CN101475548A - 一种制备手性3-取代苯酞类化合物的方法 - Google Patents
一种制备手性3-取代苯酞类化合物的方法 Download PDFInfo
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Abstract
本发明涉及一种高效制备3-取代手性苯酞类化合物的方法。系利用手性双膦配体与镍的配合物催化的不对称串联反应实现。反应条件温和,操作简便,底物适用性好,能够较高立体选择性高产率地制备得到手性3-取代苯酞类化合物,具有一定的应用前景。
Description
技术领域
本发明涉及一种高效制备手性3-取代苯酞类化合物的方法。
背景技术
苯酞是一类具有3-氢苯并呋喃酮结构的化合物。这类化合物广泛存在于自然界特别是植物中,普遍都具有良好的生理活性(Devon,T.K.;Scott,A.I.Handbookof Naturally Occurring Compounds;Academic Press:New York,1975;Vol.1,pp.249-264.)。如已上市的新药:(S)-3-正丁基苯酞((S)-3-Butylphthalide),最早是从芹菜籽油中提取出来的,故又名芹菜甲素,具有抗血栓、抗炎症、改善线粒体功能、抑制自由基、抑制细胞凋亡、保护细胞神经等作用((a)Yu,S.;You,S.;Chen,H.Yaoxue Xuebao 1984,101,486;.(b)Sato,H.;Yorozu,H.;Yamaoka,S.Biomed.Res.1993,14,385;(c)Wang,X.W.Drugs Future 2000,25,16;(d).Huang,L.;Dai,L.-X.;Du,C.-P.;Wu,L.Chemistry an Biology in Chiral Medicine,2002,Chapter 2(inChinese).(黄量,戴立信,杜灿屏,吴镭《手性药物的化学与生物学》,第二章,化学工业出版社,2002));Vermistatin和(-)-Alcyopterosin E都具有很强的细胞毒性((a)Palermo,J.A.;Rodriguez Brasco,M.F.;Spagnuolo,C.;Seldes,A.M.J.Org.Chem.2000,65,4482;(b)Witulski,B.;Zimmermann,A.;Gowans,N.D.Chem.Commun.2002,2984.);而Fuscionarin通过作用于人类CCR5受体(Yoganathan,K.;Rossant,C.;Ng,S.;Huang,Y.;Butler,M.S.;Buss,A.D.J.Nat.Prod.2003,66,1116.),可以阻断HIV病毒进入细胞的过程而达到很好的抗HIV的效果;Cytosporone E则具有很强的抗真菌作用(Dekker,K.A.;Inagaki,T.;Gootz,T.D.;Kanede,K.;Nomura,E.;Sakakibara,T.;Sakemi,S.;Sugie,Y.;Yamauchi,Y.;Yoshikawa,N.;Kojima,N.J.Antibiot.1997,50,833.)。可见,此类手性3-位取代的苯酞衍生物具有广泛的医药价值。除此以外,3-位芳基取代的苯酞类化合物也是用以合成具有多芳环结构天然产物的重要中间体((a).Sartori,G.;Bigi,F.;Tao,X.;Porta,C.;Maggi,R.;Predieri,G.;Lanfranchi,M.;Pellinghelli,M.A.J.Org.Chem.1995,60,6588;(b).Taunton,J.;Wood,J.L.;Schreiber,S.L.J.Am.Chem.Soc.1993,115,10378;(c).Katsuura,K.;Snieckus,V.Can.J.Chem.1987,65,124;(d).Katsuura,K.;Snieckus,V.Tetrahedron Lett.1985,26,9;(e).Uemura,M.;Take,K.;Isobe,K.;Minami,T.;Hayashi,Y.Tetrahedron 1985,41,5771;(f).Uemura,M.;Take,K.;Hayashi,Y.J.Chem.Soc.,Chem.Commun.1983,858;(g).Broadhurst,M.J.;Hassall,C.H.J.Chem.Soc.,Perkin Trans.I 1982,2227;(h).Snieckus,V.Heterocucles 1980,14,1649;(i).Kim,K.S.;Spatz,M.W.;Johnson,F.Tetrahedron Lett.1979,20,331.)。
