嘧啶酮衍生物的微波合成*

馬 旺, 劉永亮, 郭寶銘, 鐘為慧

(浙江工業(yè)大學(xué) 藥學(xué)院 浙江省制藥工程重點實驗室,浙江 杭州 310014)

嘧啶酮衍生物是一類重要的雜環(huán)化合物，具有抗免疫[1]、抗艾滋[2]、抗神經(jīng)衰弱[3]、抗腫瘤[4]、抗菌[5]等藥理活性。合成4H-嘧啶[1,2-b]噠嗪-4-酮的傳統(tǒng)方法[6～8]由3-(二甲基氨基)丙烯酸與3-氨基噠嗪在乙酸中反應(yīng)完成。

Baylis-Hillman反應(yīng)是一類形成碳-碳鍵、生成多個官能團分子的有效方法，由于Baylis-Hillman加成物(1a～1k)具有多個能進一步轉(zhuǎn)換的官能團，被廣泛用于雜環(huán)化合物的合成[9～13]。

本文借鑒文獻方法，設(shè)計了新的合成路線：在微波輔助下，1a～1k與4-氨基-6-氯嘧啶(2)或2-氨基-噻唑(3)反應(yīng)，快速合成了兩類嘧啶酮衍生物——3-取代-7-氯-4H-嘧啶[1,2-b]噠嗪-4-酮(4a～4k)和6-取代-5H-噻唑[3,2-a]嘧啶-5-酮(5a,5g,5i,5j, Scheme 1)，收率81%～98%,其結(jié)構(gòu)經(jīng)1H NMR，13C NMR， IR和MS確證。

1 實驗部分

1．1 儀器與試劑

B-540型電熱熔點儀(溫度計未校正)；Varian-400 MHz型核磁共振儀(DMSO-d6為溶劑，TMS為內(nèi)標(biāo))；Thermo NicoletAvatar 370型紅外光譜儀(KBr壓片)；Thermo Finnigan LCQ型質(zhì)譜儀；APEX (Bruker) mass Ⅲ型質(zhì)譜儀；APEX微波合成儀。所用試劑均為分析純。

Scheme1

1.2 4的合成通法

氮氣保護，在反應(yīng)瓶中依次加入1a～1k2 mmol， 2 2 mmol的乙酸溶液10 mL，混合均勻后將反應(yīng)瓶置微波反應(yīng)器中，磁力攪拌下于115 ℃/300 W反應(yīng)5 min～15 min。冷卻至室溫，加冰水(50 mL)析出沉淀，過濾，濾餅依次用水、乙醇洗滌，減壓干燥得4a～4k。實驗結(jié)果與表征數(shù)據(jù)分別見表1和表2。

