134.13(d,J=20.1),133.84(d,J=20.4Hz),133.64(d,J=21.2Hz),133.32(d,J=19.1Hz),132.86(d,J=18.9Hz),132.78,132.08(d,J=17.5Hz),131.89,131.56,130.34129.91,129.52,129.37,129.27(d,J=17.7Hz),95.11(d,J=24.5Hz),77.68(d,J=16.4Hz),77.45(d,J=14.5Hz),75.51(d,J=18.9Hz),74.84(d,J=4.6Hz),74.11(d,J=10.4Hz),73.61(d,J=2.1Hz),73.54(d,J=9.9Hz),72.15(d,J=2.1Hz),71.61(d,J=2.1Hz),68.61(d,J=9.1Hz),36.87(s),35.75,30.46,20.57.31P NMR(162MHz,DMSO-d6)δ-17.72,-25.43.HRMS(ESI):[M+H+]Calc.C53H57FeN2OP2S,887.3018,found887.3026。
实施例3:配体L7的合成
在50mL反应瓶中加入化合物IIa(611.5mg,1mmol)和化合物IIId(220.7mg,1.5mmol)以及二氯甲烷15mL,25℃下反应2小时。反应完毕,二氯甲烷萃取,无水硫酸钠干燥,柱层析(石油醚:乙酸乙酯=10:1,体积比)分离得到黄色固体L7(0.42g,收率51%)。
1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),7.40–7.24(m,20H),7.23–7.18(m,5H),6.71(q,J=7.7Hz,1H),4.51(s,2H),4.21(d,J=3.3Hz,2H),3.92(s,1H),3.64(s,1H),3.22(s,1H),2.17(s,3H),1.53(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ181.51,175.51,141.89(d,J=10.1Hz),139.56(d,J=10.1Hz),139.51(d,J=10.1Hz),138.14(d,J=9.1Hz),136.82(d,J=21.1Hz),135.13(d,J=20.1Hz),133.75(d,J=19.1Hz),133.42(d,J=19.1Hz),132.38,131.79,131.56,130.34,129.91,129.52,129.37,128.75(d,J=6Hz),128.51(d,J=6Hz),128.41,128.12,127.5196.88(d,J=24.1Hz),75.39(d,J=22.6Hz),73.95(d,J=5.3Hz),73.65(d,J=5.6Hz),72.98(d,J=6.8Hz),72.81,72.56(d,J=3.7Hz),72.16(d,J=3.6Hz),71.61(d,J=2.1Hz),67.84.31PNMR(100MHz,DMSO-d6)δ-18.71,-26.73.HRMS(ESI):[M+H+]Calc.C45H40FeN2O2P2,759.1987,found 759.1979。
实施例4:配体L8的合成:
化合物IIb可参照实施例1中IIa的合成方法来制备:将实施例1步骤(2)中50mL40%的甲氨水溶液,替换成50mL 40%的氨水溶液即可制得化合物IIb。
在50mL反应瓶中加入化合物IIb(611.5mg,1mmol)和化合物IIIb(226.8mg,1.5mmol)以及二氯甲烷15mL,25℃下反应2小时。反应完毕,二氯甲烷萃取,无水硫酸钠干燥,柱层析(石油醚:乙酸乙酯=10:1,体积比)得黄色固体L8(0.52g,收率63%)。
1H NMR(400MHz,DMSO-d6)δ10.87(d,J=7.0Hz,1H),8.30(s,1H),7.40–7.24(m,20H),6.83(s,2H),5.59(p,J=7.1Hz,1H),4.51(s,2H),4.23(d,J=3.3Hz,2H),4.02(s,1H),3.74(s,1H),3.38(s,1H),2.27(s,3H),2.18(s,6H),1.63(d,J=6.8Hz,3H).13C