陳志衛(wèi), 劉峰帆, 蘇為科

(浙江工業(yè)大學(xué) 藥學(xué)院 制藥工程教育部重點(diǎn)實(shí)驗(yàn)室,浙江 杭州 310014)

吡唑類化合物廣泛存在于天然產(chǎn)物和非天然產(chǎn)物中，具有抗菌、抗血糖、抗炎、抗腫瘤等[1～4]藥理活性。傳統(tǒng)的合成方法一般用苯肼與1,3-二羰基化合物反應(yīng)得到，往往存在或多或少的缺點(diǎn)[5～9]，如反應(yīng)步驟多、原料難得、反應(yīng)時(shí)間長(zhǎng)、使用毒性溶劑或貴金屬催化劑等。

本文參考文獻(xiàn)[9,10]方法，環(huán)己酮(1a)與取代苯肼(2a～2f)在乙醇中于室溫反應(yīng)脫水合成取代苯腙(3a～3f); 3與雙(三氯甲基)碳酸酯(BTC)與DMF制備所得的Vilsmeier試劑作用環(huán)合制得吡唑類化合物(4a～4f, Scheme 1)，總收率82%～86%。擴(kuò)展底物考察了環(huán)戊酮(1g)，環(huán)庚酮(1h)與四氫萘酮(1i)與2a的反應(yīng)(產(chǎn)物4g～4i, Scheme 2)，總收率40%～88%。4的結(jié)構(gòu)經(jīng)1H NMR,13C NMR, IR和MS表征，其中4b,4c,4e,4f和4h為新化合物。

1 實(shí)驗(yàn)部分

1．1 儀器與試劑

WRS-1A型數(shù)字熔點(diǎn)儀(溫度未校正);Varian-400 MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo));Thermo Nicolet Avatar 370型紅外光譜儀(KBr壓片);Trace DSQ FINNIGSN型質(zhì)譜儀。

Scheme2

所用試劑均為市售分析純。

1.2 合成

(1) 3的合成(以3a為例)

在兩口燒瓶中加入1a0.98 g(10 mmol),苯肼(2a) 1.08 g(10 mmol)和乙醇5 mL，攪拌下于室溫反應(yīng)15 min。冷卻至0 ℃，抽濾，濾餅用少量乙醇洗滌，干燥得白色固體3a，收率98%。

用類似方法合成3b～3h。合成3i需加乙酸60 mg(0.1 mmol)作催化劑，回流反應(yīng)30 min。

(2)4的合成(以4a為例)

在兩口燒瓶中加入DMF 15 mL，攪拌下于0 ℃分次加入BTC 1.93 g(6.5 mmol)，加畢，自然升溫至室溫制得Vilsmeier試劑。冷卻至0 ℃，加入3a1.84 g(9.8 mmol)，升至室溫反應(yīng)10 min。傾入冰水(20 mL)中，充分?jǐn)嚢?，用飽和NaHCO3溶液調(diào)節(jié)至pH 8，用乙酸乙酯(3 ×15 mL)萃取，合并有機(jī)層，用水(3×15 mL)洗滌，乙酸乙酯(3×15 mL)萃取,合并萃取液，用無水硫酸鈉干燥，濃縮后經(jīng)硅膠柱層析[洗脫劑：V(石油醚) ∶V(乙酸乙酯)=16 ∶1]分離得4a。

表 1 合成4的實(shí)驗(yàn)結(jié)果Table 1 Experamental results of synthesizing 4

用類似方法合成4b～4f和4h。4g和4i于65 ℃反應(yīng)18 min合成，后處理方法同4a。4的實(shí)驗(yàn)結(jié)果見表1。

4a:1H NMRδ: 7.54(d,J=7.6 Hz, 2H, ArH), 7.52(s, 1H, CH), 7.31(t,J=7.6 Hz, 2H, ArH), 7.12(t,J=7.2 Hz, 1H, ArH), 2.69(t,J=6.0 Hz, 2H, CH2), 2.52(t,J=6.0 Hz, 2H, CH2), 1.75～1.80(m, 2H, CH2), 1.66～1.70(m, 2H, CH2);13C NMRδ: 151.0, 140.4, 129.3(2C), 125.1, 123.4, 118.3(2C), 118.0, 23.6, 23.5, 23.5, 20.7; IRν: 3 050, 2 930, 2 855, 1 592, 1 506, 1 461, 1 378, 1 334 cm-1。

