馮振, 李金蓮, 申希峰, 韓榮弼

( 延邊大學(xué) 理學(xué)院，吉林 延吉 133002 )

0 引言

樺木醇(betulin)又名白樺醇酯，是一種天然的羽扇豆烷型五環(huán)三萜類化合物，具有消炎[1-2]、抗HIV[3-5]、抗腫瘤[6-9]等功效.為了進(jìn)一步開發(fā)和利用樺木醇，近年來學(xué)者們對樺木醇的結(jié)構(gòu)開展了較多的修飾研究[10].H.Kommera等[11]研究發(fā)現(xiàn)，樺木酸的C-3羥基和樺木醇的C-28羥基接入氯乙酰后，其衍生物對10種癌細(xì)胞都顯示出極大的活性.目前已有含胺基的化合物藥物被應(yīng)用到臨床中，用于治療癌癥、抑郁等[12-16].黃駿凱等[17]研究發(fā)現(xiàn)，在大黃酸中引入不同胺基合成的大黃酸衍生物，對人骨肉瘤細(xì)胞的抑制活性顯著高于大黃酸.鑒于上述研究的啟示，本文以樺木醇為起始物，用9種仲胺和二胺在其C-3、C-28 和C-30上進(jìn)行修飾，合成了31種樺木醇胺衍生物，并利用1H-NMR、13C-NMR、MALDI-TOF-MS和FT-IR 對其結(jié)構(gòu)進(jìn)行了表征.

1 實驗部分

1.1 主要儀器與試劑

傅立葉變換紅外光譜儀,Shimadzu公司;300 MHz核磁共振儀,Bruker公司;飛行時間質(zhì)譜儀,Shimadzu公司.氯乙酰氯、二氯甲烷、乙腈、吡啶、對二甲氨基吡啶、三苯基氯甲烷、無水碳酸鉀、三氯甲烷、無水乙醇、甲醇、二胺、吡咯烷、哌啶、嗎啉、哌嗪、二甲基甲酰胺、乙二醇二甲醚、四氫呋喃、四氯化碳、乙酸酐、硅膠(300～400目)、分子篩，國藥集團(tuán)化學(xué)試劑有限公司；氫化鈣，天津市化學(xué)試劑研究所有限公司;無水硫酸鎂、三乙胺、氫氧化鈉、吡啶對甲苯磺酸鹽、偶氮二異丁腈、N-溴代琥珀酰亞胺，天津市科密歐化學(xué)試劑有限公司；二氯甲烷和乙腈在氫化鈣中回流，然后蒸餾并用分子篩保存?zhèn)溆?

1.2 合成方法

1.2.1系列化合物2、4、6的合成

樺木醇由樺樹皮(來自長白山地區(qū)的白樺樹)提取所得，樺木醇中間體1、3、5和7均來自韓榮弼課題組前期工作所得[18].將用精制乙腈溶解的中間體1、3、5和無水碳酸鉀置于50 mL圓底燒瓶中，室溫攪拌5 min后加入仲胺，并繼續(xù)在室溫下攪拌至反應(yīng)物消失(或加入二胺，在80 ℃油浴下攪拌至反應(yīng)物消失)；將產(chǎn)物用二氯甲烷或者乙酸乙酯溶解后水洗3次，然后用石油醚和乙酸乙酯體系或三氯甲烷和甲醇體系進(jìn)行洗脫.系列化合物2、4、6的合成路線見圖1.

圖1 系列化合物2、4、6的合成路線

28-O-[2-(吡咯烷-1-基)乙酰基]-樺木醇(2a) 白色固體;Rf=0.49，V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 429,2 945,2 871,1 736,1 641,1 187,1 005,882;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.60(1H,s),4.35(1H,d,J=10.2 Hz),3.93(1H,d,J=10.2 Hz),3.40(2H,d,J=4.8 Hz),3.16～3.24(1H,m),2.70(4H,s),2.40～2.50(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z554[M+H]+.

28-O-[2-(哌啶-1-基)乙?；鵠-樺木醇(2b) 白色固體;Rf=0.29，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 448,2 940,1 738,1 642,1 178,1 108,883;1H NMR(300 MHz,CDCl3):δ4.71(1H,s),4.70(1H,s),4.35(1H,d,J=10.5 Hz),3.91(1H,d,J=10.5 Hz),3.15～3.28(3H,m),2.38～2.64(5H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z568[M+H]+.