NMR(400MHz,DMSO-d6)δ184.32,175.11,140.82,138.32(d,J=9.9Hz),137.56(d,J=5.4Hz),137.03(d,J=9.7Hz),136.13(s),135.62(d,J=21.1Hz),134.13(d,J=20.1),133.84(d,J=20.4Hz),133.64(d,J=21.2Hz),133.42(d,J=19.1Hz),132.76(d,J=18.9Hz),132.78,132.08(d,J=17.5Hz),131.89,131.56,130.34129.91,129.52,129.37,129.27(d,J=17.7Hz),93.11(d,J=24.5Hz),77.86(d,J=16.4Hz),77.62(d,J=14.5Hz),75.61(d,J=18.9Hz),74.54(d,J=4.6Hz),74.11(d,J=10.4Hz),73.81(d,J=2.1Hz),73.54(d,J=9.9Hz),72.15(d,J=2.1Hz),71.61(d,J=2.1Hz),68.61(d,J=9.1Hz),51.84,24.43,20.57.31P NMR(162MHz,DMSO-d6)δ-18.22,-26.13.HRMS(ESI):[M+H+]Calc.C47H44FeN2OP2S,803.2072,found 803.2066。
实施例5:配体L9的合成
化合物IIc可参照实施例1中IIa的合成方法来制备,制备步骤重复实施例1,不同之处仅在于“将步骤(1)中的氯代二苯基膦(80mmol),替换为氯代-二(3,5二甲基苯基)膦(80mmol)”,即制得化合物IIc。
在50mL反应瓶中加入化合物IIc(723.5mg,1mmol)和化合物IIIb(310mg,1.5mmol)以及二氯甲烷15mL,25℃下反应2小时。反应完毕,二氯甲烷萃取,无水硫酸钠干燥,柱层析(石油醚:乙酸乙酯=10:1,体积比)得黄色固体L9(0.53g,收率56.8%)。
1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.54(t,J=7.8Hz,2H),7.40–7.25(m,12H),6.83(q,J=7.6Hz,1H),4.31(s,2H),4.23(d,J=3.3Hz,2H),3.98(s,1H),3.74(s,1H),3.28(s,1H),2.27(s,3H),2.18(s,24H),2.08(s,6H),1.92(s,3H),1.53(d,J=6.8Hz,3H).13C NMR(100MHz,DMSO-d6)δ180.51,175.51,140.62,138.12(d,J=9.9Hz),137.56(d,J=5.4Hz),137.03(d,J=9.7Hz),136.13(s),135.62(d,J=21.1Hz),134.13(d,J=20.1),133.84(d,J=20.4Hz),133.64(d,J=21.2Hz),133.42(d,J=19.1Hz),132.76(d,J=18.9Hz),132.78,132.08(d,J=17.5Hz),131.89,131.56,130.34129.91,129.52,129.37,129.27(d,J=17.7Hz),96.88(d,J=24.1Hz),77.68(d,J=16.4Hz),77.45(d,J=14.5Hz),75.51(d,J=18.9Hz),74.84(d,J=4.6Hz),74.11(d,J=10.4Hz),73.61(d,J=2.1Hz),73.54(d,J=9.9Hz),72.15(d,J=2.1Hz),71.61(d,J=2.1Hz),68.61(d,J=9.1Hz),37.87,24.43,23.54,22.78,21.21 20.57.31PNMR(162MHz,DMSO-d6)δ-18.72(s),-24.43(s).HRMS(ESI):[M+H+]Calc.C56H62FeN2OP2S,929.3481,found 929.3489。
实施例6:贵金属催化剂的制备及布瓦西坦的不对称合成
(1)将配体L2(8.98mg,0.011mmol),金属前体Rh(NBD)2BF4(3.4mg,0.01mmol)加入反应瓶中,氩气氛围下加入二氯甲烷1mL,25℃下搅拌1小时,制得Rh催化剂溶液。
(2)在高压釜中加入底物S1(225.3mg,1mmol),二氯甲烷0.5mL,加入步骤(1)所制备的Rh催化剂溶液(1mL,0.01mmol),用氮气置换空气三次,然后充入H2至6.0MPa,35℃下反应48小时。反应完毕后释放氢气,反应液经过硅胶过滤得226mg中间体S2,收率99%,HPLC纯度99%,ee值为91%。
(3)耐压管中加入中间体S2(225.3mg,1mmol),7M的氨甲醇溶液3mL,90℃下反应5小时,反应完毕后,浓缩除去溶剂,得到205mg布瓦西坦S3,收率96.5%,HPLC纯度98%,ee值91%。
