CN101885742B - 一种手性双膦酰二胺化合物及其合成方法 - Google Patents
一种手性双膦酰二胺化合物及其合成方法 Download PDFInfo
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Abstract
Description
一、技术领域
本发明涉及一种手性化合物及其制备方法,具体地说是一种含有手性噁唑啉基的膦酰胺化合物及其合成方法。
二、背景技术
手性膦噁唑啉及金属的配合物在Didls-Alder(狄乐斯-艾而特)二烯环加成反应、Michael(米歇尔)缩合反应、Friedel-Crafts(傅瑞德-克拉佛兹)缩合反应、Aldol(醇醛)、亨利反应、腈硅化等反应等许多反应中表现出良好的不对称催化活性和高对映选择性,因而受到广泛的关注[1-4]。
(1)(a)Glos,M.;Reiser,O.Org.Lett.2000,2(14),2045.(b)Braga,A.L.Vargas,F.;Sehnem,J.A.;Braga,R.C.J.Org.Chem.2005,70(22),9021.(c)Breit,B.;Schmidt,Y.;Chem.Rev.2008,108(8),2928.(d)McManus,H.A.;Guiry,P.J.J.Org.Chem.2002,67(24),8566.
(2)Wang,W.B.;Fang,J.M.J.Org.Chem.1998,63,1356.
(3)(a)Fu,G.C.Acc.Chem.Res.2006,39(11),853.(b)Hargaden,G.C.;Patrick J.Guiry,P.J.Chem.Rev.2009,109(6),2505.(c)McManu,H.A.;Guiry,P.J.Chem.Rev.2004,104(9),4151.
(4)(a)Takamichi,Y.;Masatoshi,O.;Takahiro,K.;Dai,M.;Kiyoshi,S.;Motowo,Y.Tetrahedron:Asymmetry2003,14,3275.(b)Cristina G.-Y.,P.J.;Frank R.;Günter,H.Organometallics 2004,23,5459.(c)Delphine,F.;Montserrat,G.,Francisco,J.,Guillermo,M.;Mercè,R.,Miguel,A.M.,;José,M.Organometallics 2004,23(13),3197.(d)Koch,G.;Guy,C.;Loiseleur,O.;Pfaltz,A.;Pretot,R.;Schaffner,S.;Schnider,P.;Von Matt,P.Recueil des Travaux Chimiques des Pays-Bas 1995,114(4/5),206.(e)Sprinz,J.;Helmchen,G.Tetra.Lett.1993,34(11),1769.(f)Franco,D.;Gomez,M.;Jimenez,F.;Muller,G.;Rocamora,M.;Maestro,M.A.;Mahia,J.,Organometallics 2004,23(13),3197.
申请人长期从事不对称化合物的研制,并陆续申请了发明专利,ZL200610096004.X、CN101016311A、CN101099936A、200810020198.4、CN101279954A、200810022278.3、200910116614.5。
三、发明内容
本发明旨在为不对称合成领域特别是制备手性药物化合物提供一种高效手性催化剂,所要解决的技术问题是遴选并合成该手性催化剂。
本发明所称的手性膦化合物是化学名称为双{N-2-[(4S)-4,5-二氢化-4-R-2-噁唑啉基]-二苯基-苯基膦酰二胺,有以下化学结构式:
式中R选自-CH2CH(CH3)2(1′,1′-二甲基乙基)或-CH(CH3)2(1′-甲基乙基)或-Ph(苯基)或-CH2Ph(苄基)。
本化合物作为手性催化剂,可用于腈硅化反应,并取得较好的催化效果。
本手性膦化合物的合成方法为两步,第一步以2-氰基苯胺(2-氨基苯腈)和L-氨基醇反应制备中间体2-[(4S)-4,5-二氢化-4-R-2-噁唑啉基]苯胺,第二步上述中间体与苯基膦酰二氯[(Ph)POCl2]合成目标产物,流程示意如下:
所述的L-氨基醇选自L-亮氨醇或L-缬氨醇或L-苯甘氨醇或L-苯丙氨醇。上述各L-氨基醇分别与2-氰基苯胺反应时闭环形成噁唑啉基,其携带的R基依次为-CH2CH(CH3)2、-CH(CH3)2、-Ph和-CH2Ph。
本手性膦化合物的合成方法是先制备中间体后合成目标产物,包括反应、分离和纯化,其特征是制备中间体的反应由2-氰基苯胺和L-氨基醇在无水无氧条件下和催化剂无水ZnCl2存在时于氯苯溶剂中回流反应24小时,然后分离、纯化,即反应结束后脱去氯苯,加水溶解后用氯仿萃取,萃取相脱溶后用柱层析纯化;合成目标产物的反应是所制备的中间体与二苯基膦酰氯在无水无氧条件下于甲苯和三乙胺混合溶剂中回流反应24小时,然后分离、纯化,即反应结束后脱去溶剂,用柱层析纯化。
四、附图说明
图1、图2、图3、图4、图5、图8、图11、图14分别是中间体1a、1b、1c、1d和化合物2a、2b、2c、2d的1HNMR图。
图6、图9、图12、图15、分别是化合物2a、2b、2c、2d的13CNMR图。
图7、图10、图13、图16、分别是化合物2a、2b、2c、2d的31PNMR图。
五、具体实施方式
(一)中间体1a~1d的制备
1、中间体1a 2-[(4S)-4,5-二氢化-4-(1′,1′-二甲基乙基)-2-噁唑啉基]苯胺的制备在100mL两口瓶中,无水无氧条件下,加入无水ZnCl2 60mg(0.37mmol),40mL氯苯,2-腈基苯胺1.0g(8.47mmol),L-亮氨醇3g,将混合物在高温下回流24h,停止反应,减压以除去溶剂,,将剩余物用水溶解,并用CHCl3(20mLx2)萃取,有机相用无水硫酸钠干燥,旋转除去溶剂,将粗产品用石油醚/二氯甲烷(4∶1)柱层析,得无色油状液体1.1g,产率60%;[a]5 D=-17.26°(c=2.17,CHCl3):1HNMR(500MHz,CDCl3,27℃),δ(ppm)=7.72~7.76(dd,J=2Hz,2.5Hz,1H),7.20~7.26(m,1H),6.67~6.73(m,2H),6.15(s,1H),4.38~4.43(m,2H),3.88~3.94(m,1H),1.88~1.93(m,1H),1.64~1.72(m,1H),1.40~1.48(m,1H),1.01~1.05(m,6H).
2、中间体1b 2-[(4S)-4,5-二氢化-4-(1′-甲基乙基)-2-噁唑啉基]苯胺的制备:
取2-氰基苯胺1.0g(5.6mmol),L-缬氨醇3g,制备方法同例1。产率60%。[a]5 D=-11.88°(c=1.09,CHCl3):1HNMR(500MHz,CDCl3,27℃),δ(ppm)=12.38(s,1H),7.66~7.68(dd,J=2.5,2.5Hz,1H),7.38(t,1H),7.06~7.03(d,J=14Hz,1H),6.89(t,1H),4.39~4.42(m,1H),4.12~4.13(m,2H),1.78~1.82(m,1H),0.96~1.06(dd,J=11,11.5Hz,1H).
3、中间体1c 2-[(4S)-4,5-二氢化-4-(苯基)-2-噁唑啉基]苯胺的制备:
取2-氰基苯胺1.0g,L-苯甘氨醇3g,反应步骤同例1,产率58%;[a]5 D=195.8°(c=0.25,CHCl3):1HNMR(500MHz,CDCl3,27℃),δ(ppm)=7.74(d,J=7.5Hz,1H),7.28~7.37(m,6H),6.68~6.72(m,1H),6.13(s,2H),5.45(t,1H),4.68(t,1H),4.12(t,J=0.5Hz,1H).
4、中间体1d 2-[(4S)-4,5-二氢化-4-(苄基)-2-噁唑啉基]苯胺的制备:
取2-氰基苯胺1.0g,L-苯丙氨醇3g,反应步骤同例1,产率61%;[a]5 D=25.12°(c=1.29,CHCl3):1HNMR(400MHz,CDCl3,27℃),δ(ppm)=7.66~7.68(dd,J=1H),7.18~7.29(m,6H),6.62~6.68(m,2H),6.08(s,2H),4.56~4.60(m,1H),4.25(t,J=4Hz,1H),3.98~4.02(m,1H),3.08~3.98(dd,J=4Hz,8Hz,1H),2.72~2.77(dd,J=8Hz,8Hz,1H).
