CN106866730A - 一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法 - Google Patents
一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法 Download PDFInfo
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Abstract
一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法,其用到的催化体系是钯的手性双磷配合物。对一系列亚胺膦酸酯不对称氢化能得到相应的手性胺基膦酸酯,其对映体过量可达到99%。本发明操作简便实用易行,催化剂商业可得,反应条件温和。此外,通过不对称氢化合成手性胺基膦酸酯,对映选择性高,产率好,且反应具有绿色原子经济性,对环境友好。
Description
技术领域
本发明涉及一种应用钯的均相体系高度对映选择性催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法。
背景技术
光学活性的胺基膦酸与氨基酸在结构上具有相似性,同样具备广泛的生理活性,可作为酶抑制剂,抗真菌剂,抗菌剂和抗癌剂等(参考文献一:(a)Senten,K.;L.;Van der Veken,P.;De Meester,I.;Lambeir,A.-M.;Scharpé,S.;Haemers,A.;Augustyns,K.J.Comb.Chem.2002,5,336.(b)Maier,L.;Diel,P.J.Phosphorous,Sulfur Silicon Relat.Elem.1994,90,259.(c)Grembecka,J.;Mucha,A.;Cierpicki,T.Kafarski,P.J.Med.Chem.2003,46,2641.Yao,G.;Ye,M.;Huang,R.;Li,Y.;Pan,Y.;Xu,Q.;Liao,Z.;Wang,H.Bioorg.Med.Chem.Lett.2014,24,501.)。基于此,胺基膦酸及其衍生物的不对称合成受到了科研工作者的广泛关注,根据成键方式的不同,手性胺基膦酸及其衍生物的合成策略主要包括立体选择性的C-P键形成,C-C键形成,C-N键形成,C-H键形成(参考文献二:(a)M.;Rojas-Cabrera,H.;Cativiela,C.Tetrahedron2009,65,17.(b)M.;Viveros-Ceballos,J.L.;Cativiela,C.;Sayago,F.J.Tetrahedron2015,71,1745.)。
近年来,过渡金属催化的不对称氢化策略通过构建C-H键合成手性胺基膦酸及其衍生物,以其直接高效、原子经济性等特点吸引了科研工作者的注意。一系列工作主要是通过铑、钌金属催化剂催化烯胺膦酸酯的不对称氢化,均能获得较好的结果(参考文献三:(a)Ma,J.-A.Chem.Soc.Rev.2006,35,630.(b)U.;Hoppe,I.;Thiele,A.Liebigs Ann.Chem.1985,555.(c)Holz,J.;Stürmer,R.;Schmidt,U.;Drexler,H.-J.;Heller,D.;Krimmer,H.-P.;A.Eur.J.Org.Chem.2001,4615.(d)Zhang,Z.;Tamura,K.;Mayama,D.;Sugiya,M.;Imamoto,T.J.Org.Chem.2012,77,4184.)。但该方法存在的主要缺陷是无法合成β-位为季碳的胺基膦酸及其衍生物;在2008年,Goulioukina小组发展了一种均相铑催化亚胺膦酸酯底物的不对称氢化反应(参考文献四,(a)Goulioukina,N.S.;Bondarenko,G.N.;Lyubimov,S.E.;Davankov,V.A.;Gavrilov,K.N.;Beletskaya,I.P.Adv.Synth.Catal.2008,350,482.(b)Goulioukina,N.S.;Shergold,I.A.;Bondarenko,G.N.;Ilyin,M.M.;Davankov,V.A.;Beletskaya,I.P.Adv.Synth.Catal.2012,354,2727.),为合成手性胺基膦酸及其衍生物提供了一种新方法。基于我们小组在亚胺底物氢化方面所做的工作(参考文献五,Chen,Q.-A.;Ye,Z.-S.;Duan,Y.;Zhou,Y.-G.Chem.Soc.Rev.2013,42,497.),我们设想能否采用相同的策略,利用均相钯催化亚胺膦酸酯底物进行不对称氢化反应来合成手性胺基膦酸及其衍生物。
发明内容
本发明的目的是提供一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法。本发明操作简便实用,对映选择性高,产率好,且反应具有原子经济性,环境友好等优点。
为实现上述目的,本发明的技术方案如下:
本发明以钯的手性双膦配合物催化剂,分子筛为添加剂,以实现亚胺膦酸酯的不对称氢化,反应式和条件如下:
式中:
温度:0-50℃;
溶剂:有机溶剂;
时间:15-24小时;
金属前体:三氟醋酸钯
手性配体:双膦配体;
添加剂:分子筛;
催化剂的制备方法为:把钯的金属前体和手性双膦配体在1.0mL丙酮中室温搅拌1-3小时,然后真空浓缩除去丙酮。
所述R1、R2分别为C1-C10的烷基,苯基及含有取代基的苯环,取代基为F、Cl、Me、MeO中的一种取代基或二种取代基;
