一鍋法合成3-腈基-4苯并吡喃酮類化合物*

陳志衛(wèi), 楊艷艷, 閆偉華, 蘇為科

(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)

苯并吡喃環(huán)廣泛地存在于天然產(chǎn)物和非天然產(chǎn)物中，3-腈基-4苯并吡喃酮類化合物(2)具有抗艾滋病毒[1]、抗過敏[2]、抗腫瘤[3]、以及抗菌[4]等廣泛藥理活性。傳統(tǒng)的合成方法通常分為三步[5]，鄰羥基苯乙酮(1)在POCl3/DMF作用下先生成3-甲?；猍6～9]，隨后與鹽酸羥胺發(fā)生肟化，最后在對甲苯磺酸[10]或硫酸[11～13]等催化劑的作用下脫水得2。最近Reddy G J等[14]報道了一鍋法合成2。

本文綜合文獻方法，設(shè)計了新的合成路線：1在Vilsmeier試劑作用下環(huán)合得中間體3-甲?；?，所得中間體不經(jīng)分離純化，直接與鹽酸羥胺反應(yīng)合成了一系列2(2a～2k, Scheme 1),收率47%～74%,其結(jié)構(gòu)經(jīng)1H NMR, IR和MS確證。

Scheme1

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(CDCl3或DMSO-d6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。

所用試劑均為分析純，用前未經(jīng)純化處理。

1．2 2的合成通法

在三口燒瓶中加入雙(三氯甲基)碳酸酯(BTC) 5.40 g(18 mmol)和二氯甲烷10 mL,攪拌下于0 ℃(冰浴冷卻)滴加DMF 4.75 g(65 mmol)的二氯甲烷溶液10 mL，滴畢， 撤去冰浴，自然升溫至室溫制得BTC/DMF Vilsmeier試劑。

在Vilsmeier試劑中加入1 9 mmol,攪拌下于25 ℃～30 ℃反應(yīng)10 h;于0 ℃緩慢滴加鹽酸羥胺1.23 g(18mmol)的DMF(4.75 g, 52 mmol)溶液，滴畢,于室溫反應(yīng)4 h。加入適量冰水稀釋后用二氯甲烷(3×10 mL)萃取，合并有機層，用飽和NaHCO3溶液調(diào)至中性，用飽和食鹽水洗滌，無水硫酸鈉干燥，濾液減壓濃縮至干，用乙醇重結(jié)晶得2。實驗結(jié)果見表1。

2a:1H NMRδ: 7.53～7.57(m, 2H, ArH), 7.80(t,J=8.8 Hz, 1H, ArH), 8.27(d,J=4.0 Hz, 1H, ArH), 8.43(s, 1H, CH); IRν: 2 242, 1 663, 1 618 cm-1; MSm/z: 171(M+)。

2b～2k的表征數(shù)據(jù)[15]與Scheme 1吻合。

表 1 實驗結(jié)果Table 1 Experamental results

2 結(jié)果與討論

BTC參與的化學(xué)反應(yīng)條件比較溫和，收率較高，既安全又方便，且環(huán)境友好，因而在醫(yī)藥化工中間體的合成中有極為廣泛的應(yīng)用。本文以BTC替代文獻方法中的POCl3制成Vilsmeier試劑成功地合成了2，反應(yīng)過程中沒有產(chǎn)生容易造成環(huán)境富氧化的磷酸鹽，環(huán)境友好。

本實驗重點考察了原料配比和反應(yīng)溫度對收率的影響。反應(yīng)結(jié)果表明n(1) ∶n(BTC) ∶n(DMF) ∶n(鹽酸羥胺)=1 ∶2 ∶13 ∶2時收率較高。在較佳的物料配比情況下，考察了反應(yīng)溫度對收率的影響，實驗結(jié)果表明較佳反應(yīng)溫度為25 ℃～30 ℃，當(dāng)反應(yīng)溫度低于25 ℃時，反應(yīng)時間大大延長，反應(yīng)溫度高于30 ℃時，反應(yīng)選擇性下降，收率降低。由表1可知，1的取代基對收率也有一定的影響，除1k外，芳環(huán)上具有吸電子取代基一般有利于反應(yīng)的進行。

本工藝反應(yīng)條件溫和，操作簡單易行，環(huán)境友好，收率相對較高，適合規(guī)模化生產(chǎn)3-睛基-4苯并吡喃酮類化合物。

[1] Mahmood N, Piacente S, Pizza C,etal. The anti-HIV activity and mechanisms of action of pure compounds isolated from Rosa damascena[J].Biochem Biophys Res Commun,1996,229(1):73-79.

[2] Nohara A, Ishiguro T, Ukawa K,etal. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines[J].J Med Chem,1985,28:559-568.

[3] Ishar M P S, Singh G, Singh S,etal. Design,synthesis,and evaluation of novel 6-chloro-/fluorochromone derivatives as potential topoisomerase inhibitor anticancer agents[J].Bioorg Med Chem Lett,2006,16(5):1366-1370.

[4] Menichincheri M, Ballinari D, Bargiotti A,etal. Catecholic flavonoids acting as telomerase inhibitors[J].J Med Chem,2004,47:6466-6475.

[5] Nohara A, Umetani T, Sanno Y. A facile synthesis of chromone-3-carbo-xaldehyde,chromone-3-carboxylic acid and 3-hydroxymethylchromone[J].Tetrahedron Lett,1973,14(22):1995-1998.