存在于自然界中的大多数苯酞类化合物都是单一的对映异构体(S-构型),并且研究还发现该类化合物的光学纯度对其生理活性有很大的影响(Hung,T.V.;Mooney,B.A.;Prager,R.H.;Tippett,J.M.Aust.J.Chem.1981,34,383.)。因此开发不对称制备高光学纯度苯酞化合物的方法引起了化学家们的密切关注。目前主要的方法有利用手性辅基进行不对称诱导((a)Asami,M.;Mukaiyama,T.Chem.Lett.1980,17;(b)Meyers,A.I.;Hanagan,M.A.Tetrahedron 1983,39,1991;(c)Alexakis,A.;Sedrani,R.;Normant,J.F.Tetrahedron:A.symmetry 1990,1,283;(d)Takahashi,H.;Tsubuki,T.;Higashiyama,K.Synthesis 1992,681;(e)Matsui,S.;Uejima,A.;Suzuki,Y.;Tanaka,K.J.Chem.Soc.,Perkin Trans.11993,701.),利用手性硼试剂进行不对称还原(Ramachandran,P.V.;Chen,G.M.;Brown,H.C.Tetrahedron Lett.1996,37,2205.),利用拆分方法得到单一异构体((a)Pirkle,W.H.;Sowin,T.J.J.Org.Chem.1987,52,3011;(b)Kosaka,M.;Sekiguchi,S.;Naito,J.Chirality 2005,17,218.),利用微生物进行不对称反应(Kitayama,T.Tetrahedron Lett.1997,38,3765.),及利用不对称催化反应((a)Kitamura,M.;Ohkuma,T.;Inoue,S.et.al.J.Am.Chem.Soc.1988,110,629;(b)Ohkuma,T.;Kitamura,M.;Noyori,R.TetrahedronLett.1990,31,5509;(c)Soal,K.;Hori,H;Kawahara,M.Tetrahedron Asymmetry1991,2,253;(d)Watanabe,M.;Hashimoto,N.;Araki,S.;Butsugan Y.J.Org.Chem.1992,57,742;(e)Chang,H.-T.;Jeganmohan,M.;Cheng,C.-H.Chem.Eur.J.2007,13,4356.)等等。利用不对称催化反应是更高效经济的方法,然而,目前发展的方法相对还不是很成熟,存在选择性不高,有副反应发生,反应体系不够简单实用等问题。因此开发更加高效、简单和实用的方法将是比较有意义的工作。
发明内容
本发明的目的是提供一种制备高光学纯度的3-取代手性苯酞类化合物的方法。该方法是利用手性双膦配体与镍(Ni)配合物催化的不对称串联反应实现,即利用不同构型的手性配体,可以得到不同构型的3-取代手性苯酞类化合物。
本发明的合成方法可以由下述典型反应式表示:
其中,R1为氢、C1~8的烷基、C1~8的卤代烷基、C1~4的烷氧基、苯基、萘基、噻吩基、喹啉基、苯氧基、卤代苯氧基、苄氧基、苯硫基、卤代苯硫基或者R5或/和R6取代的苯基;R5为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基或C1~4的卤代烷基;
R2或/和R3为氢、卤素、C1~4的烷基、萘基、C1~4的烷氧基或者R2和R3为-CH=CH-CH=CH-、-OCH2O-;或者R1和R2为-CH=CH-CH=CH-、-OCH2O-;
或者R1和R2为苯并基;
R4为C1~8的烷基、噻吩基、喹啉基、苯基、萘基、苄基、苯乙基或者R5或/和R6取代的苯基;R5为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基、C1~4的卤代烷基或者R7;R7为H或-OCH2O-;或者R5和R6为苯并基;
R8为C1~4的烷基,推荐为甲基;
X为卤素碘、溴或氯;
Ni配合物可以是二(三苯基膦)二氯化镍(NiCl2(PPh3)2)、二氯化镍(NiCl2)、二(三苯基膦)二溴化镍(NiBr2(PPh3)2)、二溴化镍(NiBr2)、二(三苯基膦)二碘化镍(NiI2(PPh3)2)、二碘化镍(NiI2)、四(三苯基膦)镍(Ni(PPh3)4)、二羰基二(三苯基膦)镍(Ni(CO)(PPh3)2)或者二(乙酰丙酮)合镍(Ni(acac)2)等;