28-O-[2-(嗎啉-4-基)乙酰基]-樺木醇(2c) 白色固體;Rf=0.27，V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 481,2 946,1 744,1 641,1 193,1 117,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.61(1H,s),4.37(1H,d,J=10.8 Hz),3.92(1H,d,J=10.8 Hz),3.72～3.84(4H,t,J=4.8 Hz),3.13～3.32(3H,m),2.61(4H,d,J=5.1 Hz),2.37～2.54(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z570[M+H]+.

28-O-[2-(哌嗪-1-基)乙?；鵠-樺木醇(2d) 白色固體;Rf=0.23，V(乙酸乙酯)∶V(甲醇)=1∶1;IR(KBr,cm-1):3 238,2 941,1 748,1 642,1 183,1 157,880;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.60(1H,s),4.35(1H,d,J=10.8 Hz),3.91(1H,d,J=10.8 Hz),3.13～3.33(3H,m),2.95(4H,t,J=4.8 Hz),2.57(4H,d,J=2.1 Hz),2.38～2.52(1H,m),1.69(3H,s),1.26(3H,s),1.04(3H,s),0.98(3H,s),0.83(3H,s),0.77(3H,s);TOF-MS:m/z569[M+H]+.

28-O-(二甲氨基乙酰基)-樺木醇(2e) 無色液體;Rf=0.08，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.07,110.0,150.2,171.7,172.3.

28-O-(二乙氨基乙?；?-樺木醇(2f) 無色液體;Rf=0.21，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二丙氨基乙酰基)-樺木醇(2g) 無色液體;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=20∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二丁氨基乙?；?-樺木醇(2h) 無色液體;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二戊氨基乙?；?-樺木醇(2i) 無色液體;Rf=0.39,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3,28-二-O-[2-(吡咯烷-1-基)乙?；鵠-樺木醇(4a) 無色液體;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 949,1 745,1 641,1 182,1 158,881;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.52～4.68(2H,m),4.36(1H,d,J=11.1 Hz),3.92(1H,d,J=11.1 Hz),3.42(4H,d,J=3.9 Hz),2.74(8H,s),2.37～2.56(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.86(3H,s),0.84(3H,s);TOF-MS:m/z665[M+H]+.

3,28-二-O-[2-(哌啶-1-基)乙?；鵠-樺木醇(4b) 無色液體;Rf=0.28,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 936,1 748,1 643,1 175,1 130,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.48～4.68(2H,m),4.36(1H,d,J=11.1 Hz),3.90(1H,d,J=11.1 Hz),3.21(4H,d,J=7.2 Hz),2.25～2.70(9H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.85(6H,s);TOF-MS:m/z693[M+H]+.

3,28-二-O-[2-(嗎啉-4-基)乙?；鵠-樺木醇(4c) 無色液體;Rf=0.23,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 949,1 745,1 641,1 192,1 117,868;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.50～4.64(2H,m),4.37(1H,d,J=11.1 Hz),3.90(1H,d,J=11.1 Hz),3.78(8H,t,J=3.9 Hz),3.25(4H,d,J=7.5 Hz),2.63(8H,d,J=3.3 Hz),2.38～2.52(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.86(3H,s),0.85(3H,s);TOF-MS:m/z697[M+H]+.

3,28-二-O-[2-(哌嗪-1-基)乙?；鵠-樺木醇(4d) 白色固體;Rf=0.18,V(三氯甲烷)∶V(甲醇)=5∶1;IR(KBr,cm-1):3 424,2 946,1 743,1 637,1 183,1 014,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.51～4.67(2H,m),4.37(1H,d,J=11.7 Hz),3.91(1H,d,J=11.7 Hz),3.23(4H,d,J=8.7 Hz),2.98(8H,s),2.61(8H,s,J=2.1 Hz),2.22～2.51(3H,m),1.70(3H,s),1.05(3H,s),0.99(3H,s),0.86(9H,s);TOF-MS:m/z695[M+H]+.

3,28-二-O-(二甲氨基乙?；?-樺木醇(4e) 無色液體;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 945,1 742,1 641,1 456,1 389,1 196,1 103,883;1H NMR(300 MHz,CDCl3):δ4.66(1H,s),4.51～4.56(2H,m),4.31(1H,d,J=11.1 Hz),3.88(1H,d,J=11.1 Hz),4.11～4.23(4H,m),2.30～2.46(12H,m),1.68(3H,s),1.04(3H,s),0.94(3H,s),0.82(9H,s);13C NMR(75 MHz,CDCl3):δ14.8,16.0,16.2,16.6,18.2,19.1,20.8,23.8,25.2,27.1,28.0,29.6,29.8,34.1,34.7,37.1,37.6,37.8,38.4,41.0,42.8,45.3,45.4,46.5,47.8,48.8,50.3,55.3,60.4,60.5,62.9,81.1,110.0,150.1,170.6,171.2.