[6] Reynolds G A, Vannallan J A. The reactions of 2,2-difluoro-4-methylnaphtho[1,2-e]-1,3,2-dioxaborin and its [2,1-e]isomer withN,N-dimethylformamide[J].Heterocyclic Chem,1969,6:375-377.

[7] Harnisch H. Chromone-3-carboxaldehyde[J].Justus Liebigs Ann Chem,1972,765:8-14.

[8] Borrell J I, TeixidJ, Schuler E,etal. Solid-supported synthetic equivalents of 3-formylchromone and chromone[J].Tetrahedron Lett, 2001,42(31):5331-5334.

[9] Ali M M, Sana S, Rajanna K C,etal. Ultrasonically accelerated vilsmeier haack cyclisation and formylation reactions[J].Synth Commun,2002,32(9):1351-1356.

[10] Abdel-Rahman A H, Magret M G, Abdel-Aziz S E,etal. Synthesis of new benzo[h]- and benzo[f]chromeno[2,3-b]-pyridine-5-ones[J].Heteroatom Chem,2006,17(1):2-7.

[11] Akira N, Hisashi K, Taketshi S,etal. Synthesis of 3-(1H-tetrazol-5-yl)chromones,a new series of antiallergic substances[J].J Med Chem,1977,20:141-145.

[12] Hsung R P, Zificsak C A, Wei L L,etal. A rare acid-promoted elimination ofo-methyl oximes:A practical synthesis of 3-cyano-4-benzopyrones[J].J Org Chem,1999,64:8736-8740.

[13] Reddy G J, Latha D, Thirupath Aiah C,etal. An efficient one step conversion of 3-formylchro-mones into 3-cyanochromones[J].Org Prep Proced Int,2004,36(3):287-289.

[14] Reddy G J, Latha D, Thirupathaiah C,etal. A mild,one-pot synthesis of 3-cyano-4-benzopyrones from 2-hydroxyacetophenones[J].Tetrahedron Lett,2004,45(4):847-848.

[15]2b:1H NMRδ: 2.38(s, 3H, CH3), 2.38(s, 3H, CH3), 7.98(s, 1H, ArH), 8.35(s, 1H, ArH), 8.37(s, 1H, CH);13C NMRδ: 19.4, 20.6, 102.7, 112.5, 118.5, 121.2, 126.0, 136.8, 146.2, 154.3, 161.8, 172.3; IRν: 2 234, 1 667, 1 624 cm-1; MSm/z: 199(M+).2c:1H NMRδ: 2.53(s, 3H, CH3), 7.33～7.34 (m, 2H, ArH), 8.13(d,J=6.8 Hz, 1H, ArH), 8.37(s, 1H, CH);13C NMRδ: 21.9, 102.9, 112.3, 118.2, 121.1, 126.0, 128.6, 147.2, 155.9, 161.9, 172.2; IRν: 2 240, 1 658, 1 619 cm-1; MSm/z: 185(M+).2d:1H NMRδ: 2.49(s, 3H, CH3), 7.44(d,J=8.8 Hz, 1H, ArH), 7.58(d,J=4.0 Hz, 1H, ArH), 8.04(t, 1H, ArH), 8.38(s, 1H, CH); IRν: 2 236, 1 664, 1 618 cm-1; MSm/z: 185(M+).2e:1H NMRδ: 7.52(t,J=12 Hz, 1H, ArH), 7.57～7.59(m, 1H, ArH), 7.91(d,J=7.6 Hz, 1H, ArH), 8.41(s, 1H, CH); IRν: 2 239, 1 660, 1 628 cm-1; MSm/z: 189(M+).2f:1H NMRδ: 7.52(d,J=8.8 Hz, 1H, ArH), 7.72～7.75(m, 1H, ArH), 8.22(d,J=2.4 Hz, 1H, ArH), 8.41(s, 1H, CH); IRν: 2 240, 1 665, 1 611 cm-1; MSm/z: 205(M+).2g:1H NMRδ: 7.46(d,J=9.2 Hz, 1H, ArH), 7.87～7.89(m, 1H, ArH), 8.38(d,J=2.4 Hz, 1H, ArH), 8.41(s, 1H, CH); IRν: 2 234, 1 662, 1 612 cm-1; MSm/z: 249(M+).2h:1H NMRδ: 8.05(s, 1H, CH), 8.66(d,J=12.0 Hz, 1H, ArH), 9.03(m, 1H, ArH), 9.35(s, 1H, ArH); IRν: 2 238, 1 660, 1 613 cm-1; MSm/z: 216(M+).2i:1H NMRδ: 7.34～7.36(m, 1H, ArH), 7.48(d,J=5.6 Hz, 1H, ArH), 7.59(d,J=2.4 Hz, 1H, ArH), 8.39(s, 1H, CH); IRν: 2 242, 1 660, 1 618 cm-1; MSm/z: 191(M+).2j:1H NMRδ: 7.83(s, 1H, ArH), 8.13(s, 1H, ArH), 8.59(s, 1H, CH);13C NMRδ: 103.5, 111.3, 124.3, 125.1, 125.2, 133.2, 135.5, 150.2, 161.9, 170.7; IRν: 2 239, 1 659, 1 624 cm-1; MSm/z: 239(M+).2k:1H NMRδ: 2.52(s, 3H, CH3), 8.25(d,J=2.4 Hz, 1H, ArH), 8.44(s, 1H, CH), 9.00(s, 1H, ArH);13C NMRδ: 20.5, 103.1, 120.9, 126.5, 129.4, 131.4, 136.5, 139.0, 146.3, 163.7, 173.9; IRν: 2 242, 1 664, 1 612 cm-1; MSm/z: 201(M+).