本发明的方法中利用的手性双膦配体可以是2,3-二(二苯基膦)丁烷、1,3-二(二苯基膦)戊烷、1,2-二(二苯基膦)丙烷、1,1’-二(二苯基膦)二茂铁、6,6’-二(二苯基膦)-2,2’,3,3’-四氢-5,5’-联苯并(1,4)-二氧六环、2’-二苯基膦苯基-4-异丙基-4,5-二氢噁唑、[2-桥环戊基-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二对甲基苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二[二(对甲氧基间二叔丁基苯基)膦]、2,2’-二(二苯基膦)联萘或2,2’-二(二对甲基苯基膦)联萘等;典型化合物的结构式如下:
本发明的方法中,用分子式为R1、R2、R3或R4取代的邻卤苯甲酸酯类化合物1作为底物,在反应浓度为0.01~1mol/L,与底物相比,0.05~0.2当量的二价或零价的镍化合物和手性双膦配体作为催化剂,催化量酸酐和酸为添加剂,在有机溶剂中和1.5~4当量的Zn存在下,与另一个芳香醛R4CHO在室温反应1.5到20小时,得到手性苯酞类化合物。例如以大于80%的收率,42%~82%的ee值得到手性苯酞类化合物。
催化量酸酐和酸的添加能够非常有效地促进反应的进行,与底物相比,推荐使用0~1当量酸酐和0~0.5当量酸。进一步推荐使用0.2~0.6当量酸酐和0.1~0.2当量酸。例如添加0.5当量的酸酐和0.1当量的酸,能比较明显地加快反应。所述酸酐可以为乙酸酐、丁二酸酐、邻苯二甲酸酐、苯甲酸酐、酒石酸酐或苹果酸酐等;酸可以为脂肪酸、苯甲酸或者其他R6取代的苯甲酸;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基、C1~4的卤代烷基或者-OCH2O-等。
所述的有机溶剂可以是苯、甲苯、石油醚或C1~4的卤代烷烃如二氯甲烷、氯仿等。
本发明选择的实验结果列表如下:
本发明的方法所得到的产物ee值虽然在42~82%左右,但大部分化合物通过一次重结晶可得到>95%ee。代表性的化合物如3a,以乙醇为溶剂,可以从67%ee值重结晶得到96%ee值的化合物。
本发明的方法通过镍催化的非常高效的串联反应,能够高选择性高产率地制备得到较高光学纯度的3-取代手性苯酞类化合物,底物适用性比较好,几乎没有副反应发生,有较好的应用前景。
具体实施方法
通过下述实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1
3a的合成
干燥的5mL反应瓶中通入高纯氩气,加入0.15~15mmol底物3,5-二甲氧基2-溴苯甲酸甲酯(1a),0.03~3mmol NiCl2(PPh3)2,0.03~3mmol手性配体,0.45~45mmol活化的锌粉,抽换气两次,加入0.5~50mL干燥甲苯,室温搅拌5min后,慢慢滴加入0.3~30mmol PhCHO(2a),放置入50℃油浴,搅拌反应一定时间,反应结束后,硅藻土过滤,浓缩,硅胶柱层析纯化,得到相应的苯酞化合物,产率和ee值参见表1(负值表示产物构型相反)。
表1
实施例2
3a的合成
干燥的5mL反应瓶中通入高纯氩气,加入0.15~15mmol底物3,5-二甲氧基2-溴苯甲酸甲酯(1a),0.03~3mmol Ni配合物,0.03~3mmol手性配体(R)-12((R)-BINAP),0.45~45mmol活化的锌粉,0.015~15mmol苯甲酸,0.075~7.5mmol丁二酸酐,抽换气两次,加入0.5~50mL干燥甲苯,室温搅拌5min后,慢慢滴加入0.3~30mmol PhCHO(2a),继续室温反应一定时间,反应结束后,硅藻土过滤,浓缩,硅胶柱层析纯化,得到相应的苯酞化合物3a,产率和ee值参见表2。
表2
实施例3
3a的合成
干燥的5mL反应瓶中通入高纯氩气,加入0.15~15mmol底物3,5-二甲氧基2-溴苯甲酸甲酯(1a),0.03~3mmol NiCl2(PPh3)2,0.03~3mmol(R)-BINAP,0.45~45mmol活化的锌粉,0.015~15mmol苯甲酸,0.075~7.5mmol酸酐,抽换气两次,加入0.5~50mL干燥甲苯,室温搅拌5min后,慢慢滴加入0.3~30mmolPhCHO(2a),继续室温反应一定时间,反应结束后,硅藻土过滤,浓缩,硅胶柱层析纯化,得到相应的苯酞化合物3a,转化率、产率和ee值参见表3。
表3
实施例4
3a的合成
