新型含吡唑基[1,2,4]噁二唑-[5,4-d][1,5]苯并硫氮雜卓衍生物的合成與表征

方慶華,費(fèi)婷虹,周英雷,劉方明

(1. 杭州師范大學(xué)健康管理學(xué)院,浙江 杭州 310036;2. 杭州師范大學(xué)材料與化學(xué)化工學(xué)院，浙江 杭州 310036)

新型含吡唑基[1,2,4]噁二唑-[5,4-d][1,5]苯并硫氮雜卓衍生物的合成與表征

方慶華1,費(fèi)婷虹2,周英雷2,劉方明2

(1. 杭州師范大學(xué)健康管理學(xué)院,浙江 杭州 310036;2. 杭州師范大學(xué)材料與化學(xué)化工學(xué)院，浙江 杭州 310036)

以[1,5]苯并硫氮雜卓衍生物1a-l和含吡唑基的氯代肟4為起始原料，通過(guò)1,3-偶極環(huán)加成的方法合成了一系列新型含吡唑基[1,2,4]噁二唑-[5,4-d][1,5]苯并硫氮雜卓衍生物.并通過(guò)元素分析、1H NMR，MS，IR對(duì)這類(lèi)化合物進(jìn)行了表征.

[1,5]苯并硫氮雜卓;1,3-偶極環(huán)加成;[1,2,4]噁二唑;吡唑

1,5-苯并硫氮雜卓是一類(lèi)具有廣譜活性的七元雜環(huán)化合物，具有很好的抗高血壓[1]、抗抑郁[2]、抗凝血[3]、抗動(dòng)脈硬化[4]、抗-HIV[5]、殺菌[6]等作用，近幾十年來(lái)引起許多化學(xué)家的廣泛關(guān)注，其中許多含有1,5-苯并硫氮雜卓雜環(huán)的藥物已被用于臨床.例如正在使用的藥物地爾硫卓被作為鈣通道阻斷劑[7]、鈣離子通道拮抗劑[8]、抗驚厥劑和安神劑[9].五元雜環(huán)吡唑及其衍生物也表現(xiàn)出廣泛的藥理活性，如抗高血糖[10-11]、抗細(xì)菌[12]、抗抑郁[13]、抗炎[14]和抗腫瘤[15].此外，[1,2,4]噁二唑也是一類(lèi)具有各種藥理活性的五元環(huán)[16].

在[1,5]苯并硫氮雜卓上引入其他的雜環(huán)將大大提高其藥理活性[17-19]，此外，在[1,5]苯并硫氮雜卓環(huán)的2位或4位引入一個(gè)雜環(huán)，將產(chǎn)生比母體分子更多的活性[20].據(jù)此，筆者設(shè)計(jì)并通過(guò)1,3-偶極環(huán)合加成的方法合成了一系列新型的三環(huán)稠環(huán)化合物，其有望表現(xiàn)出更好的藥理活性.合成路線如圖1所示.

圖1 目標(biāo)產(chǎn)物的合成路線Fig. 1 The synthetic route of the target product

1 實(shí)驗(yàn)部分

1.1 儀器與試劑

合成所用的試劑均為分析純或化學(xué)純.北京泰克X-5顯微熔點(diǎn)儀(溫度計(jì)未校正)，Bruker Tensor27紅外光譜儀(KBr)，Agilent-5975質(zhì)譜儀，Varian Mercury-Plus400型核磁共振儀(內(nèi)標(biāo)TMS，溶劑為CDCl3)，Perkin-Elmer2400 CHN元素分析儀.2,4-二芳基-1,5-苯并硫氮雜卓1a-l的合成參照文獻(xiàn)[21]，1-苯基-3-甲基-5-苯氧基-4-吡唑甲醛2 的合成參照文獻(xiàn)[22].

1.2 1-苯基-3-甲基-5-苯氧基-吡唑甲醛肟3的合成

取20.0 mmol 1-苯基-3-甲基-5-苯氧基-4-吡唑甲醛2溶于50.0 mL乙醇中，室溫?cái)嚢柘碌渭?16.0 mg鹽酸羥胺和464.0 mg醋酸鈉的水溶液.有大量固體析出后，再加熱回流10 min.靜置過(guò)夜，抽濾，水洗，所得固體用乙醇/水重結(jié)晶，得到產(chǎn)物3.

