章 煒, 徐 亮
(四川大學(xué) 華西藥學(xué)院 天然藥物化學(xué)系,四川 成都 610041)
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·快遞論文·
通信聯(lián)系人: 徐亮,副教授, Tel. 028-85503046, E-mail: liangxu@scu.edu.cn
新型2,4-二取代四氫吡咯-3-羧酸衍生物的合成
章煒, 徐亮*
(四川大學(xué) 華西藥學(xué)院 天然藥物化學(xué)系,四川 成都610041)
摘要:N-三甲硅甲基苯甲醛亞胺為非穩(wěn)定型亞甲胺基葉立德前體,在磷酸催化下與取代噁唑烷酮烯烴經(jīng)1,3-偶極環(huán)加成反應(yīng)合成了10個(gè)具有cis-trans立體結(jié)構(gòu)的新型2,3,4-三取代四氫吡咯-3-羧酸衍生物(3a~3j),收率65%~75%,其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-MS表征。3b的立體結(jié)構(gòu)經(jīng)X-單晶衍射確證。
關(guān)鍵詞:N-三甲硅甲基苯甲醛亞胺; 非穩(wěn)定型亞甲胺基葉立德; 1,3-偶極環(huán)加成; 四氫吡咯-3-羧酸; 合成
取代四氫吡咯類化合物具有高度的生物活性,如抗菌[1]、抗流感病毒[2]、酶抑制[3]和受體拮抗[4]等。其中,2,3,4-三取代四氫吡咯衍生物由于具有與內(nèi)皮素受體A的顯著選擇性拮抗作用而受到學(xué)者的高度重視。如具有2,4-二取代四氫吡咯-3-羧酸結(jié)構(gòu)的阿曲生坦及其異構(gòu)體[5]。目前,阿曲生坦已進(jìn)入治療晚期前列腺癌的的III期臨床研究階段[6],對(duì)高血壓代謝綜合癥、慢性腎病和非小細(xì)胞肺癌等疾病的臨床研究也已取得一定成果[7-8]。
合成2,4-二芳基取代的四氫吡咯-3-羧酸衍生物的方法主要有:Michael加成[5,9],Mannich環(huán)化[10]和芳基鋰與亞胺加成[11]等。這些方法均存在步驟長,選擇性和收率偏低等缺點(diǎn)。1,3-偶極環(huán)加成反應(yīng)是合成取代四氫吡咯最直接有效的方法。Tsuge O等[12]以N-硅甲基醛亞胺為原料,在醋酸和水作用下生成非穩(wěn)定胺基葉立德,再與肉桂酸甲酯發(fā)生1,3-偶極環(huán)加成反應(yīng),合成了不易分離的三取代四氫吡咯順反異構(gòu)體混合物,收率約70%。本課題組用類似的方法進(jìn)一步研究,發(fā)現(xiàn)該反應(yīng)條件對(duì)于其它含富電子芳基取代的烯酯底物,收率也較差(約30%)。
為提高反應(yīng)收率,本文以N-三甲硅甲基苯甲醛亞胺(1)為非穩(wěn)定型亞甲胺基葉立德前體,在磷酸催化下與取代噁唑烷酮烯烴(2a~2j)經(jīng)1,3-偶極環(huán)加成反應(yīng),合成了10個(gè)具有cis-trans立體結(jié)構(gòu)的2,3,4-三取代四氫吡咯-3-羧酸衍生物(3a~3j, Scheme 1),收率65%~75%,其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-MS表征。3b的立體結(jié)構(gòu)經(jīng)X-單晶衍射確證。
Scheme 1
1實(shí)驗(yàn)部分
Varian Unity NOVA-400 MHz/54型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標(biāo));Waters Q-TOF-Premier型質(zhì)譜儀。
1按文獻(xiàn)[13]方法合成;硅膠,200~300目,青島海洋化工廠;GF254硅膠板,煙臺(tái)江友硅膠開發(fā)有限公司;其余所用試劑均為分析純。
氬氣保護(hù)下,在反應(yīng)管中加入1 153 mg(0.8 mmol)和重蒸乙腈1 mL,攪拌使其溶解;加入苯取代噁唑烷酮烯烴(2a)87 mg(0.4 mmol)和磷酸2 μL,于室溫反應(yīng)至終點(diǎn)。加入乙酸乙酯2 mL,依次用飽和NaHCO3溶液和飽和食鹽水洗滌,用無水Na2SO4干燥,蒸除溶劑后經(jīng)硅膠柱層析[洗脫劑:A=V(石油醚) ∶V(乙酸乙酯)=1 ∶1]純化得白色固體3a。
以2b~2j替代2a,用類似的方法合成白色固體3b~3f和無色油狀液體3g~3j。