干燥的5mL反应瓶中通入高纯氩气,加入0.15~15mmol底物3,5-二甲氧基2-溴苯甲酸甲酯(1a),0.03~3mmol NiCl2(PPh3)2,0.03~3mmol(R)-BINAP,0.45~45mmol活化的锌粉,0.015~15mmol苯甲酸,0.075~7.5mmol丁二酸酐,抽换气两次,加入0.5~50mL干燥甲苯,室温搅拌5min后,慢慢滴加入0.3~30mmol PhCHO(2a),继续室温反应一定时间,反应结束后,硅藻土过滤,浓缩,硅胶柱层析纯化,得到产物3a,为白色固体,产率为90%,ee值为67%。
CDCl3)δ(ppm)170.63,162.75,155.16,135.88,130.51,128.89,128.44,128.20,127.33,105.20,98.39,81.60,55.90,55.64;ESI-MS(m/z,%):271.2(M++H),293.1(M++Na);FT-IR(KBr)ν 3089,3007,1769,1504,1458,1321cm-1;HRMS(MALDI).计算值(Calculated For)C16H15O4 +1:271.0982;实测值(found):271.0965;HPLC(手性柱AD-H(Chiralcel AD-H),己烷/异丙醇(hexane/i-PrOH)=80:20(v/v),流速(flow rate)=0.7mL/min)tR=12.9min(minor),tR=13.5min(major).
实施例5
3b的合成
操作同实施例4,产率84%,ee73%。
155.04,131.78,130.12,129.14(d,J=11.0Hz),128.09,115.38(d,J=21.8Hz),105.16,98.43,80.73,55.85,55.59;ESI-MS(m/z,%):289(M++H),311(M++Na);FT-IR(KBr)ν 2841,1777,1625,1608,1513,1361,1232,1038,991,859,763cm-1;HRMS(MALDI).Calculated For C16H14O4F+1:289.0880;found:289.0871;HPLC(Chiralcel OD-H,hexane/i-PrOH=90:10(v/v),flow rate=0.7mL/min)tR=16.5min(minor),tR=23.2min(major).
实施例6
3c的合成
操作同实施例4,产率92%,ee79%。
163.00,151.95(t,J=12.9Hz),148.57(q,J=19.8Hz),133.09,133.04,129.54,127.88,123.59(q,J=10.3Hz),117.23(q,J=18.4Hz),116.28(q,J=18.9Hz),105.21,98.56,79.98(d,J=1.1Hz),55.84,55.60;ESI-MS(m/z,%):307(M++H),329(M++Na);FT-IR(KBr)ν 2935,1765,1619,1505,1321,1227,1115,1035,987,829,749cm-1;HRMS(MALDI).Calculated For C16H13O4F2 +1:307.0779;found:307.0776;HPLC(Chiralcel OD-H,hexane/i-PrOH=80:20(v/v),flow rate=0.7mL/min)tR=10.8min(minor),tR=14.2min(major).
实施例7
3d的合成
操作同实施例4,产率99%,ee79%。
3.87(s,3H,OMe),3.73(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.06,163.08,155.01,136.25,132.90,132.57,130.44,129.49,129.20,127.86,126.58,105.32,98.67,79.83,55.94,55.68;ESI-MS(m/z,%):339(M++H),361(M++Na);FT-IR(KBr)ν 2840,1766,1751,1629,1504,1328,1118,1041,990,848cm-1;HRMS(MALDI).Calculated For C16H15Cl2O4 +1:341.0326;found:341.0342;HPLC(Chiralcel AD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.5mL/min)tR=12.9min(minor),tR=14.2min(major).