1.3 α-1-苯基-3-甲基-5-苯氧基-4-吡唑甲醛肟4的合成

取10.0 mmol1-苯基-3-甲基-5-苯氧基-4-吡唑甲醛肟3溶于12.5 mL DMF中，分次緩慢加入15.0 mmol NCS，反應(yīng)控制在35 ℃以下，直到反應(yīng)液可以使?jié)駶?rùn)的淀粉碘化鉀試紙無(wú)色或弱色為止，將反應(yīng)液倒入80.0 mL水中，用乙醚萃取2次，將萃取液用水洗3次，無(wú)水Na2SO4干燥，旋干，氯仿/石油醚重結(jié)晶，得到化合物4.淺黃色晶體.產(chǎn)率(%)：86，熔點(diǎn)：146～148 ℃; MS(EI)m/z(%)：327(M+)，291，274，143，77(100)，51.

1.4 3a,5-二芳基-1-(1-苯基-3-甲基-5-苯氧基-吡唑-4-基)-3a,4,5,11-4H-[1,2,4]噁二唑[5,4-d]1,5-苯并硫氮雜卓的合成3a-1

將2,4-二芳基-1,5-苯并硫氮雜卓(1.0 mmol)、吡唑甲醛氯肟(2.0 mmol)溶于干燥的二氯甲烷中，在室溫?cái)嚢柘碌渭有抡舻娜野?2.0 mmol)，繼續(xù)攪拌48 h，TLC檢測(cè)，反應(yīng)結(jié)束后濾去銨鹽，減壓濃縮，用V(乙酸乙酯)∶V(石油醚)=1∶8柱層析得到淡黃色或白色固體.

3a:淺黃色晶體; 產(chǎn)率(%): 23.1; m.p.: 192～194 ℃; IR(KBr)ν/cm-1: 3 076(Ar—H),1 635(C=N), 1 479(C=C), 1 357(C—N), 763(C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.72～6.43(m, 24H, Ar—H), 3.20 (dd, 1H, H5x,Jax=5.52 Hz,Jbx=10.32 Hz), 2.63 (dd, 1H, H4a,Jax=5.52 Hz,Jab=13.08 Hz), 2.55 (s, 3H, —CH3), 2.42 (dd, 1H, H4b,Jbx=10.32 Hz,Jab=13.08 Hz); MS(EI)m/z(%): 606 (M+), 502, 409, 304, 211, 105(100); Anal. calcd for C38H30N4O2S: C 75.22, H 4.98, N 9.23 ; Found: C 75.11, H 5.03, N 9.19.

3b: 淺黃色晶體; 產(chǎn)率(%): 25.5; m.p.: 241～243 ℃; IR(KBr)ν/cm-1: 3 058 (Ar—H), 1 634 (C=N), 1 479 (C=C), 1 355 (C—N), 764 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.68～6.51 (m, 23H, Ar—H), 3.30 (dd, 1H, H5x,Jax=5.64 Hz,Jbx=10.40 Hz), 2.69 (dd, 1H, H4a,Jax=5.64 Hz,Jab=13.12 Hz), 2.57 (s, 3H, -CH3), 2.48 (dd, 1H, H4b,Jbx=10.40 Hz,Jab=13.12 Hz); MS(EI)m/z(%): 640 (M+), 502, 409, 304, 211, 105(100); Anal. calcd for C38H29ClN4O2S: C 71.18, H 4.56, N 8.74 ; Found: C 71.13, H 4.61, N 8.69.

3c: 淺黃色晶體; 產(chǎn)率(%): 31.0; m.p.: 209～210 ℃; IR(KBr)ν/cm-1: 3 059 (Ar—H), 1 635 (C=N), 1 487 (C=C), 1 349 (C—N), 762 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.67～6.63 (m, 23H, Ar—H), 3.80 (s,3H,-OCH3), 3.27 (dd, 1H, H5x,Jax=5.48 Hz,Jbx=10.36 Hz), 2.67 (dd, 1H, H4a,Jax=5.48 Hz,Jab=13.08 Hz), 2.56 (s, 3H, -CH3), 2.48 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.08 Hz); MS(EI)m/z(%): 636 (M+), 502, 409, 304, 211, 105(100); Anal. calcd for C39H32N4O3S: C 73.56, H 5.07, N 8.80 ; Found: C 73.55, H 5.12, N 8.76.