4b:1H NMRδ: 7.53(s, 1H, CH), 7.51(d,J=5.6 Hz, 2H, ArH), 6.92(d,J=9.2 Hz, 2H, ArH), 2.82(s, 3H, OCH3), 2.77(t,J=6.4 Hz, 2H, CH2), 2.60(t,J=6.4 Hz, 2H, CH2), 1.82～1.88(m, 2H, CH2), 1.74～1.80(m, 2H, CH2);13C NMRδ: 157.4, 150.4, 134.1, 123.7, 120.1(2C), 117.6(2C), 114.2, 55.5, 23.5(2C), 20.8(2C); IRν: 2 929, 2 853, 1 638, 1 564, 1 516, 1 378, 1 250 cm-1; HR-MS(ESI): Calcd for C14H17N2O{[M+H]+} 229.134 1, found 229.134 9。

4c:1H NMRδ: 7.56(d,J=6.8 Hz, 2H, ArH), 7.54(s, 1H, CH), 6.92(d,J=9.2 Hz, 2H, ArH), 2.76(t,J=6.0 Hz, 2H, CH2), 2.60(t,J=6.0 Hz, 2H, CH2), 1.80～1.88(m, 2H, CH2), 1.74～1.80(m, 2H, CH2);13C NMRδ: 151.4, 138.7, 130.6, 129.1(2C), 123.4, 119.4, 118.5(2C), 23.5, 23.4, 23.4, 20.7; IRν: 2 937, 2 855, 1 596, 1 567, 1 501, 1 375, 829, 813, 786 cm-1; HR-MS(ESI): Calcd for C13H14N2Cl{[M+H]+} 233.084 6, found 233.084 1。

4e:1H NMRδ: 7.65～7.67(m, 1H, ArH), 7.56(s , 1H, CH), 7.46～7.48(m, 1H, ArH), 7.28(t,J=8.8 Hz, 1H, ArH), 7.13～7.16(m, 1H, ArH), 2.75(t,J=6.0 Hz, 2H, CH2), 2.59(t,J=6.0 Hz, 2H, CH2), 1.81～1.88(m, 2H, CH2), 1.73～1.79(m, 2H, CH2);13C NMRδ: 151.4, 142.6, 138.7, 130.6, 129.4, 129.1, 123.4, 119.4, 118.5, 23.5, 23.4, 23.3, 20.7; IRν: 2 854, 1 596, 1 491, 1 373, 792, 777, 679 cm-1; HR-MS(ESI): Calcd for C13H14N2Cl{[M+H]+} 233.084 6, found 233.084 9。

4f:1H NMRδ: 7.56(s, 1H, CH), 7.47(s, 1H, ArH), 7.35(d,J=8.0 Hz, 1H, ArH), 7.23(t,J=8.0 Hz, 1H, ArH), 7.00(d,J=7.6 Hz, 1H, ArH), 2.76(t,J=6.4 Hz, 2H, CH2), 2.58(t,J=6.4 Hz, 2H, CH2), 2.36(s, 3H, CH3), 1.81～1.86(m, 2H, CH2), 1.72～1.78(m, 2H, CH2);13C NMRδ: 150.7, 140.0, 139.0, 128.7, 126.0, 123.4, 119.1, 117.8, 115.2, 23.5, 23.4, 23.4, 21.4, 20.7; IRν: 2 981, 2 854, 1 611, 1 496, 1 375 cm-1; HR-MS(ESI): Calcd for C14H17N2{[M+H]+} 213.139 2, found 213.139 1。