实施例8
3e的合成
操作同实施例4,产率99%,ee77%。
3.86(s,3H,OMe),3.70(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.21,163.09,155.00,135.43,135.38,131.83,129.66,129.37,129.11,128.59,127.31,105.18,98.61,77.30,55.93,55.67;ESI-MS(m/z,%):339(M++H),361(M++Na);FT-IR(KBr)ν 2840,1766,1751,1629,1504,1328,1118,1041,990,848cm-1;HRMS(MALDI).Calculated For C16H13Cl2O4 +1:339.0185;found:339.0185;HPLC(Chiralcel AD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.5mL/min)tR=12.4min(minor),tR=13.6min(major).
实施例9
3f的合成
操作同实施例4,产率95%,ee73%。
CDCl3)δ(ppm)170.36,162.91,155.07,134.70,134.49,130.05,128.68,128.67,128.05,105.24,98.51,80.66,55.92,55.65;ESI-MS(m/z,%):305(M++H),327(M++Na);FT-IR(KBr)ν 3012,2843,1774,1629,1504,1493,1038,996cm-1;HRMS(MALDI).Calculated For C16H14O4Cl+1:305.0583;found:305.0575;HPLC(Chiralcel OD-H,hexane/i-PrOH=90:10(v/v),flow rate=0.7mL/min)tR=17.3min(minor),tR=24.3min(major).
实施例10
3g的合成
操作同实施例4,产率84%,ee75%。
Hz,J2=1.5Hz1H,Ph),6.80(s,1H,CH),6.66(d,J=1.8Hz,1H,Ph),3.87(s,3H,OMe),3.69(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.44,162.93,155.08,134.67,133.07,130.23,129.83,129.58,128.69,128.46,126.89,105.13,98.50,78.00,55.90,55.64;ESI-MS(m/z,%):305(M++H),327(M++Na);FT-IR(KBr)ν 2845,1758,1507,1337,1032,966,762cm-1;HRMS(MALDI).CalculatedFor C16H14O4Cl+1:305.0582;found:305.0575;HPLC(Chiralcel AD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.5mL/min)tR=13.8min(minor),tR=14.6min(major).
实施例11
3h的合成
操作同实施例4,产率82%,ee76%。
3.89(s,3H,OMe),3.70(s,3H,OMe),2.54(s,3H,Me);13C NMR(75MHz,CDCl3)δ(ppm)170.65,162.68,155.07,137.34,133.44,130.57,130.17,128.87,128.77,126.67,125.91,105.02,98.46,78.82,55.83,55.58,19.10;ESI-MS(m/z,%):285(M++H),307(M++Na);FT-IR(KBr)ν 2964,1759,1610,1508,1262,1029,800cm-1;HRMS(MALDI).Calculated For C17H17O4 +1:285.1136;found:285.1121;HPLC(Chiralcel AD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.5mL/min)tR=13.2min(minor),tR=14.3min(major).
实施例12
3i的合成
操作同实施例4,产率79%,ee 63%。
(ppm)170.64,162.68,155.16,138.78,132.89,130.56,129.13,128.31,127.26,105.14,98.35,81.57,55.87,55.64,21,19;ESI-MS(m/z,%):285(M++H),307(M++Na);FT-IR(KBr)ν 2843,1757,1627,1504,1324,1289,1118,1039,964,761cm-1;HRMS(MALDI).Calculated For C17H17O4 +1:285.1117;found:285.1121;HPLC(Chiralcel OD-H,hexane/i-PrOH=90:10(v/v),flow rate=0.7mL/min)tR=14.7min(minor),tR=21.8min(major).
实施例13
3j的合成
操作同实施例4,产率95%,ee79%。
CH),3.88(s,3H,OMe),3.71(s,3H,OMe),2.46(s,3H,Me),2.34(s,3H,Me);13CNMR(75MHz,CDCl3)δ(ppm)170.60,162.66,155.16,137.21,136.21,133.29,130.66,130.19,128.99,125.37,124.45,105.01,98.52,79.17,55.86,55.62,20.66,14.96;ESI-MS(m/z,%):299(M++H),321(M++Na);FT-IR(KBr)ν 2996,2837,1754,1627,1496,1363,1330,1156,1127,1043,791,746cm-1;HRMS(MALDI).Calculated For C18H19O4 +1:299.1279;found:299.1278;HPLC(Chiralcel OD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=8.8min(minor),tR=12.8min(major).