3,28-二-O-(二丙氨基乙?；?-樺木醇(4g) 無色液體;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 955,1 730,1 643,1 460,1 383,1 180,1 096,978;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.59(1H,s),4.49～4.54(1H,m),4.30(1H,d,J=11.1 Hz),3.87(1H,d,J=11.1 Hz),3.28(4H,d,J=6.9 Hz),2.54(8H,t,J=7.8 Hz),2.39～2.48(1H,m),1.68(3H,s),1.03(3H,s),0.97(3H,s),0.90(6H,s),0.87(6H,s),0.85(9H,s);13C NMR(75 MHz,CDCl3):δ11.8,14.8,16.1,16.2,16.8,18.3,19.2,20.8,21.0,23.9,25.2,27.1,28.1,29.7,29.9,34.2,34.7,37.2,37.7,37.9,38.5,41.0,42.8,46.5,47.8,48.9,50.4,55.2,55.5,56.5,56.6,62.7,81.1,110.0,150.2,171.5,172.2.

3,28-二-O-(二丁氨基乙?；?-樺木醇(4h) 無色液體;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 953,1 730,1 643,1 460,1 381,1 176,1 098,883;1H NMR(300 MHz,CDCl3):δ4.69(1H,s),4.59(1H,s),4.49～4.55(1H,m),4.30(1H,d,J=11.0 Hz),3.88(1H,d,J=11.0 Hz),3.33(4H,d,J=6.1 Hz),2.57(8H,t,J=7.8 Hz),2.40～2.49(1H,m),1.69(3H,s),1.03(3H,s),0.97(3H,s),0.88(3H,s),0.93(6H,s),0.90(6H,s),0.85(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.7,18.3,19.2,20.6,20.9,23.9,25.2,27.1,28.1,29.6,29.8,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.2,54.3,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.4.

3,28-二-O-(二戊氨基乙酰基)-樺木醇(4i)無色液體;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(m,1H),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-[2-(吡咯烷-1-基)乙?；鵠-樺木醇(6a) 白色固體;Rf=0.25,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 404,2 941,1 743,1 639,1 184,1 104,879;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.51～4.65(2H,m),3.82(1H,d,J=10.2 Hz),3.26～3.44(3H,m),2.67(4H,s),2.33～2.49(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.87(6H,s);TOF-MS:m/z554[M+H]+.

3-O-[2-(哌啶-1-基)乙?；鵠-樺木醇(6b)白色固體;Rf=0.30,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 454,2 941,1 744,1 639,1 185,1 104,880;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.47～4.65(2H,m),3.81(1H,d,J=10.8 Hz),3.35(1H,d,J=10.8 Hz),3.19(2H,d,J=1.2 Hz),2.53(4H,t,J=5.1 Hz),2.31～2.48(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z568[M+H]+.

3-O-[2-(嗎啉-4-基)乙?；鵠-樺木醇(6c)白色固體;Rf=0.28,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 448,2 941,1 743,1 635,1 196,1 117,898;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.47～4.66(2H,m),3.71～3.88(5H,m),3.35(1H,d,J=10.8 Hz),3.23(2H,s),2.63(4H,d,J=3.6 Hz),2.32～2.49(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z570[M+H]+.

3-O-[2-(哌嗪-1-基)乙?；鵠-樺木醇(6d)白色固體;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=1∶1;IR(KBr,cm-1):3 436,2 940,1 739,1 644,1 192,1 029,881;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.49～4.66(2H,m),3.80(1H,d,J=10.8 Hz),3.34(1H,d,J=10.8 Hz),3.21(2H,s),2.95(4H,t,J=4.2 Hz),2.58(4H,d,J=3.3 Hz),2.31～2.49(1H,m),1.70(3H,s),1.03(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z569[M+H]+.

3-O-(二甲氨基乙?；?-樺木醇(6e) 無色液體;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

穿著夫妻的鞋子，走著朋友的步子，兩人突然變得客氣起來了，見面問好分別問候，相互恢復(fù)了刪除的好友和朋友圈的資格。半月后，王樹林回家陪兒子，順便疏通了一下下水道，自然，當(dāng)夜他就躺在了辛娜的床上。又半月，王樹林要買車，喊了辛娜來參考。一周后，王樹林開著新車去了辛娜的單位，辛娜不在，說是請假了，辛娜的同事說，你怎么做老公的，老婆請假都不知道，開啥子玩笑？窘得王樹林一臉赤紅。這不，幾天后，辛娜打來電話，在辦公室嘈雜的背景聲中說，老公，下班別做飯了，我們出去吃。