4g:1H NMRδ: 7.80(s, 1H, CH), 7.48～7.39(m, 1H, ArH), 7.27～7.29(m, 1H, ArH), 7.03～7.09(m, 2H, ArH), 2.72～2.94(m, 4H, CH2), 2.49～2.56 (m, 2H, CH2);13C NMRδ: 155.9, 143.4, 140.5, 124.4, 120.3, 119.6, 119.3, 118.3, 111.1, 28.7, 25.9, 24.5; IRν: 2 930, 2 849, 1 659, 1 610, 1 468, 965, 760 cm-1。

4h:1H NMRδ: 7.57(d,J=7.6 Hz, 2H, ArH), 7.55(s, 1H, CH), 7.35(t,J=7.6 Hz, 2H, ArH), 7.15(t,J=7.6 Hz, 1H, ArH), 2.83(t,J=6.0 Hz, 2H, CH2), 2.57(t,J=6.0 Hz, 2H, CH2), 1.80～1.86(m, 2H, CH2), 1.62～1.73(m, 4H, CH2);13C NMRδ: 155.8, 139.9, 129.0(2C), 125.0, 124.6, 123.2, 118.0(2C), 31.9, 29.9, 29.5, 27.9, 25.4; IRν: 2 914, 2 844, 1 574, 1 504, 1 388, 1 327 cm-1; HR-MS(ESI): Calcd for C14H17N2{[M+H]+} 213.139 2, found 213.139 5。

4i:1H NMRδ: 7.98(d,J=7.6 Hz, 1H, ArH), 7.73(d,J=7.6 Hz, 2H, ArH), 7.69(s, 1H, CH), 7.43(t,J=8.0 Hz, 2H, ArH), 7.26～7.30(m, 1H, ArH), 7.20～7.26(m, 3H, ArH), 2.98(t,J=7.2 Hz, 2H, CH2), 2.86(d,J=7.2 Hz, 2H, CH2);13C NMRδ: 149.4, 140.1, 136.6, 129.2, 129.0(2C), 128.1, 127.5, 126.6, 125.5, 123.1, 122.3, 118.5, 118.4(2C), 29.5, 19.2; IRν: 2 929, 1 596, 1 561, 1 502, 1 470, 1 440, 1 376, 1 321, 1 276 cm-1。

2 結(jié)果與討論

應(yīng)用BTC替代傳統(tǒng)的POCl3與DMF制備新型的Vilsmeier試劑與相應(yīng)底物進(jìn)行環(huán)合反應(yīng)制備目標(biāo)化合物的優(yōu)點(diǎn)在于反應(yīng)條件溫和，化學(xué)選擇性高，而且可以避免后處理中產(chǎn)生容易造成環(huán)境富氧化的磷酸鹽。在4i的合成中， Vilsmeier試劑的使用量由文獻(xiàn)[9]的6 eq降為2 eq，反應(yīng)時(shí)間由6 h降為0.25 h。

本實(shí)驗(yàn)重點(diǎn)考察了環(huán)合反應(yīng)中原料配比和溫度對(duì)收率的影響，對(duì)其工藝進(jìn)行了考察，結(jié)果表明n(3) ∶n(BTC) ∶n(DMF)=1.00 ∶0.66 ∶2.00時(shí)收率較高。隨后對(duì)反應(yīng)溫度也進(jìn)行了考察，15 ℃～30 ℃為較佳溫度，當(dāng)反應(yīng)溫度低于15 ℃時(shí)，反應(yīng)時(shí)間要延長(zhǎng)，反應(yīng)溫度高于30 ℃時(shí)，反應(yīng)選擇性下降，收率降低。由表1可知，苯肼上的取代基對(duì)收率有一定的影響，芳環(huán)上具有給電子取代基一般有利于反應(yīng)的進(jìn)行，強(qiáng)吸電子基團(tuán)不反應(yīng)(未得到4d)。環(huán)戊酮的反應(yīng)收率相對(duì)較低(如4g的收率僅40%)。

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