所述添加剂为分子筛,反应所用的分子筛为或中的一种或二种以上;
所述三氟醋酸钯和双膦配体为市售且未经处理。
反应步骤为:
在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%-5mol%)和手性膦配体(式1中底物用量的2.4mol%-6.0mol%),氮气置换后加入丙酮,室温搅拌1-3小时,得催化剂;然后真空浓缩除去丙酮,氮气下加入三氟乙醇,将此溶液转到预先放有亚胺膦酸酯和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气(600psi-1000psi),0℃-50℃下反应15-24小时;释放氢气,除去溶剂后直接柱层析分离得到纯的产物。
所述催化剂为三氟醋酸钯和双膦配体的配合物,三氟醋酸钯及双膦配体均为市售且无需任何处理。
所述添加剂为分子筛,反应所用的分子筛为或中的一种或二种以上。反应中分子筛使用量为相对于0.1mmol的式1中底物分子筛用量为50mg-100mg。
所述反应溶剂为甲苯、二氯甲烷、三氟乙醇、四氢呋喃中的一种或两种的混合。
本发明具有以下优点
1.反应活性和对映选择性高,反应完全,生成产物专一,核磁氢谱没有检测到副反应,使得能分离方便,能获得高的对映体过量纯品。
2.能得到各种类型的手性胺基膦酸酯,例如支链、五元环、六元环。
3.催化剂制备方便,反应操作简便实用。
4.氢化反应条件温和。
5.比较传统的合成方法,此方法能用少量的手性催化剂得到大量手性胺基膦酸酯,实现手性增值,而且还可以通过改变配体的构型而获得不同构型的手性胺基膦酸酯。
具体实施方式
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
实施例1:条件的优化
在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%)和手性膦配体(式1中底物用量的2.4mol%),氮气置换后加入1mL丙酮,室温搅拌1-3小时,得催化剂。然后真空浓缩,氮气下加入1.5mL有机溶剂,将此溶液转到预先放有底物1a(39.5mg,0.1mmol)和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气600psi,40℃反应24小时。慢慢释放氢气,除去溶剂后直接柱层析分离得到纯的产物,反应式和配体结构如下:
其产率为分离收率,产物的对映体过量用手性液相色谱测定,详见表1。
表1.N-对甲苯磺酰基α-酮亚胺膦酸酯1a的不对称氢化a
实施例2:钯催化不对称氢化合成各种手性胺基膦酸酯2
在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%)和手性膦配体(式1中底物用量的2.4mol%),氮气置换后加入1mL丙酮,室温搅拌1-3小时,得催化剂。然后真空浓缩,氮气下加入1.5mL三氟乙醇/二氯甲烷=体积比2/1混合溶剂,将此溶液转到预先放有底物1(0.1mmol)和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气600psi,40℃反应24小时。慢慢释放氢气,除去溶剂后直接柱层析分离得到纯的产物,反应式和配体结构如下:
产率为分离收率,产物的对映体过量用手性液相色谱测定,见表2。
表2.钯催化不对称氢化合成各种手性胺基膦酸酯2a
实施例3:钯催化不对称氢化合成各种手性胺基膦酸酯4
在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%)和手性膦配体(式1中底物用量的2.4mol%),氮气置换后加入1mL丙酮,室温搅拌1-3小时,得催化剂。然后真空浓缩,氮气下加入1.5mL三氟乙醇/二氯甲烷=体积比2/1混合溶剂,将此溶液转到预先放有底物1(0.1mmol)和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气600psi,40℃反应24小时。慢慢释放氢气,除去溶剂后直接柱层析分离得到纯的产物,反应式和配体结构如下:
产率为分离收率,产物的对映体过量用手性液相色谱测定,见表3。
表3.钯催化不对称氢化合成各种手性胺基膦酸酯4a
实施例4:钯催化不对称氢化合成各种手性胺基膦酸酯5
在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%)和手性膦配体(式1中底物用量的2.4mol%),氮气置换后加入1mL丙酮,室温搅拌1-3小时,得催化剂。然后真空浓缩,氮气下加入1.5mL三氟乙醇/二氯甲烷=体积比2/1混合溶剂,将此溶液转到预先放有底物1(0.1mmol)和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气600psi,40℃反应24小时。慢慢释放氢气,除去溶剂后直接柱层析分离得到纯的产物,反应式和配体结构如下:
产率为分离收率,产物的对映体过量用手性液相色谱测定,见表4。
表4.钯催化不对称氢化合成各种手性胺基膦酸酯6a