3a:1H NMRδ: 7.36~7.21(m, 10H), 4.91(d,J=10.0 Hz, 1H), 4.71(t,J=9.2 Hz, 10.0 Hz, 1H), 4.11~4.02(m, 2H), 3.71~3.58(m, 3H), 3.15(t,J=10.8 Hz, 1H), 3.01(m, 1H);13C NMRδ:172.1, 152.9, 141.1, 140.1, 128.6, 128.0, 127.8, 127.7, 127.6, 126.7, 66.2, 61.7, 56.9, 55.2, 48.0, 42.3; HR-MSm/z: Calcd for C20H20N2O3{[M+H]+}336.373 6, found 336.373 9。
3b:Rf=0.55(展開劑:A=1 ∶2,下同);1H NMRδ: 7.30(m, 8H), 6.99(t,J=8.8 Hz, 8.4 Hz, 2H), 4.90(d,J=10.2 Hz, 1H), 4.64(t,J=9.2 Hz, 9.6 Hz, 1H), 4.05(m, 2H), 3.66(m, 3H), 3.09(t,J=10.4 Hz, 10.8 Hz, 1H), 2.99(m, 1H);13C NMRδ: 171.9, 162.8, 160.4, 152.9, 140.1, 136.6, 129.2, 129.1, 128.0, 127.7, 127.6, 115.4, 115.2, 65.9, 61.7, 57.1, 55.0, 47.1, 42.3; HR-MSm/z: Calcd for C20H19N2O3F{[M+H]+}354.374 9, found 354.374 7。
3c:Rf=0.48;1H NMRδ: 7.39~7.29(m, 6H), 7.28~7.20(m, 2H), 7.16~7.10(m, 2H), 4.94(d,J=10.0 Hz, 1H), 4.83(t,J=8.8 Hz, 10.0 Hz, 1H), 4.36(m, 1H), 4.05(m, 1H), 3.64(m, 3H), 3.02(m, 1H), 2.49(s, 3H);13C NMRδ: 172.5, 152.9, 139.9, 139.3, 136.7, 130.4, 128.6, 128.0, 127.7, 127.6, 126.4, 126.4, 126.3, 66.3, 61.6, 56.7, 55.3, 43.5, 42.3, 19.9; HR-MSm/z: Calcd for C21H22N2O3{[M+H]+}350.411 0, found 350.411 4。
3d:Rf=0.45;1H NMRδ: 7.31(m, 4H), 6.85~6.79(m, 2H), 6.76(d,J=8.0 Hz, 1H), 5.93(s, 2H), 4.89(d,J=10.0 Hz, 1H), 4.63(t,J=9.6 Hz, 10.0 Hz, 1H), 4.10~4.00(m, 2H), 3.73~3.60(m, 3H), 3.11(d,J=10.8 Hz, 1H), 3.02(m, 1H);13C NMRδ: 172.2, 158.9, 158.3, 152.9, 132.9, 132.2, 128.7, 128.7, 113.9, 113.3, 65.4, 61.7, 56.9, 55.2, 55.1, 55.0, 47.2, 42.3; HR-MSm/z: Calcd for C21H20N2O5{[M+H]+}380.393 9, found 380.394 4。
3e:Rf=0.60;1H NMRδ: 8.41(d,J=8.4 Hz, 1H), 7.86(d,J=8.0 Hz, 1H), 7.76(d,J=8.0 Hz, 1H), 7.62(d,J=6.8 Hz, 1H), 7.58(m, 1H), 7.47(m, 2H), 7.42(d,J=6.8 Hz, 2H), 7.32(m,J=6.8 Hz, 7.6 Hz, 2H), 7.29(m, 1H), 5.09~4.92(m, 2H), 4.03(m, 1H), 3.86(dd,J=7.2 Hz, 7.2 Hz, 1H), 3.69(m, 1H), 3.58(m, 1H), 3.18(t,J=10.4 Hz, 10.4 Hz, 1H), 3.03(m, 1H);13C NMRδ: 172.6, 139.8, 137.5, 133.9, 132.1, 128.7, 128.1, 127.8, 127.6, 127.2, 126.1, 125.6, 123.7, 123.5, 66.5, 61.6, 56.2, 55.9, 42.9, 42.3; HR-MSm/z: Calcd for C24H22N2O3{[M+H]+}386.443 1, found 386.442 4。