3-O-(二乙氨基乙?；?-樺木醇(6f) 無色液體;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H，s),1.02(3H，s),0.96(3H，s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二丙氨基乙?；?-樺木醇(6g) 無色液體;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=20∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二丁氨基乙?；?-樺木醇(6h) 無色液體;Rf=0.21,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二戊氨基乙?；?-樺木醇(6i) 無色液體;Rf=0.38,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

1.2.2系列化合物9的合成

將用質(zhì)量分?jǐn)?shù)為2%的氫氧化鈉甲醇溶液溶解的化合物8a-d置于圓底燒瓶中，回流攪拌至反應(yīng)物消失；旋干溶劑后用二氯甲烷溶解，再用飽和氯化鈉溶液洗有機(jī)層3～4次.化合物8a-d的合成路線見圖2.

圖2 系列化合物9的合成路線

3,28-二-O-乙酰-30-(1-吡咯烷基)樺木醇(8a) 白色固體;Rf=0.34,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 924,2 855,1 739,1 460,1 260,1 240,1 026;1H NMR(300 MHz,CDCl3):δ4.97(1H,s),4.79(1H,s),4.40～4.60(1H,m),4.27(1H,d,J=11.1 Hz),3.85(1H,d,J=11.1 Hz),2.72～3.01(2H,m),2.27～2.57(5H,m),2.09(3H,s)，2.06(3H,s),1.05(3H,s),0.99(3H,s),0.86(6H,s)，0.85(3H,s).

3,28-二-O-乙酰-30-(1-哌啶基)樺木醇(8b) 白色固體;Rf=0.62,V(石油醚)∶V(乙酸乙酯)=5∶1;IR(KBr,cm-1):2 923,2 854,1 738,1 462,1 261,1 243,1 027,885;1H NMR(300 MHz,CDCl3):δ5.04(1H,s),4.77(1H,s),4.37～4.56(1H,m),4.28(1H,d,J=11.1 Hz),3.84(1H,d,J=11.1 Hz),2.67～2.98(2H,m),2.21～2.54(5H,m),2.08(3H,s),2.06(3H,s),1.05(3H,s),0.98(3H,s),0.86(6H,s),0.85(3H,s).

3,28-二-O-乙酰-30-(4-嗎啉基)樺木醇(8c) 白色固體;Rf=0.63,V(石油醚)∶V(丙酮)=2∶1;IR(KBr,cm-1):2 923,2 854,1 736,1 460,1 261,1 076,1 023;1H NMR(300 MHz,CDCl3):δ5.15(1H,s),4.84(1H,s),4.39～4.58(1H,m),4.28(1H,d,J=11.1 Hz),3.85(1H,d,J=11.1 Hz),3.62～3.79(4H,m),2.72～3.04(2H,m),2.21～2.63(5H,m),2.08(3H,s),2.06(3H,s),1.05(3H,s),) 0.98(3H,s),0.86(6H,s),0.85(3H,s).

N,N′-二-(3，28-二-O-乙酰-30-樺木醇基)哌嗪(8d) 白色固體;Rf=0.45,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 924,2 854,1 736,1 373,1 258,1 023;1H NMR(300 MHz,CDCl3):δ4.98(2H,s),4.79(2H,s),4.42～4.59(2H,m),4.27(2H,d,J=11.1 Hz),3.85(2H,d,J=11.1 Hz),2.71～2.99(4H,m),2.24～2.62(10H,m),2.09(6H,s),2.06(6H,s),1.05(6H,s),0.99(6H,s),0.86(12H,s),0.85(6H,s);TOF-MS:m/z1 134[M+H]+.

30-(1-吡咯烷基)樺木醇(9a) 白色固體;Rf=0.11,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 349,2 942,2 870,1 460,1 032;1H NMR(300 MHz,CDCl3):δ4.92(1H,s),4.90(1H,s),3.79(1H,d,J=10.8 Hz),3.35(1H,d,J=10.8 Hz),3.17～3.25(1H,m),2.93～2.97(2H,m);TOF-MS:m/z510[M+H]+.

30-(1-哌啶基)樺木醇(9b) 白色固體;Rf=0.51,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 411,2 938,2 867,1 458,1 033;1H NMR(300 MHz,CDCl3):δ4.88(1H,s),3.80(1H,d,J=11.1 Hz),3.34(1H,d,J=11.1 Hz),3.20(1H,m),2.88～3.19(1H,m),2.76～2.84(2H,m);TOF-MS:m/z526[M+H]+.