实施例7:贵金属催化剂的制备及布瓦西坦的不对称合成
(1)将配体L9(10.22mg,0.011mmol),金属前体Rh(NBD)2BF4(3.4mg,0.01mmol)加入反应瓶中,氩气氛围下加入二氯甲烷1mL,25℃下搅拌1小时,制得Rh催化剂溶液。
(2)在高压釜中加入底物S1(1mmol,225.3mg),二氯甲烷0.5mL,加入步骤(1)所制备的Rh催化剂溶液(1mL,0.01mmol),用氮气置换空气三次,然后充入H2至6.0MPa,35℃下反应48小时。反应完毕后释放氢气,反应液经过硅胶过滤得227mg中间体S2,收率99%,HPLC纯度99%,ee值为95%。
(3)耐压管中加入中间体S2(227mg,1mmol),7M的氨甲醇溶液3mL,90℃下反应5小时,反应完毕后,浓缩除去溶剂,得到200mg布瓦西坦S3,收率94.2%,HPLC纯度99%,ee值95%。
实施例8:贵金属催化剂的制备及布瓦西坦的不对称合成
(1)将配体L7(8.34mg,0.011mmol),金属Rh(COD)2BF4(3.4mg,0.01mmol)加入反应瓶中,氩气氛围下加入二氯甲烷1mL,25℃下搅拌1小时,制得Rh催化剂溶液。
(2)在高压釜中加入底物S1(1mmol,225.3mg),二氯甲烷0.5mL,加入步骤(1)所制备的Rh催化剂溶液(1mL,0.01mmol),用氮气置换空气三次,然后充入H2至6.0MPa,35℃下反应48小时。反应完毕后释放氢气,反应液经过硅胶过滤得225.3mg中间体S2,收率96%,HPLC纯度99%,ee值为81.4%。
(3)耐压管中加入中间体S2(225.3mg,0.99mmol),7M的氨甲醇溶液3mL,90℃下反应5小时,反应完毕后,浓缩除去溶剂,得到203mg布瓦西坦S3,收率96.6%,HPLC纯度97%,ee值81.4%。
实施例9:贵金属催化剂的制备及布瓦西坦的不对称合成
实施例9的实验过程重复实施例6,不同之处仅在于“将配体L2(0.011mmol)替换成其他配体(0.011mmol)”,最终制得布瓦西坦S3。实施例9中采用不同的其他配体,最终布瓦西坦S3产物对应的实验结果汇总于表1中。
表1
本说明书所述的内容仅仅是对发明构思实现形式的列举,本发明的保护范围不应当被视为仅限于实施例所陈述的具体形式。
Claims (10)
2.如权利要求1所述的一种二茂铁骨架的手性双膦配体,其特征在于所述R1、R2中,芳基为苯基或取代苯基,取代苯基的苯环上取代基数量为1~3个,选自C1~C4烷基;所述R4中,芳基为苯基或取代苯基,取代苯基的苯环上取代基数量为1~3个,选自C1~C4烷基或C1~C4卤代烷基。
5.如权利要求4所述的一种二茂铁骨架的手性双膦配体的制备方法,其特征在于所述的如式(II)所示的双膦取代的二茂铁-α-乙胺衍生物、式(III)所示的芳甲酰基异氰酸酯或芳甲酰基异硫氰酸酯的物质的量之比为1:1.0~2.0;反应温度为20~30℃,反应时间为1~5小时;
所述的有机溶剂为二氯甲烷、丙酮或乙腈,如式(II)所示的双膦取代的二茂铁-α-乙胺衍生物在有机溶剂中的浓度为0.02~0.1mol/L,优选为0.05~0.07mol/L。
6.一种贵金属催化剂,其特征在于为由权利要求1所述的二茂铁骨架的手性双膦配体与过渡金属前体络合所得的配合物。
7.如权利要求6所述的一种贵金属催化剂,其特征在于过渡金属为Ru、Rh、Ir或Pd中任意的一种。
8.如权利要求6或7所述的一种贵金属催化剂,其特征在于过渡金属前体选自:Pd(COD)Cl2、Pd(PPh3)4、PdCl2(PPh3)2、Pd(dba)2、Pd(OAc)2、[Rh(NBD)2]BF4、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(acac)(CO)]2、Rh(ethylene)2(acac)、Rh(ethylene)2Cl2、RhCl(PPh3)3、Rh(CO)2Cl2、RuCl2(COD)、[Ru(COD)2]Cl、[Ir(NBD)2Cl]2、Ir(NBD)2)BF4、[Ir(COD)Cl]2或[Ir(COD)2]BF4中的任意一种;
二茂铁骨架的手性双膦配体与过渡金属前体的摩尔比为1:0.8~1.2。
9.一种如权利要求6所述的贵金属催化剂在不对称氢化反应中的应用。
10.如权利要求9所述的应用,其特征在于所述贵金属催化剂用于催化不对称氢化反应合成布瓦西坦。
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