表 1 合成4的實驗結(jié)果Table 1 Experimental results of synthesizing 4

表 2 4的表征數(shù)據(jù)Table 2 Characteristic data of 4

續(xù)表2

Comp1H NMR δ(J/Hz)13C NMR δ(J/Hz)IR ν/cm-14c3.76(s, 2H, CH2), 7.25～7.28(m, 1H, ArH), 7.29～7.32(m, 2H, ArH), 7.41(t, J=0.4, 1H, ArH), 7.71(d, J=9.6, 1H, b-H), 7.74(d, J=9.6, 1H, a-H), 8.51(s, 1H, c-H)33.0, 126.2, 127.0, 127.6, 128.5, 130.0, 130.1, 132.8, 134.7, 139.1, 141.1, 145.6, 147.3, 167.01 642, 1 541, 1 4894d3.75(s, 2H, CH2), 7.32～7.38(m, 4H, ArH), 7.71(d, J=9.6, 1H, b-H), 7.74(d, J=9.6, 1H, a-H ), 8.45 (s, 1H, c-H)32.7, 127.4, 128.1(2C), 130.1, 130.7(2C), 130.9, 134.7, 137.6, 138.9, 145.6, 147.3, 167.03 089, 3 052, 1 625, 1 541, 1 4864e3.90(s, 2H, CH2), 7.26～7.31(m, 1H, ArH), 7.39～7.43(m, 2H, a,b-H), 7.62(s, 1H, ArH), 7.32(s, 1H, c-H)25.1(d, J=3.0), 114.7(d, J=22.8), 122.7(d, J=18.2), 125.5(d, J=25.8), 125.7, 129.9(d, J=9.9), 130.4, 134.7, 134.8, 137.4, 145.9, 147.3, 161.1(d, J= 245.7), 166.73 033, 1 633, 1 594, 1 4784f3.90(s, 2H, CH2), 7.59(t, J=8.0, 1H, ArH), 7.71(d, J=9.6, 1H, b-H), 7.76(d, J=9.6, 1H, a-H), 7.84(d, J=8.0, 1H, ArH), 8.08(dq, J=1.2, 8.0, 1H, ArH), 8.24(t, J=1.2, 1H, ArH), 8.63(s, 1H, c-H)33.0, 121.4, 123.4, 126.6, 129.6, 130.2, 134.8, 135.8, 139.4, 140.9, 145.7, 147.4, 147.7, 167.03 084, 1 644, 1 541, 1 3444g3.72(s, 5H, CH2, OCH3), 6.78(dd, J=2.8, 8.0, 1H, ArH), 6.89(s, 1H, ArH), 6.91(d, J=2.8, 1H, ArH), 7.20(t, J=8.0, 1H, ArH), 7.70(d, J=9.6, 1H, b-H), 7.74(d, J= 9.6, 1H, a-H), 8.32(s, 1H, c-H)33.3, 54.9, 111.6, 114.7, 121.1, 127.8, 129.2, 130.1, 134.7, 138.7, 139.9, 145.5, 147.1, 159.2, 167.03 095, 1 643, 1 581, 1 4894h3.74(s, 2H, CH2), 7.11(t, J=8.8, 2H, ArH), 7.38(dd, J=5.6, 8.8, 2H, ArH), 7.70(d, J=9.6, 1H, b-H), 7.74(d, J=9.6, 1H, a-H), 8.41(s, 1H, c-H)32.6, 114.9(J=21.2, 2C), 127.8, 130.2, 130.7(J=8.3, 2C), 134.6, 134.7, 138.8, 145.6, 147.2, 160.9(J=240.4), 167.13 087, 3 008, 1 642, 1 543, 1 4934i3.96(s, 2H, CH2), 6.94～6.98(m, 2H, ArH), 7.34(dd, J=0.8, 4.8, 1H, ArH), 7.71(d, J=9.6, 1H, b-H), 7.75(d, J=9.6, 1H, a-H), 8.39(s, 1H, c-H)27.6, 124.6, 126.1, 126.8, 127.3, 130.2, 134.7, 138.7, 140.3, 145.7, 147.2, 166.83 082, 1 641, 1 541, 1 4904j0.90(s, 3H, CH3), 0.92(s, 3H, CH3), 1.40～1.46(m, 2H, e-H), 1.52～1.59(m, 1H, d-H), 2.42(t, J=7.2, 2H, f-H), 7.70(d, J=9.6, 1H, b-H), 7.74(d, J=9.6, 1H, a-H), 8.37(s, 1H, c-H)22.3(2C), 25.7, 27.3, 36.1, 129.1, 130.0, 134.7, 137.9, 145.4, 146.9, 167.43 033, 2 951, 1 634, 1 593, 1 541, 1 4824k0.91(t, J=6.8, 3H, CH3), 1.26～1.39(m, 4H, e-H), 1.62～1.67(m, 2H, d-H), 2.58(t, J=7.6, 2H, f-H), 7.34(d, J=10.0, 1H, b-H), 7.60(d, J=10.0, 1H, a-H), 7.92(s, 1H, c-H)13.9, 21.9, 26.6, 27.7, 31.0, 128.9, 130.0, 134.7, 137.9, 145.4, 146.9, 167.43 034, 2 925, 1 635, 1 593, 1 541, 1 481