(二)化合物2a~2d的合成
5、化合物2a双{N-[(4S)-4,5-二氢化-4-(1′,1′-二甲基乙基)-2-噁唑啉基]}二苯基-苯基膦酰二胺
在100mL两口瓶中,无水无氧条件下,加入40mL甲苯,2-[(4S)-4,5-二氢化-4-(1′,1′-二甲基乙基)-2-噁唑啉基]苯胺(中间体1a)1.4g(6.42mmol),三乙胺20mL,苯基膦酰二氯0.6mL(3.00mmol),将混合物加热回流24h,停止反应,减压以除去溶剂,将粗产品用石油醚/二氯甲烷(1∶9)柱层析,得淡黄色液体0.82g,产率49%;[a]5 D=11.16°(c=0.089,CHCl3):1HNMR(500MHz,CDCl3,27℃),δ(ppm)=10.90~10.98(dd,J=12Hz,13.5),7.96~7.99(m,2H),7.64~7.72(m,3H),7.43~7.52(m,3H),7.24~7.26(m,2H),6.84~6.86(m,2H),4.21~4.37(m,4H),3.77~3.79(m,2H),3.83(t,1H),1.23~1.32(m,4H),1.12~1.16(m,4H),0.66~0.72(m,12H).13CNMR(125MHz,CDCl3,27℃)163.63(x2),143.18(x2),132.30(x2,132.14,132.02(x2),131.82,131.82(x2),131.72(x2),129.26(x2),128.69(x2),128.55(x2),119.81,119.69,118.09,118.05,71.77,64.62,64.57,45.68,45.54,25.22,23.44,23.26,21.85,21.80.13PNMR:4.907,IR(KBr):3076,2958,2925,2869,1636,1583,1501,1466,1438,1385,1365,1309,1258,1216,1162,1139,1122,1162,1061,946,905,854,809,750,694,622,537,479;HRMS(EI):m/z(%):calcd for C32H39N4O3P:558.2760;found:558.2767.
6、化合物2b双N-2-[(4S)-4,5-二氢化-4-(1′-甲基乙基)-2-噁唑啉基]二苯基-苯基膦酰二胺的合成:
中间体2-[(4S)-4,5-二氢化-4-(1′-甲基乙基)-2-噁唑啉基]苯胺(中间体1b)与苯基膦酰二氯的合成方法同例5。
淡黄色液体,产率47%;[a]5 D=-11.8°(c=0.67,CHCl3):
1HNMR(500MHz,CDCl3,27℃)δ(ppm)=11.00(d,J=20.5Hz,1H),7.98~8.03(m,2H),7.69~7.76(m,4H),7.42~7.48(m,3H),7.24~7.26(m,2H),6.84(m,1H),4.27~4.30(m,2H),3.90~3.95(m,4H),1.46~1.52(m,2H),0.61~0.72(m,12H).13CNMR(125MHz,CDCl3,27℃)163.90(x2),143.32(x2),132.11(x2),131.90(x2),131.72(x2),129.40(x2),128.69(x2),128.60(x2),119.82(x2),118.18(x2),72.65(x2),69.36(x2),33.00(x2),18.85(x2),18.38(x2).13PNMR(300MHz,CDCl3,27℃),δ(ppm)=4.884.IR(KBr):3075,2960,2904,1634,1583 1500,1437,1360,1305,1156,1269,1254,1217,1122,1064,950,897,751,729,695,621,507.HRMS(EI):m/z(%):calcd for C30H35N4O3P:530.2447;found:530.2444.