3f:Rf=0.50;1H NMRδ: 7.29(m, 6H), 6.29(m, 1H), 6.13(d,J=2.8 Hz, 1H), 4.83(m, 2H), 4.17(m, 1H), 4.09(m, 1H), 3.71~3.64(m, 3H), 3.18(t,J=10.0 Hz, 10.4 Hz, 1H), 3.04(m, 1H);13C NMRδ: 172.2, 154.6, 152.8, 141.6, 139.3, 127.9, 127.7, 127.4, 110.0, 105.3, 66.0, 61.6, 53.9, 52.3, 42.3, 41.3; HR-MSm/z: Calcd for C18H18N2O4{[M+H]+}326.346 5, found 326.347 2。
3g:Rf=0.52;1H NMRδ: 7.32(d,J=4.0 Hz, 4H), 7.21(m, 2H), 7.17(t,J=3.2 Hz, 3.2 Hz, 1H), 6.95(d,J=3.2 Hz, 1H), 4.89(d,J=10.0 Hz, 1H), 4.67(t,J=9.2 Hz, 9.6 Hz, 1H), 4.37(m, 1H), 4.09(m, 1H), 3.07(m, 3H), 3.17(t,J=10.8 Hz, 10.4 Hz, 1H), 3.03(m, 1H);13C NMRδ: 171.7, 152.8, 144.4, 139.9, 128.0, 127.7, 127.6, 126.8, 124.3, 124.1, 123.5, 65.5, 61.7, 57.7, 55.2, 42.9, 42.3; HR-MSm/z: Calcd for C18H18N2O3S{[M+H]+}342.412 1, found 342.411 8。
3h:Rf=0.25;1H NMRδ: 7.30(m, 5H), 5.66(m, 2H), 4.55(m, 2H), 4.08(m, 1H), 3.67(m, 2H), 3.56(m, 1H), 3.03(m, 1H), 2.75(m, 2H), 2.20(m, 1H), 2.08(m, 3H), 1.79(m, 1H), 1.67(m, 1H), 1.28(m, 1H);13C NMRδ: 173.7, 139.0, 127.8, 127.4, 127.2, 127.2, 126.9, 126.8, 125.8, 125.7, 66.6, 61.4, 48.6, 48.3, 42.4, 37.6, 30.8, 30.2, 30.0, 27.1, 25.0; HR-MSm/z: Calcd for C20H24N2O3{[M+H]+}340.416 2, found 340.417 0。
3i:Rf=0.58;1H NMRδ: 7.25(m, 5H), 4.59(d,J=9.6 Hz, 1H), 4.30(t,J=7.2 Hz, 8.8 Hz, 1H), 4.10(m, 1H), 3.70~3.63(m, 2H), 3.51(m, 1H), 3.08(m, 1H), 2.82(m, 1H), 2.62(m, 1H), 1.50(m, 2H), 1.28(m, 6H), 0.87(m, 3H);13C NMRδ: 173.4, 162.4, 139.7, 127.8, 127.4, 127.2, 65.8, 61.5, 54.7, 53.2, 42.9, 42.4, 33.5, 32.3, 27.9, 22.4, 13.9; HR-MSm/z: Calcd for C19H26N2O3{[M+H]+}330.421 3, found 330.421 0。
3j:Rf=0.45;1H NMRδ: 7.28(m, 5H), 4.51(d,J=2.8 Hz, 2H), 4.08(m, 1H), 3.67(m, 2H), 3.51(m, 1H), 3.03(m, 1H), 2.71(m, 1H), 2.62(m, 1H), 1.65(m, 1H), 0.96(m, 6H);13C NMRδ: 173.1, 160.3, 139.1, 127.8, 127.4, 127.2, 66.8, 61.5, 54.7, 53.2, 42.9, 31.8, 27.6, 22.5, 14.0; HR-MSm/z: Calcd for C17H22N2O3{[M+H]+}302.368 2, found 302.368 0。