2 結(jié)果與討論

2.1 實驗條件優(yōu)化

以1a作底物合成4a為例，無溶劑或乙酸作溶劑，對比傳統(tǒng)加熱方式與微波合成，結(jié)果見表3。由表3可見，微波合成更清潔、經(jīng)濟，收率最高可達95%。

表 3 4a的微波合成與常規(guī)合成法的比較Table 3 Synthesis comparison between microwave irradiation and conventional heating of 4a

2.2 底物結(jié)構(gòu)對反應(yīng)的影響

以乙酸為溶劑，于115 ℃反應(yīng)5 min,其余反應(yīng)條件同1.2,比較底物結(jié)構(gòu)對反應(yīng)的影響，結(jié)果見表4。從表4可以看出，當(dāng)1a和1b的酯基由-OMe變?yōu)?OEt時，4a和4b的收率都略有下降;當(dāng)1的R由芳基變?yōu)橥榛?1j和1k)時，4j和4k的收率也明顯降低。

表 4 底物結(jié)構(gòu)對反應(yīng)的影響Table 4 Effect of substrate on the yield of 4

2.3 擴展反應(yīng)

以乙酸為溶劑，1a,1g,1i或1j與3于115 ℃反應(yīng)5 min,其余反應(yīng)條件同1.2制得5a,5g,5i和5j,其結(jié)果與文獻[14]方法的比較見表5。由表5可見，微波合成不僅大縮短了反應(yīng)時間，而且可以提高收率。

5a: 淡黃色晶體,m.p.227.9 ℃～230.1 ℃;1H NMRδ: 3.87(s, 2H, CH2), 7.21～7.98(m, 6H, ArH), 7.73(d,J=4.4 Hz, 1H, g-H), 8.16(s, 1H, c-H); ESI-MSm/z: 243(M++1, 100%)。

表 5 5的微波合成*與常規(guī)合成法的比較Table 5 Synthesis comparison between microwave irradiation and conventional heating of 5

*以乙酸為溶劑，1a,1g,1i或1j與3于115 ℃反應(yīng)5 min,其余反應(yīng)條件同1.2

5g: 灰色粉末,m.p.204.1 ℃～205.1 ℃;1H NMRδ: 3.65(s, 2H, CH2), 3.73(s, 3H, OCH3), 6.79(dd,J=2.8 Hz, 8.4 Hz, 1H, ArH), 6.82(d,J=9.2 Hz, A1H, rH), 6.87(s, 1H, ArH), 7.21(t,J=7.2 Hz, 1H, ArH), 7.26(d, 1H,J=4.4 Hz, h-H), 7.73(d,J=4.4 Hz, 1H, g-H), 8.13(s, 1H, c-H); ESI-MSm/z: 273(M++1, 100%)。

5i: 灰色粉末,m.p.192.5 ℃～193.2 ℃;1H NMRδ: 3.89(s, 2H, CH2), 6.96(m, 2H, h-H, ArH), 7.28 (d,J=4.8 Hz, 1H, ArH), 7.34(t,J=3.6 Hz, 1H, ArH), 7.76(d,J=4.4 Hz, 1H, g-H), 8.27(s, 1H, c-H); ESI-MSm/z: 249(M++1, 100%)。

5j: 褐色晶體,m.p.145.7 ℃～146.9 ℃;1H NMR(CDCl3)δ: 0.88(s, 6H, CH3), 1.43(q,J=8.0 Hz, 2H, f-H), 1.55～1.60(m, 1H, d-H), 2.46(t,J=8.0 Hz, 2H, e-H), 6.84(d,J=4.8 Hz, 1H, h-H), 7.41(d,J=4.8 Hz, 1H, g-H), 7.86(s, 1H, c-H); ESI-MSm/z: 223(M++1, 100%)。

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