7、化合物2c双N-2-[(4S)-4,5-二氢化-4-(苯基)-2-噁唑啉基]二苯基-二苯基膦酰胺的合成:
中间体2-[(4S)-4,5-二氢化-4-(苯基)-2-噁唑啉基]苯胺(中间体1c)与苯基膦酰二氯的合成方法同例5。
淡黄色液体,产率45%;[a]5 D=+172.3°(c=0.85,CHCl3):
1HNMR(500MHz,CDCl3,27℃)δ(ppm)=11.92(d,J=12Hz,1H),7.67~7.87(m,6H),6.88~7.26(m,17H),5.27(t,J=0.5Hz,1H),5.08(t,J=0.5Hz,1H),4.56~4.68(m,3H),4.00~4.10(m,1H).13CNMR(125MHz,CDCl3,27℃)165.02(x2),143.52,143.34,141.90,141.84,132.71(x2),132.07(x2),131.54,131.44,129.55(x2),128.80(x2),128.72(x2),128.61(x2),127.57,127.46,126.46,126.36,120.00(x2),119.92(x2),118.42,118.38,118.06,118.02,73.12,73.02,69.62,69.53.13PNMR(300MHz,CDCl3,27℃),δ(ppm)=5.474.IR(KBr):3062,2957,2924,2853,1633,1602,1584,1499,1455,1437,1361,1301,1265,1218,1164,1136,1122,1065,1047,954,910,752,731,697,645,621,514,475.;HRMS(EI):m/z(%):calcd for C36H31N4O3P:598.2134;found:598.2131.
8、化合物2d双N-2-[(4S)-4,5-二氢化-4-(苄基)-2-噁唑啉基]二苯基-苯基膦酰二胺的合成:
中间体2-[(4S)-4,5-二氢化-4-(苄基)-2-噁唑啉基]苯胺(中间体1d)与苯基膦酰二氯的合成方法同例5。
淡黄色液体,产率46%;[a]5 D=-3.6°(c=0.208,CH2Cl2):1HNMR(500MHz,CDCl3,27℃)δ(ppm)=10.84~10.92(dd,J=11Hz,12.5Hz,2H),7.98~8.02(m,2H),7.60~7.71(m,3H),7.41~7.71(m,6H),7.04~7.27(m,11H),6.85~6.87(m,2H),4.43~4.45(m,2H),4.23~4.26(m,2H),3.97~3.98(m,2H),2.92~2.95(dd,J=5Hz,5.5Hz,1H),2.79~2.83(dd,J=8.5Hz,8.5Hz,1H),13CNMR(125MHz,CDCl3,27℃)164.21(x2),143.18,143.04,137.68(x2),137.54(x2),132.46(x2),132.27(x2),131.58(x2),131.49(x2),129.35(x2),129.14(x2),128.72(x2),128.60(x2),128.55(x2),126.61,126.52,119.99,119.88,118.21,118.02,70.34(x2),67.60,67.46,41.62(x2).31PNMR(300MHz,CDCl3,27℃),δ(ppm)=4.281.IR(KBr):3462,3028,2924,2853,1635,1562,1493,1455,1439,1365,1315,1246,1161,1142,1082,1054,971,926,750,699,540.HRMS(EI):m/z(%):calcd for C38H35N4O3P:626.2447;found:626.2452.
(三)本化合物在腈硅化反应中的应用
9:2-邻甲苯基-2-(三甲硅氧基)丙腈
2-(4-o-methylphenyl)-2-(trimethylsilyloxy)acetonitrile的制备
0.2mmol催化剂2a,2b,2c and 2d(1mmol),2-甲基苯甲醛0.1mL,TMSCN 0.3ml(3.3mmol)相继在20~30℃下加入,3天后,加入水淬灭经柱层后(石油醚/二氯甲烷:5/1),得无色油状液体。1H NMR(300MHz,CDCl3)7.56-7.59(m,0.9Hz,2H),7.31-7.34(m,3H),5.43(s,1H),0.16(s,9H).13C NMR(75MHz,CDCl3)136.1,128.8(x2),126.2(x2),119.1,63.5,-0.39(x3).
催化剂 | 溶剂 | 温度(℃) | 反应时间(天) | 产率% | ee% |
2a | 无水甲醇 | 20-30 | 3d | 99 | 95 |
2b | 无水甲醇 | 20-30 | 3d | 99 | 96 |
2c | 无水甲醇 | 20-30 | 3d | 99 | 99 |
2d | 无水甲醇 | 20-30 | 3d | 99 | 90 |
Claims (2)
1.一种手性双膦酰二胺化合物,其特征是有以下化学结构式:
式中R选自-CH2CH(CH3)2或-CH(CH3)2或-ph或-CH2ph。
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