3d: 淺黃色晶體; 產(chǎn)率(%): 27.3; m.p.: 172～174 ℃; IR(KBr)ν/cm-1: 3 055 (Ar—H), 1 631 (C=N), 1 480 (C=C), 1 347 (C—N), 763 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.69～6.58 (m, 23H, Ar—H), 3.27 (dd, 1H, H5x,Jax=5.44 Hz,Jbx=10.36 Hz), 2.68 (dd, 1H, H4a,Jax=5.44 Hz,Jab=13.16 Hz), 2.58 (s, 3H, -CH3), 2.47 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.16 Hz); MS(EI)m/z(%): 651 (M+), 502, 409, 304, 211, 105(100); Anal. calcd for C38H29N5O4S: C 70.03, H 4.49, N 10.75 ; Found: C 69.98, H 4.53, N 10.74.

3e: 淺黃色晶體; 產(chǎn)率(%): 22.2; m.p.: 250～251 ℃; IR(KBr)ν/cm-1: 3 038 (Ar—H), 1 634 (C=N), 1 488 (C=C), 1 342 (C—N), 762 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.68～6.56 (m, 23H, Ar—H), 3.34 (dd, 1H, H5x,Jax=5.52 Hz,Jbx=10.28 Hz), 2.72 (dd, 1H, H4a,Jax=5.52 Hz,Jab=13.12 Hz), 2.57 (s, 3H, -CH3), 2.45 (dd, 1H, H4b,Jbx=10.28 Hz,Jab=13.12 Hz); MS(EI)m/z(%): 640 (M+), 536, 443, 304, 245, 139(100); Anal. calcd for C38H29ClN4O2S: C 71.18, H 4.56, N 8.74 ; Found: C 71.17, H 4.61, N 8.68.

3f: 淺黃色晶體; 產(chǎn)率(%): 24.1; m.p.: 196～198 ℃; IR(KBr)ν/cm-1: 3 039 (Ar—H), 1 631 (C=N), 1 482 (C=C), 1 337 (C—N), 763 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.63～6.55 (m, 22H, Ar—H), 3.29 (dd, 1H, H5x,Jax=5.60 Hz,Jbx=10.36 Hz), 2.71 (dd, 1H, H4a,Jax=5.60 Hz,Jab=13.20 Hz), 2.57 (s, 3H, -CH3), 2.44 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.20 Hz); MS(EI)m/z(%): 674 (M+), 536, 443, 304, 245, 139(100); Anal. calcd for C38H28Cl2N4O2S: C 67.55, H 4.18, N 8.29 ; Found: C 67.49, H 4.25, N 8.28.

3g: 淺黃色晶體; 產(chǎn)率(%): 30.4; m.p.: 181～183 ℃; IR(KBr)ν/cm-1: 3 033 (Ar—H), 1 640 (C=N), 1 481 (C=C), 1 352 (C—N), 761 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.64～6.57 (m, 22H, Ar—H), 3.81 (s,3H,-OCH3), 3.30 (dd, 1H, H5x,Jax=5.56 Hz,Jbx=10.36 Hz), 2.71 (dd, 1H, H4a,Jax=5.56 Hz,Jab=13.16 Hz), 2.57 (s, 3H, -CH3), 2.44 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.16 Hz); MS(EI)m/z(%): 670 (M+), 536, 443, 304, 245, 139(100); Anal. calcd for C39H31ClN4O3S: C 69.79, H 4.66, N 8.35 ; Found: C 69.77, H 4.69, N 8.37.