(S)-二乙基(4-甲基苯磺酰氨基)(苯基)甲基磷酸酯(2a):收率为93%,对映选择性过量为96%,旋光为-16.22(浓度为0.74g/100mL,CHCl3),已知化合物,白色固体,熔点为130-131℃,Rf=0.50(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.55(dd,J=9.9Hz,JPH=4.2Hz,1H),7.45(d,J=8.3Hz,2H),7.23-7.12(m,2H),7.12-7.02(m,3H),6.91(d,J=8.0Hz,2H),4.82(dd,J=9.9Hz,JPH=24.4Hz,1H),4.32-4.25(m,2H),3.91-3.81(m,1H),3.63-3.53(m,1H),2.24(s,3H),1.37(t,J=7.1Hz,3H),1.03(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ142.7,138.2(d,JPC=1.8Hz),133.8,129.0,128.5(d,JPC=5.9Hz),128.2(d,JPC=2.2Hz),127.8(d,JPC=2.9Hz),127.2,64.3(d,JPC=7.0Hz),63.7(d,JPC=7.0Hz),55.6(d,JPC=157.2Hz),21.4,16.6(d,JPC=6.0Hz),16.2(d,JPC=5.6Hz);31P NMR(160MHz,CDCl3)δ19.6.高效液相色谱(HPLC):手性柱(IA-H),254nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为13.2min和22.6min(主要)。
(S)-二甲基(4-甲基苯磺酰氨基)(苯基)甲基磷酸酯(2b):收率为97%,对映选择性过量为94%,旋光为-26.00(浓度为0.60g/100mL,CHCl3),已知化合物,白色固体,熔点为169-170℃,Rf=0.10(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.47(d,J=8.1Hz,2H),7.27-7.21(m,3H),7.15-7.06(m,3H),6.95(d,J=8.0Hz,2H),4.85(dd,J=9.0Hz,JPH=24.4Hz,1H),3.88(d,JPH=10.7Hz,3H),3.40(d,JPH=10.6Hz,3H),2.25(s,3H);13C NMR(100MHz,CDCl3)δ143.0,138.1(d,JPC=1.6Hz),133.6,129.1,128.4(d,JPC=2.2Hz),128.4(d,JPC=6.0Hz),128.1(d,JPC=2.9Hz),127.2,55.1(d,JPC=157.2Hz),54.8(d,JPC=7.2Hz),54.1(d,JPC=7.0Hz),21.5;31P NMR(160MHz,CDCl3)δ22.1-21.7(m).高效液相色谱(HPLC):手性柱(IA-H),254nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为14.4min和19.7min(主要)。
(S)-二异丙基(4-甲基苯磺酰氨基)(苯基)甲基磷酸酯(2c):收率为98%,对映选择性过量为96%,旋光为-9.75(浓度为0.80g/100mL,CHCl3),已知化合物,白色固体,熔点为190-191℃,Rf=0.60(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.43(d,J=8.2Hz,2H),7.19(d,J=7.4Hz,2H),7.10-6.97(m,4H),6.91(d,J=8.1Hz,2H),4.92-4.81(m,1H),4.74(dd,J=9.7Hz,JPH=24.6Hz,1H),4.40-4.29(m,1H),2.24(s,3H),1.38(t,J=6.5Hz,6H),1.21(d,J=6.2Hz,3H),0.76(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ142.6,138.3(d,JPC=1.8Hz),134.1,129.0,128.7(d,JPC=5.9Hz),128.1(d,JPC=2.2Hz),127.7(d,JPC=2.9Hz),127.2,73.0(d,JPC=7.3Hz),72.7(d,JPC=7.3Hz),56.1(d,JPC=158.8Hz),24.5(d,JPC=3.3Hz),24.3(d,JPC=2.9Hz),24.0(d,JPC=5.9Hz),23.0(d,JPC=6.2Hz),21.5;31P NMR(160MHz,CDCl3)δ18.0.高效液相色谱(HPLC):手性柱(IA-H),254nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为12.1min和21.5min(主要)。
(S)-二苄基(4-甲基苯磺酰氨基)(苯基)甲基磷酸酯(2d):收率为93%,对映选择性过量为95%,旋光为+20.12(浓度为0.84g/100mL,CHCl3),已知化合物,白色固体,熔点为136-137℃,Rf=0.70(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.67(dd,J=9.9Hz,JPH=4.2Hz,1H),7.49(d,J=8.3Hz,2H),7.38-7.21(m,10H),7.15(dd,J=7.7,6.2Hz,1H),7.08-7.01(m,4H),6.85(d,J=8.1Hz,2H),5.25-5.10(m,2H),4.99(dd,J=9.9Hz,JPH=24.6Hz,1H),4.78(dd,J=7.3Hz,JPH=11.7Hz,1H),4.48(dd,J=9.0Hz,JPH=11.7Hz,1H),2.21(s,3H);13C NMR(100MHz,CDCl3)δ142.8,138.2(d,JPC=1.7Hz),136.2(d,JPC=6.1Hz),135.8(d,JPC=5.9Hz),133.7,129.1,128.7,128.61,128.58,128.57,128.55,128.50,128.4(d,JPC=2.3Hz),128.3,128.0(d,JPC=2.9Hz),127.9,127.2,69.5(d,JPC=7.2Hz),68.8(d,JPC=7.1Hz),55.7(d,JPC=157.4Hz),21.5;31P NMR(160MHz,CDCl3)δ23.1-12.8(m).