实施例14
3k的合成
干燥的5mL反应瓶中通入高纯氩气,加入0.15~15mmol底物1k,0.03~3mmol NiCl2(PPh3)2,0.03~3mmol(R)-BINAP,0.45~45mmol活化的锌粉,0.075~7.5mmol丁二酸酐,抽换气两次,加入0.5~50mL新蒸的甲苯,室温搅拌5min后(反应液很快变为深红褐色),慢慢滴加入0.3~30mmol底物件甲氧基苯甲醛2k,室温继续搅拌反应一定时间,反应结束后,硅藻土过滤,浓缩,硅胶柱层析纯化,得到产物3k,为白色固体,产率为94%,ee值为76%。
Hz,1H,Ph),6.31(s,1H,CH),3.87(s,3H,OMe),3.77(s,3H,OMe),3.71(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.51,162.72,159.49,155.14,137.38,130.31,129.43,128.12,119.58,114.27,112.89,105.15,98.40,81.38,55.84,55.6l,55.15;ESI-MS(m/z,%):301.2(M++H),323.2(M++Na);FT-IR(KBr)ν 3010,2940,2842,1753,1743,1492,1335,1283,1041,792,751cm-1;HRMS(MALDI).Calculated For C17H17O5 +1:301.1083;found:301.1071;HPLC(Chiralcel OD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=9.4min(minor),tR=14.6min(major).
实施例15
31的合成
操作同实施例14,转化率65%,产率70%,ee67%。
OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.62,162.72,160.01,155.19,130.53,128.78,128.49,127.95,113.84,105.20,98.37,81.49,55.92,55.69,55.23;ESI-MS(m/z,%):301(M++H),323(M++Na);FT-IR(KBr)ν 2840,1767,1516,1323,1118,1037cm-1;HRMS(MALDI).Calculated For C17H17O5 +1:301.1072;found:301.1071HPLC(Chiralcel OD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=11.2min(minor),tR=13.8min(major).
实施例16
3m的合成
操作同实施例14,转化率40%,产率66%,ee74%。
(ppm)170.37,162.75155.11,148.07,147.69,130.13,129.60,128.35,121.59,108.07,107.41,105.13,101.20,98.34,81.45,55.86,55.64;ESI-MS(m/z,%):315(M++H),337(M++Na);FT-IR(KBr)ν 2901,1770,1628,1500,1447,1361,1322,1255,1118,1036,989,931,846,764cm-1;HRMS(MALDI).Calculated For C17H15O6 +1:315.0860;found:315.0863;HPLC(Chiralcel OD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=12.2min(minor),tR=15.9min(major).
实施例17
3n的合成
操作同实施例14,转化率30%,产率88%,ee82%。
CDCl3)δ(ppm)170.47,162.87155.27,153.24,138.42,131.50,130.20,128.29,105.31,104.43,98.66,81.67,60.81,56.15,55.96,55.74;ESI-MS(m/z,%):361(M++H),383(M++Na);FT-IR(KBr)ν 2952,2837,1761,1595,1507,1426,1324,1124,1035,954,730cm-1;HRMS(MALDI).Calculated For C19H21O7 +1:361.1285;found:361.1282;HPLC(Chiralcel OD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=12.7min(minor),tR=20.5min(major).
实施例18
3o的合成
操作同实施例4,产率98%,ee78%。
1H,Ph),7.05(d,J=1.8Hz,1H,Ph),7.02(s,1H,Ph),6.75(d,J=1.8Hz,1H,CH),3.91(s,3H,OMe),3.68(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.38,162.94,155.47,133.80,131.93,131.00,129.99,129.40,129.34,128.69,126.68,125.94,125.14,124.97,123.60,105.18,98.87,78.52,55.97,55.60;ESI-MS(m/z,%):321(M++H),343(M++Na);
FT-IR(KBr)ν 1772,1757,1624,1504,1325,1116,1037,965,779cm-1;HRMS(MALDI).Calculated For C20H17O4 +1:321.1141;found:321.1121;HPLC(ChiralcelOD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=13.2min(minor),tR=21.8min(major).