2結(jié)果與討論
以3i的合成為例,研究了多種質(zhì)子酸催化劑(Cat)對(duì)3i總收率的影響,結(jié)果見表1。
表 1 催化劑對(duì)3i收率的影響*
**Cat 10 mmol%, H2O 100 mol%,其余反應(yīng)條件同1.2;a未加水;b總收率;cp-nitrobenzoic acid
由表1可見,磷酸的催化效果最好,總收率85%;是否加水,對(duì)磷酸的催化效果無影響。其可能原因在于:磷酸的多質(zhì)子取代模式對(duì)烯烴底物的活化和偶極子的生成具有雙重催化作用。
以H3PO4(10 mol%)為催化劑,乙腈為溶劑,其余反應(yīng)條件同1.2,對(duì)底物(2b~2j)進(jìn)行拓展,考察了該反應(yīng)的底物普適性,結(jié)果見Scheme 1。由Scheme 1可見,芳基取代(2a~2c),芳雜環(huán)取代(2d, 2f, 2g)和稠環(huán)芳烴取代(2e)的噁唑烷酮烯烴,均能以較高收率(>70%)合成最終產(chǎn)物,脂肪烴基取代(2h~2j)的烯烴在此條件下合成的4-烷基取代四氫吡咯衍生物,收率也較高(>65%)。 2,3-cis與2,3-trans兩種異構(gòu)體的比例約為6 ∶1~8 ∶1。異構(gòu)體可通過硅膠柱層析分離。
以3b為例,利用單晶X-射線單晶衍射對(duì)主要異構(gòu)體的立體化學(xué)結(jié)構(gòu)進(jìn)行表征,結(jié)果見圖1。
圖 1 3b的晶體結(jié)構(gòu)圖
3結(jié)論
合成了10個(gè)具有cis-trans立體結(jié)構(gòu)的新型2,3,4-三取代四氫吡咯-3-羧酸衍生物,收率較高(65%~75%)。該研究工作為尋找對(duì)ETA受體具有更高選擇性與抑制活性的候選藥物奠定了一定基礎(chǔ)。
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Synthesis of Novel 3,4-Disubstituted
Pyrrolidine-3-carboxylic Acid Derivatives
ZHANG Wei,XU Liang*
(Department of Natural Materia Medica, West China School of Pharmacy, Sichuan University, Chengdu 610041, China)
Abstract:Ten novel cis-trans-2,4-disubstituted pyrrolidine-3-carboxylic acid derivatives(3a~3j) in yield of 65%~75% were synthesized by 1,3-dipolar cycloaddition reaction of N-(trimethylsilylmethyl)benzaldehyde imine with α,β-unsaturated oxazolidinone amides, using phosphoric acid as catalyst. The structures were characterized by1H NMR,13C NMR and HR-MS. The stereochemical structure of 3b was confirmed by X-ray single crystal diffraction.
Keywords:N-(trimethylsilylmethyl)benzaldehyde imine; unstabilized azomethine ylide; 1,3-dipolar cycloaddition; pyrrolidine-3-carboxylic acid; synthesis
中圖分類號(hào):O623.731; O626.24
文獻(xiàn)標(biāo)志碼:A
DOI:10.15952/j.cnki.cjsc.1005-1511.2016.01.15099
作者簡介:章煒(1990-),男,漢族,安徽蕪湖人,碩士研究生,主要從事天然藥物合成的研究。 E-mail: 948397896@qq.com
基金項(xiàng)目:國家自然科學(xué)基金資助項(xiàng)目(20902061)
收稿日期:2015-04-18;
修訂日期:2015-11-19