高效液相色谱(HPLC):手性柱(IA-H),254nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为25.8min和30.1min(主要)。
(S)-二异丙基((4-氟苯基)(4-甲基苯磺酰氨基)甲基)磷酸酯(2e):收率为91%,对映选择性过量为97%,旋光为-7.04(浓度为0.81g/100mL,CHCl3),已知化合物,白色固体,熔点为143-144℃,Rf=0.60(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.60(dd,J=10.0Hz,JPH=4.1Hz,1H),7.42(d,J=8.3Hz,2H),7.21-7.19(m,2H),6.90(d,J=8.1Hz,2H),6.68(t,J=8.6Hz,2H),4.97-4.88(m,1H),4.75(dd,J=10.1Hz,JPH=24.9Hz,1H),4.45-4.34(m,1H),2.24(s,3H),1.43(d,J=6.2Hz,1H),1.40(d,J=6.1Hz,1H),1.23(d,J=6.2Hz,3H),0.83(d,J=6.1Hz,3H);13C NMR(100MHz,CDCl3)δ162.4(dd,JFC=246.7Hz,JPC=3.2Hz),142.8,138.4(d,JPC=2.1Hz),130.4(dd,JFC=8.2Hz,JPC=6.0Hz),130.1(d,JPC=3.2Hz),129.0,127.2,114.9(dd,JFC=21.5Hz,JPC=2.2Hz),73.3(d,JPC=7.3Hz),72.6(d,JPC=7.5Hz),55.4(d,JPC=160.7Hz),24.6(d,JPC=3.2Hz),24.3(d,JPC=3.4Hz),24.0(d,JPC=5.7Hz),23.2(d,JPC=5.7Hz),21.5;31P NMR(160MHz,CDCl3)δ17.5(d,JFP=4.9Hz);19F NMR(376MHz,CDCl3)δ-114.6(d,JPF=4.8Hz).高效液相色谱(HPLC):手性柱(IA-H),230nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为16.3min和25.4min(主要)。
(S)-二异丙基((4-氯苯基)(4-甲基苯磺酰氨基)甲基)磷酸酯(2f):收率为93%,对映选择性过量为94%,旋光为-4.42(浓度为0.86g/100mL,CHCl3),已知化合物,白色固体,熔点为183-184℃,Rf=0.70(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.82(dd,J=10.1Hz,JPH=3.9Hz,1H),7.40(d,J=8.3Hz,2H),7.14-7.12(m,2H),6.95-6.88(m,4H),5.01-4.90(m,1H),4.74(dd,J=10.2Hz,JPH=25.1Hz,1H),4.47-4.38(m,1H),2.26(s,3H),1.46(d,J=6.1Hz,1H),1.42(d,J=6.2Hz,1H),1.25(d,J=6.1Hz,3H),0.87(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ142.9,138.3(d,JPC=1.8Hz),133.6(d,JPC=3.3Hz),132.7,130.1(d,JPC=5.9Hz),128.9,128.0(d,JPC=2.2Hz),127.2,73.4(d,JPC=7.3Hz),72.6(d,JPC=7.3Hz),55.5(d,JPC=160.7Hz),24.6(d,JPC=2.9Hz),24.2(d,JPC=3.7Hz),24.0(d,JPC=5.9Hz),23.2(d,JPC=5.9Hz),21.5;31P NMR(160MHz,CDCl3)δ17.2.高效液相色谱(HPLC):手性柱(IA-H),230nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为20.2min和31.5min(主要)。