实施例19
3p的合成
操作同实施例4,产率88%,ee75%。
OMe);13C NMR(75MHz,CDCl3)δ(ppm)170.68,162.83,155.22,133.46,133.26,132.98,130.52,128.31,128.26,128.10,127.66,127.13,126.48,126.26,124.35,105.21,98.46,81.77,55.91,55.62;ESI-MS(m/z,%):321(M++H),343(M++Na);FT-IR(KBr)ν 2841,1754,1507,1332,1116,1035,838,821,761,745cm-1;HRMS(MALDI).Calculated For C20H17O4 +1:321.1124;found:321.1121;HPLC(ChiralcelOD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=10.1min(minor),tR=22.0min(major).
实施例20
3q的合成
操作同实施例4,转化率35%,产率93%,ee67%。
7.19-7.14(m,2H,Ph),7.57(d,J=1.5Hz,1H,CH),3.91(s,3H,OMe),3.28(s,3H,OMe);13C NMR(75MHz,CDCl3)δ(ppm)171.00,162.66,155.33,132.23,131.60,131.52,131.27,130.28,129.45,129.38,128.86,126.65,126.19,124.71,124.65,124.23,123.47,123.08,105.31,98.94,77.68,55.93,55.45;ESI-MS(m/z,%):371(M++H),393(M++Na);FT-IR(KBr)ν 1753,1605,1502,1326,1115,1041,958,728,717cm-1;HRMS(MALDI).Calculated For C24H19O4 +1:371.1295;fund:371.1278;HPLC(Chiralcel AD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.7mL/min)tR=24.0min(minor),tR=29.7min(major).
实施例21
3r的合成
操作同实施例4,产率92%,ee60%。
CH),3.92(s,3H,OMe),3.79(s,3H,OMe),3.53(dd,J1=14.1Hz,J2=3.6Hz,1H,CH),3.06(dd,J1=14.1Hz,J2=6.3Hz,1H,CH);13C NMR(75MHz,CDCl3)δ(ppm)170.36,162.34,154.79,135.49,130.02,129.52,128.71,128.07,126.60,104.61,98.29,80.25,55.74,55.64,38.56;ESI-MS(m/z,%):285.0(M++H),307.0(M++Na);FT-IR(KBr)ν 2951,1757,1610,1508,1328,1122,1044,996,852,775,733,698cm-1;HRMS(MALDI).Calculated For C17H17O4 +1:285.1131;found:285.1121;HPLC(Chiralcel OD-H,hexane/i-PrOH=90:10(v/v),flow rate=0.7mL/min)tR=15.8min(minor),tR=17.8min(major).
实施例22
3s的合成
操作同实施例4,产率88%,ee43%。
2H,CH2);13C NMR(75MHz,CDCl3)δ(ppm)170.73,162.37,154.81,140.95,130.77,129.08,128.40,128.37,128.29,128.18,125.88,104.70,98.38,79.74,55.80,55.52,34.53,30.98;ESI-MS(m/z,%):298.1(M++H),321.1(M++Na);FT-IR(KBr)ν2947,1759,1608,1508,1331,1124,1052,940,848,698cm-1;HRMS(MALDI).Calculated For C18H18O4Na+1:321.1100;found:321.1097;HPLC(Chiralcel OD-H,hexane/i-PrOH=90:10(v/v),flow rate=0.7mL/min)tR=13.5min(minor),tR=16.6min(major).
实施例23
3t的合成
操作同实施例4,产率90%,ee63%。
CDCl3)δ(ppm)170.42,155.85,147.83,147.41,136.26,135.63,129.14,128.61,127.31,120.74,102.54,81.17,61.00,60.27,56.40;ESI-MS(m/z,%):301(M++H),323(M++Na);FT-IR(KBr)ν 2942,1761,1479,1346,1103,971,701cm-1;HRMS(MALDI).Calculated For C17H17O4 +1:301.1076;found:301.1071;HPLC(ChiralcelAD-H,hexane/i-PrOH=70:30(v/v),flow rate=0.5mL/min)tR=11.6min(minor),tR=12.2min(major).