30-(4-嗎啉基)樺木醇(9c) 白色固體;Rf=0.32,V(石油醚)∶V(丙酮)=2∶1;IR(KBr,cm-1):3 411,2 944,2 867,1 455,1 035;1H NMR(300 MHz,CDCl3):δ4.92(1H,s),4.90(1H,s),3.82(1H,d,J=10.8 Hz),3.34(1H,d,J=10.8 Hz),3.20(1H,m),2.80～2.94(2H,m);TOF-MS:m/z528[M+H]+.

N,N′-二-(30-樺木醇基)哌嗪(9d) 白色固體;Rf=0.29,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 395,2 941,2 871,1 457,1 039;1H NMR(300 MHz,CDCl3):δ4.91(2H,s),3.80(2H,d,J=11.1 Hz),3.22(2H,d,J=11.1 Hz),3.18～3.19(2H,m),2.94(4H,m);TOF-MS:m/z967[M+H]+.

2 結(jié)果與分析

圖3 化合物2a的結(jié)構(gòu)

用哌嗪對中間體7的30位進(jìn)行修飾顯示(合成路線如圖2所示)，該反應(yīng)的大部分取代發(fā)生在哌嗪的兩個氮上，即主要產(chǎn)物為化合物8d.化合物8d結(jié)構(gòu)如圖4所示.由化合物8d的1H-NMR譜中的幾組氫信號(δ4.98、4.79、4.27、3.85、2.71～2.99、1.05、0.99、0.86、0.85)可知，化合物8d中存在樺木醇骨架.再由化合物8d的1H-NMR譜中哌嗪的C-1′亞甲基氫信號(δ2.24～2.62)，化合物8d的FT-IR譜中的羰基(1 736 cm-1)、酯碳氧鍵(1 258 cm-1)、碳氮鍵(1 373 cm-1)振動吸收峰，化合物8d的MALDI-TOF-MS譜中的m/z1 134分子離子峰，以及化合物8d與樺木醇Rf值的差異等可證實反應(yīng)生成的是N,N′-二-(3，28-二-O-乙酰-30-樺木醇基)哌嗪.本文所合成的其他29個樺木醇胺衍生物經(jīng)1H-NMR、13C-NMR、FT-IR 和MALDI-TOF-MS綜合解析確認(rèn)，其結(jié)構(gòu)也是均基于樺木醇骨架生成的.

圖4 化合物8d的結(jié)構(gòu)

在合成化合物4a-c的過程中，在室溫(25 ℃)下當(dāng)以化合物3和K2CO3的摩爾比為1∶2，反應(yīng)溶劑為二氯甲烷時，化合物4a的產(chǎn)率為67%，化合物4b的產(chǎn)率為65%，化合物4c的產(chǎn)率為70%.上述條件下未有化合物4d生成.當(dāng)反應(yīng)溫度為80 ℃，化合物3和K2CO3的摩爾比不變，而改變反應(yīng)溶劑時，反應(yīng)有化合物4d生成，且其產(chǎn)率隨溶劑的不同而不同.其中：以二氯甲烷作為溶劑時，化合物4d的產(chǎn)率為24%；以二甲基甲酰胺作為溶劑時，化合物4d的產(chǎn)率為33%；以乙二醇二甲醚作為溶劑時，化合物4d的產(chǎn)率為34%；以乙腈作為溶劑時，化合物4d的產(chǎn)率為47%；以四氫呋喃作為溶劑時，化合物4d的產(chǎn)率為35%；以四氯化碳作為溶劑時，化合物4d的產(chǎn)率為30%.表1為反應(yīng)物間的不同摩爾比對產(chǎn)率的影響.由表1可以看出，中間體化合物3、K2CO3、哌嗪間的不同摩爾比對化合物4d的產(chǎn)率具有很大影響，其中中間體化合物3、K2CO3、哌嗪的摩爾比為1∶4∶10，反應(yīng)溶劑為乙腈時，化合物4d的產(chǎn)率最高(68%).在中間體化合物1和5與哌嗪的實驗中，中間體與K2CO3、哌嗪的最佳摩爾比為1∶2∶5.

表1 反應(yīng)物間的不同摩爾比對產(chǎn)率的影響

3 結(jié)論

本文以樺木醇為原料，對其進(jìn)行?；桶坊蟮玫搅?1種樺木醇胺衍生物.為了提高產(chǎn)物的產(chǎn)率，對反應(yīng)條件進(jìn)行了優(yōu)化.利用波譜法對31種樺木醇胺衍生物的結(jié)構(gòu)進(jìn)行了確認(rèn).今后我們將對所合成的化合物進(jìn)行活性測試，為樺木醇及其衍生物的藥用研究提供基礎(chǔ)理論數(shù)據(jù).