(S)-二异丙基((4-溴苯基)(4-甲基苯磺酰氨基)甲基)磷酸酯(2g):收率为90%,对映选择性过量为92%,旋光为-1.10(浓度为0.82g/100mL,CHCl3),未知化合物,白色固体,熔点为194-195℃,Rf=0.70(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.40(d,J=8.3Hz,2H),7.29(dd,J=9.8Hz,JPH=4.8Hz,1H),7.13-7.11(m,2H),7.06-7.03(m,2H),6.93(d,J=8.1Hz,2H),4.95-4.84(m,1H),4.70(dd,J=9.9Hz,JPH=24.8Hz,1H),4.48-4.39(m,1H),2.29(s,1H),1.43-1.39(m,6H),1.25(d,J=6.1Hz,3H),0.88(d,J=6.2Hz,3H);13CNMR(100MHz,CDCl3)δ143.2,138.1(d,JPC=1.8Hz),133.2,131.1(d,JPC=2.2Hz),130.4(d,JPC=6.2Hz),129.1,127.2,121.9(d,JPC=3.7Hz),73.4(d,JPC=7.7Hz),72.7(d,JPC=7.7Hz),55.6(d,JPC=159.2Hz),24.6(d,JPC=3.3Hz),24.3(d,JPC=3.7Hz),24.0(d,JPC=5.9Hz),23.3(d,JPC=5.9Hz),21.6;31P NMR(160MHz,CDCl3)δ17.0.高效液相色谱(HPLC):手性柱(IA-H),230nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为21.4min和35.4min(主要)。高分辨计算为C20H28BrNO5PS[M+H]+504.0604,发现504.0604。
(S)-二异丙基((4-甲基苯磺酰氨基)(4-硝基苯基)甲基)磷酸酯(2h):收率为92%,对映选择性过量为85%,旋光为-7.91(浓度为0.86g/100mL,CHCl3),已知化合物,白色固体,熔点为200-201℃,Rf=0.50(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.85(d,J=8.4Hz,2H),7.53(dd,J=9.5Hz,JPH=4.9Hz,1H),7.44-7.39(m,4H),6.92(d,J=8.2Hz,2H),4.97-4.83(m,2H),4.57-4.46(m,1H),2.22(s,3H),1.45-1.42(m,6H),1.28(d,J=6.1Hz,3H),0.94(d,J=6.1Hz,3H);13C NMR(100MHz,CDCl3)δ147.3(d,JPC=3.3Hz),143.6,141.8,137.9(d,JPC=1.8Hz),129.5(d,JPC=5.5Hz),129.2,127.2,123.1(d,JPC=2.2Hz),74.0(d,JPC=7.3Hz),73.0(d,JPC=7.7Hz),55.7(d,JPC=157.4Hz),24.6(d,JPC=3.3Hz),24.2(d,JPC=3.7Hz),24.0(d,JPC=5.5Hz),23.5(d,JPC=5.5Hz),21.5;31P NMR(160MHz,CDCl3)δ16.0.高效液相色谱(HPLC):手性柱(IA-H),230nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为24.2min和44.5min(主要)。
(S)-二异丙基((4-甲基苯磺酰氨基)(4-甲基苯基)甲基)磷酸酯(2i):收率为96%,对映选择性过量为97%,旋光为-11.12(浓度为0.80g/100mL,CHCl3),已知化合物,白色固体,熔点为157-158℃,Rf=0.50(石油醚/乙酸乙酯=体积比1/1)。1H NMR(400MHz,CDCl3)δ7.43(d,J=7.9Hz,2H),7.05(d,J=7.1Hz,2H),6.94(d,J=7.9Hz,2H),6.85(d,J=7.6Hz,2H),6.61(s,1H),4.85-4.77(m,1H),4.67(dd,JPH=24.3,9.5Hz,1H),4.39-4.31(m,1H),2.27(s,3H),2.23(s,3H),1.37-1.35(m,6H),1.21(d,J=6.1Hz,3H),0.80(d,J=6.1Hz,3H);13CNMR(100MHz,CDCl3)δ142.7,138.3(d,JPC=1.4Hz),137.5(d,JPC=3.1Hz),131.0,129.0,128.8(d,JPC=2.2Hz),128.6(d,JPC=5.9Hz),127.3,72.8(d,JPC=7.5Hz),72.6(d,JPC=7.3Hz),55.8(d,JPC=159.0Hz),24.5,24.4(d,JPC=3.1Hz),24.0(d,JPC=5.6Hz),23.1(d,JPC=6.1Hz),21.5,21.2;31P NMR(160MHz,CDCl3)δ18.1.高效液相色谱(HPLC):手性柱(IA-H),230nm,30℃,正己烷/异丙醇=体积比65/35,流速为0.7mL/min,停留时间为15.0min和24.6min(主要)。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-4-二异丙基磷酸酯(4a):收率为90%,对映选择性过量为96%,旋光为-72.11(浓度为0.43g/100mL,CHCl3),未知化合物,白色固体,熔点为158-159℃,Rf=0.40(石油醚/乙酸乙酯=体积比2/1)。