实施例24
3u的合成
操作同实施例4,产率88%,ee71%。
135.96,130.87,129.70,129.17,129.07,128.96,128.25,127.71,126.96,124.40,123.96,120.25,82.96;ESI-MS(m/z,%):261(M++H),283(M++Na);FT-IR(KBr)ν3040,1766,1458,1305,1085,983,762,697cm-1;HRMS(MALDI).Calculated ForC18H13O2 +1:261.0914;found:261.0910;HPLC(Chiralcel AD-H,hexane/i-PrOH=80:20(v/v),flow rate=0.7mL/min)tR=16.0min(minor),tR=18.6min(major).
实施例25
重结晶操作
100mg~10g67%ee化合物3a,加热下溶于约6~600mL无水乙醇中,将该清液静置,使其自然冷却至室温,然后放置于冰箱-20℃环境下2小时,过滤掉所析出的白色固体,白色固体测得为3%ee值;母液浓缩,测得为96%ee值,重结晶收率为59%。
Claims (7)
1.一种制备手性3-取代苯酞类化合物的方法,其特征是在室温时,在锌粉、酸酐、有机酸和有机溶剂存在下,手性双膦配体与镍配合物催化剂催化底物和醛反应1.5~20小时;
其中,底物浓度为0.01~1摩尔/L,底物摩尔数和催化剂摩尔数比为20~5:1,与底物相比,采用1.5~4当量锌粉,0~1当量酸酐和0~0.5当量酸;
所述的手性双膦配体为2,3-二(二苯基膦)丁烷、1,3-二(二苯基膦)戊烷、1,2-二(二苯基膦)丙烷、1,1’-二(二苯基膦)二茂铁、6,6’-二(二苯基膦)-2,2’,3,3’-四氢-5,5’-联苯并(1,4)-二氧六环、2’-二苯基膦苯基-4-异丙基-4,5-二氢噁唑、[2-桥环戊基-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二(二对甲基苯基膦)、[(2,2,2’,2’-四甲基)-4,4’-联苯并-(1,3)二氧戊环-5,5’]-二[二(对甲氧基间二叔丁基苯基)膦]、2,2’-二(二苯基膦)联萘或2,2’-二(二对甲基苯基膦)联萘等联萘双膦配体;
所述的镍配合物催化剂是二(三苯基膦)二氯化镍、二氯化镍、二(三苯基膦)二溴化镍、二溴化镍、二(三苯基膦)二碘化镍、二碘化镍、四(三苯基膦)镍、二羰基二(三苯基膦)镍或者二(乙酰丙酮)合镍等;
所述的反应具有如下的反应式:
其中,R1为氢、C1~8的烷基、C1~8的卤代烷基、C1~4的烷氧基、苯基、萘基、噻吩基、喹啉基、苯氧基、卤代苯氧基、苄氧基、苯硫基、卤代苯硫基或者R5或/和R6取代的苯基;R5为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~4的烷硫基或C1~4的卤代烷基;
R2或/和R3为氢、卤素或C1~4的烷基、萘基、C1~4的烷氧基或者R2和R3为-CH=CH-CH=CH-、-OCH2O-;或者R1和R2为-CH=CH-CH=CH-、-OCH2O-;
或者R1和R2为苯并基;
R4为C1~8的烷基、噻吩基、喹啉基、苯基、萘基、苄基、苯乙基或者R5或/和R6取代的苯基;R5为H或R6;R6为卤素、C1~4的烷基、C1~4的烷氧基、C1~ 4的烷硫基、C1~4的卤代烷基或者R7;R7为H或-OCH2O-;或者R5和R6为苯并基;
R8为C1~4的烷基;
X为卤素碘、溴或氯。
2.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是所述的手性双膦配体具有如下结构式:
3.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是所述的酸酐是乙酸酐、丁二酸酐、邻苯二甲酸酐、苯甲酸酐、酒石酸酐或苹果酸酐。
4.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是所述的有机溶剂是苯、甲苯、石油醚或C1~4的卤代烷烃。
5.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是反应温度为20℃。
6.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是所述的有机酸是脂肪酸、苯甲酸或者其他R6取代的苯甲酸。
7.如权利要求1所述的一种制备手性3-取代苯酞类化合物的方法,其特征是所述的酸酐和酸的用量为0~1当量酸酐和0~0.5当量酸。
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CN115073395B (zh) * | 2021-03-12 | 2023-11-10 | 中国科学院大连化学物理研究所 | 一种拆分外消旋面手性环芳烷磺酰亚胺类化合物的方法 |
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