1H NMR(400MHz,CDCl3)δ7.83(dd,J=7.9Hz,JPH=0.8Hz,1H),7.36-7.32(m,1H),7.22-7.18(m,1H),7.02(d,J=8.2Hz,1H),5.72(s,1H),5.06(d,J=20.4Hz,1H),4.86-4.78(m,1H),4.69-4.61(m,1H),1.39-1.35(m,6H),1.31(d,J=6.2Hz,3H),1.09(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ151.8(d,JPC=8.9Hz),130.0(d,JPC=2.1Hz),128.0(d,JPC=3.3Hz),125.6(d,JPC=2.3Hz),119.3(d,JPC=0.6Hz),116.6(d,JPC=3.9Hz),73.9(d,JPC=7.1Hz),73.5(d,JPC=6.9Hz),54.4(d,JPC=153.7Hz),24.3(d,JPC=3.4Hz),24.2(d,JPC=4.0Hz),24.0(d,JPC=4.9Hz),23.6(d,JPC=5.4Hz);31PNMR(160MHz,CDCl3)δ14.5.高效液相色谱(HPLC):手性柱(AD-H),220nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为7.1min(主要)和7.9min。高分辨计算为C13H21NO6PS[M+H]+350.0822,发现350.0824。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-4-二乙基磷酸酯(4b):收率为85%,对映选择性过量为93%,旋光为-58.24(浓度为0.36g/100mL,CHCl3),未知化合物,白色固体,熔点为153-154℃,Rf=0.20(二氯甲烷)。1H NMR(400MHz,CDCl3)δ7.77(dd,J=7.9Hz,JPH=0.9Hz,1H),7.36-7.32(m,1H),7.22-7.18(m,1H),7.02(d,J=8.3Hz,1H),6.00(s,1H),5.11(d,J=20.7Hz,1H),4.29-4.19(m,2H),4.18-4.01(m,2H),1.37(t,J=7.1Hz,3H),1.23(t,J=7.1Hz,3H);13C NMR(100MHz,CDCl3)δ151.8(d,JPC=8.9Hz),130.0(d,JPC=2.0Hz),127.7(d,JPC=3.4Hz),125.5(d,JPC=2.2Hz),119.3,116.3(d,JPC=3.2Hz),64.7(d,JPC=6.9Hz),64.2(d,JPC=6.8Hz),53.9(d,JPC=155.5Hz),16.4(d,JPC=4.1Hz),16.4(d,JPC=4.0Hz);31P NMR(162MHz,CDCl3)δ16.7-16.5(m).高效液相色谱(HPLC):手性柱(AS-H),220nm,30℃,正己烷/异丙醇=体积比70/30,流速为0.7mL/min,停留时间为10.3min和19.6min(主要)。高分辨计算为C11H17NO6PS[M+H]+322.0509,发现322.0514。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-7-甲基-4-二异丙基磷酸酯(4c):收率为86%,对映选择性过量为99%,旋光为-75.16(浓度为0.62g/100mL,CHCl3),未知化合物,黄色固体,熔点为132-133℃,Rf=0.30(二氯甲烷)。1H NMR(400MHz,CDCl3)δ7.68(d,J=8.1Hz,1H),7.00(d,J=8.1Hz,1H),6.82(s,1H),5.79(s,1H),5.00(d,J=20.1Hz,1H),4.86-4.75(m,1H),4.70-4.59(m,1H),2.33(s,3H),1.38-1.34(m,6H),1.30(d,J=6.2Hz,3H),1.11(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ151.6(d,JPC=9.0Hz),140.6(d,JPC=2.1Hz),127.7(d,JPC=3.2Hz),126.4(d,JPC=2.3Hz),119.5,113.4(d,JPC=3.8Hz),73.7(d,JPC=7.0Hz),73.4(d,JPC=6.9Hz),54.2(d,JPC=154.5Hz),24.3(d,JPC=3.3Hz),24.2(d,JPC=4.0Hz),23.9(d,JPC=4.9Hz),23.6(d,JPC=5.4Hz),21.1;31P NMR(160MHz,CDCl3)δ14.6(d,JHP=20.1Hz).高效液相色谱(HPLC):手性柱(AS-H),220nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为6.9min和9.5min(主要)。高分辨计算为C14H23NO6PS[M+H]+364.0978,发现364.0986。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-8-甲氧基-4-二异丙基磷酸酯(4d):收率为87%,对映选择性过量为97%,旋光为-65.30(浓度为0.63g/100mL,CHCl3),未知化合物,白色固体,熔点为168-169℃,Rf=0.30(二氯甲烷)。1H NMR(400MHz,CDCl3)δ7.39(d,J=7.9Hz,1H),7.13(t,J=8.1Hz,1H),6.93(d,J=8.1Hz,1H),5.69(s,1H),5.07(d,J=20.4Hz,1H),4.86-4.78(m,1H),4.70-4.63(m,1H),3.87(s,3H),1.39-1.36(m,6H),1.31(d,J=6.1Hz,3H),1.11(d,J=6.1Hz,3H);13CNMR(100MHz,CDCl3)δ149.1,141.4(d,JPC=9.3Hz),125.1(d,JPC=2.2Hz),118.9(d,JPC=3.3Hz),117.7(d,JPC=3.5Hz),112.4,73.8(d,JPC=7.1Hz),73.4(d,JPC=6.9Hz),56.3,54.6(d,JPC=155.2Hz),24.2(d,JPC=3.4Hz),24.1(d,JPC=4.0Hz),23.9(d,JPC=4.9Hz),23.6(d,JPC=5.4Hz);31P NMR(160MHz,CDCl3)δ14.4.高效液相色谱(HPLC):手性柱(AS-H),220nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为10.0min和12.5min(主要)。高分辨计算为C14H23NO7PS[M+H]+380.0927,发现380.0930。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-7-甲氧基-4-二异丙基磷酸酯(4e):收率为90%,对映选择性过量为98%,旋光为-75.48(浓度为0.62g/100mL,CHCl3),未知化合物,白色固体,熔点为140-141℃,Rf=0.30(二氯甲烷)。1H NMR(400MHz,CDCl3)δ7.69(d,J=8.5Hz,1H),6.75-6.72(m,1H),6.52(dd,J=2.5,0.6Hz,1H),5.95(s,1H),4.97(d,J=19.7Hz,1H),4.85-4.74(m,1H),4.70-4.59(m,1H),3.78(s,3H),1.37-1.34(m,6H),1.30(d,J=6.2Hz,3H),1.12(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ160.7(d,JPC=1.7Hz),152.6(d,JPC=9.2Hz),128.6(d,JPC=3.0Hz),112.0(d,JPC=2.0Hz),108.1(d,JPC=3.5Hz),104.2,73.8(d,JPC=7.0Hz),73.3(d,JPC=6.9Hz),55.7,53.9(d,JPC=155.4Hz),24.3(d,JPC=3.3Hz),24.1(d,JPC=4.0Hz),23.9(d,JPC=4.9Hz),23.6(d,JPC=5.3Hz);31P NMR(160MHz,CDCl3)δ14.7.高效液相色谱(HPLC):手性柱(AS-H),220nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为8.1min和12.6min(主要)。高分辨计算为C14H23NO7PS[M+H]+380.0927,发现380.0929。
(S)-3,4-二氢-1,2,3-苯唑噻嗪-2,2-二氧-6-甲氧基-4-二异丙基磷酸酯(4f):收率为92%,对映选择性过量为94%,旋光为-80.51(浓度为0.74g/100mL,CHCl3),未知化合物,白色固体,熔点为133-134℃,Rf=0.25(二氯甲烷)。1H NMR(400MHz,CDCl3)δ7.36(s,1H),6.96-6.93(m,1H),6.88-6.75(m,1H),5.91-5.87(m,1H),5.02(dd,J=20.5,7.6Hz,1H),4.88-4.77(m,1H),4.74-4.623(m,1H),3.79(s,3H),1.39-1.37(m,6H),1.33(d,J=6.2Hz,3H),1.15(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ156.7(d,JPC=2.3Hz),145.5(d,JPC=8.9Hz),120.1,117.1(d,JPC=3.9Hz),116.3(d,JPC=1.9Hz),111.8(d,JPC=3.1Hz),73.9(d,JPC=7.0Hz),73.5(d,JPC=6.9Hz),55.9,54.5(d,JPC=154.3Hz),24.3(d,JPC=3.3Hz),24.2(d,JPC=4.0Hz),24.0(d,JPC=4.9Hz),23.6(d,JPC=5.3Hz);31P NMR(160MHz,CDCl3)δ14.5.高效液相色谱(HPLC):手性柱(AS-H),220nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为9.1min和13.6min(主要)。高分辨计算为C14H23NO7PS[M+H]+380.0927,发现380.0931。
(S)-二异丙基(1,1-二氧-2,3-二氢苯并[d]异噻唑-3-基)磷酸酯(6a):收率为91%,对映选择性过量为96%,旋光为-40.87(浓度为0.46g/100mL,CHCl3),未知化合物,白色固体,熔点为176-177℃,Rf=0.50(石油醚/乙酸乙酯=体积比1/2)。1H NMR(400MHz,CDCl3)δ7.82-7.78(m,2H),7.68-7.64(m,1H),7.60-7.57(m,1H),5.64(s,1H),4.99(d,J=11.2Hz,1H),4.88-4.77(m,1H),4.65-4.57(m,1H),1.35(d,J=6.2Hz,3H),1.31(d,J=6.2Hz,3H),1.28(d,J=6.2Hz,3H),1.05(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ135.3(d,JPC=5.9Hz),133.3(d,JPC=2.6Hz),132.7(d,JPC=5.7Hz),130.0(d,JPC=2.5Hz),126.0(d,JPC=2.9Hz),121.7(d,JPC=2.0Hz),73.6(d,JPC=7.2Hz),73.5(d,JPC=7.3Hz),54.7(d,JPC=161.7Hz),24.3(d,JPC=1.9Hz),24.3(d,JPC=1.9Hz),23.9(d,JPC=5.4Hz),23.6(d,JPC=5.2Hz);31P NMR(160MHz,CDCl3)δ14.8.高效液相色谱(HPLC):手性柱(OD-H),230nm,30℃,正己烷/异丙醇=体积比80/20,流速为0.8mL/min,停留时间为9.3min和10.8min(主要)。高分辨计算为C13H21NO5PS[M+H]+334.0873,发现334.0875。
(S)-二异丙基(5-甲基-1,1-二氧-2,3-二氢苯并[d]异噻唑-3-基)磷酸酯(6b):收率为99%,对映选择性过量为94%,旋光为-57.33(浓度为0.59g/100mL,CHCl3),未知化合物,白色固体,熔点为150-151℃,Rf=0.10(石油醚/乙酸乙酯=体积比2/1).1H NMR(400MHz,CDCl3)δ7.67(d,J=8.0Hz,1H),7.56(s,1H),7.36(d,J=8.0Hz,1H),5.75(s,1H),4.96-4.93(m,1H),4.88-4.77(m,1H),4.66-4.55(m,1H),2.47(s,3H),1.35(d,J=6.2Hz,3H),1.30(d,J=6.2Hz,3H),1.28(d,J=6.3Hz,3H),1.05(d,J=6.2Hz,3H);13C NMR(100MHz,CDCl3)δ144.3(d,JPC=2.6Hz),133.0(d,JPC=5.7Hz),132.6(d,JPC=6.0Hz),131.0(d,JPC=2.4Hz),126.2(d,JPC=2.9Hz),121.4(d,JPC=2.0Hz),73.5(d,JPC=3.0Hz),73.4(d,JPC=3.3Hz),54.6(d,JPC=161.2Hz),24.3(t,JPC=3.4Hz),24.0(d,JPC=5.3Hz),23.6(d,JPC=5.1Hz),22.0;31P NMR(160MHz,CDCl3)δ15.0.高效液相色谱(HPLC):手性柱(OD-H),230nm,30℃,正己烷/异丙醇=体积比90/10,流速为0.7mL/min,停留时间为21.7min和25.5min(主要)。高分辨计算为C14H23NO5PS[M+H]+348.1029,发现348.1033。
本发明应用均相钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯,其产率可达99%,对映体过量可达到99%。本发明操作简便易行,原料及催化剂均简单易得,反应条件温和。
Claims (8)
1.一种钯催化亚胺膦酸酯不对称氢化合成手性胺基膦酸酯的方法,其用到的催化体系是钯的手性双磷配合物,反应式和条件如下:
式中:
温度:0-50℃;
溶剂:有机溶剂;
时间:15-24小时;
添加剂:分子筛;
所述R1、R2分别为C1-C10的烷基,苯基及含有取代基的苯环,苯环上的取代基为F、Cl、Me、MeO中的一种或二种以上取代基,取代基个数为1-3。
2.如权利要求1所述的方法,其特征在于:
反应步骤为:在反应瓶中投入三氟醋酸钯(式1中底物用量的2mol%-5mol%)和手性膦配体(式1中底物用量的2.4mol%-6.0mol%),氮气置换后加入丙酮,室温搅拌1-3小时,得催化剂;然后真空浓缩除去丙酮,氮气下加入三氟乙醇,将此溶液转到预先放有亚胺膦酸酯和分子筛(相对于0.1mmol的式1中底物分子筛用量为50mg-100mg)的反应釜中,通入氢气(600psi-1000psi),0℃-50℃下反应15-24小时;释放氢气,除去溶剂后直接柱层析分离得到纯的产物。
3.如权利要求1所述的方法,其特征在于:催化剂的制备方法为:把钯的金属前体和手性双膦配体在丙酮中室温搅拌1-3小时,然后真空浓缩除去丙酮;金属前体:三氟醋酸钯;手性配体:双膦配体,(S)-SynPhos,(R)-SegPhos,(R)-Cl-MeO-Biphep,(R)-MeO-Biphep,(R)-DifluorPhos中的一种或二种以上;
所述催化剂为三氟醋酸钯和双膦配体的配合物,三氟醋酸钯及双膦配体均为市售且无需任何处理。
4.如权利要求1或2所述的方法,其特征在于:所述添加剂为分子筛,反应所用的分子筛为或中的一种或二种以上。
5.如权利要求1或2所述的方法,其特征在于:底物亚胺膦酸酯与催化剂的摩尔比例是50/1-20/1。
6.如权利要求1所述的合成方法,其特征在于:反应所用的有机溶剂为甲苯、二氯甲烷、三氟乙醇、四氢呋喃中的一种或两种以上的混合。
7.如权利要求1、2或6所述的合成方法,其特征在于:当亚胺膦酸酯底物用量为0.2mmol时,有机溶剂的用量为3.0mL。
8.如权利要求1或2所述的方法,其特征在于:所述反应式为亚胺膦酸酯氢化得到相应的手性胺基膦酸酯,添加剂为分子筛,溶剂为三氟乙醇/二氯甲烷=体积比2/1混合溶剂,温度为40℃时,氢气压力为600psi,配体为(R)-DifluorPhos所述结果最佳。
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