3h: 淺黃色晶體; 產(chǎn)率(%): 28.0; m.p.: 241～244 ℃; IR(KBr)ν/cm-1: 3 041 (Ar—H), 1 643 (C=N), 1 488 (C=C), 1 353 (C—N), 764 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.63～6.56 (m, 22H, Ar—H), 3.29 (dd, 1H, H5x,Jax=5.64 Hz,Jbx=10.40 Hz), 2.68 (dd, 1H, H4a,Jax=5.64 Hz,Jab=13.24 Hz), 2.58 (s, 3H, -CH3), 2.43 (dd, 1H, H4b,Jbx=10.40 Hz,Jab=13.24 Hz); MS(EI)m/z(%): 685 (M+), 536, 443, 304, 245, 139(100); Anal. calcd for C38H28ClN5O4S: C 66.51, H 4.11, N 10.21 ; Found: C 66.51, H 4.13, N 10.22.

3i: 淺黃色晶體; 產(chǎn)率(%): 29.7; m.p.: 212～216 ℃; IR(KBr)ν/cm-1: 3 029 (Ar—H), 1 647 (C=N), 1 477 (C=C), 1 342 (C—N), 761 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.62～6.57 (m, 23H, Ar—H), 3.79 (s,3H,-OCH3), 3.35 (dd, 1H, H5x,Jax=5.52 Hz,Jbx=10.28 Hz), 2.68 (dd, 1H, H4a,Jax=5.52 Hz,Jab=13.12 Hz), 2.57 (s, 3H, -CH3), 2.43 (dd, 1H, H4b,Jbx=10.28 Hz,Jab=13.12 Hz); MS(EI)m/z(%): 636 (M+), 532, 439, 306, 241, 135(100); Anal. calcd for C39H32N4O3S: C 73.56, H 5.07, N 8.80 ; Found: C 73.55, H 5.06, N 8.83.

3j: 淺黃色晶體; 產(chǎn)率(%): 28.5; m.p.: 182～184 ℃; IR(KBr)ν/cm-1: 3 031 (Ar—H), 1 650 (C=N), 1 483 (C=C), 1 350 (C—N), 761 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.64～6.58 (m, 22H, Ar—H), 3.78 (s,3H,-OCH3), 3.31 (dd, 1H, H5x,Jax=5.60 Hz,Jbx=10.36 Hz), 2.70 (dd, 1H, H4a,Jax=5.60 Hz,Jab=13.16 Hz), 2.58 (s, 3H, -CH3), 2.45 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.16 Hz); MS(EI)m/z(%): 670 (M+), 532, 439, 306, 241, 135(100); Anal. calcd for C39H31ClN4O3S: C 69.79, H 4.66, N 8.35 ; Found: C 69.77, H 4.63, N 8.37.

3k:淺黃色晶體; 產(chǎn)率(%): 30.2; m.p.: 172～174 ℃; IR(KBr)ν/cm-1: 3 035 (Ar—H), 1 633 (C=N), 1 478 (C=C), 1 337 (C—N), 761 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.63～6.57 (m, 22H, Ar—H), 3.79 (s,3H,-OCH3), 3.73 (s,3H,-OCH3), 3.35 (dd, 1H, H5x,Jax= 5.64 Hz,Jbx= 10.20 Hz), 2.72 (dd, 1H, H4a,Jax=5.64 Hz,Jab=13.12 Hz), 2.57 (s, 3H, -CH3), 2.43 (dd, 1H, H4b,Jbx=10.20 Hz,Jab=13.12 Hz); MS(EI)m/z(%): 666 (M+), 532, 439, 306, 241, 135(100); Anal. calcd for C40H34N4O4S: C 72.05, H 5.14, N 8.40 ; Found: C 72.09, H 5.17, N 8.39.

3l: 淺黃色晶體; 產(chǎn)率(%): 33.5; m.p.: 225～227 ℃; IR(KBr)ν/cm-1: 3 032 (Ar—H), 1 635 (C=N), 1 481 (C=C), 1 332 (C—N), 764 (C—S—C);1H NMR (CDCl3, 400 MHz)δ: 7.64～6.55 (m, 22H, Ar—H), 3.80 (s,3H,-OCH3), 3.29 (dd, 1H, H5x,Jax=5.60 Hz,Jbx=10.36 Hz), 2.70 (dd, 1H, H4a,Jax=5.60 Hz,Jab=13.16 Hz), 2.58 (s, 3H, -CH3), 2.43 (dd, 1H, H4b,Jbx=10.36 Hz,Jab=13.16 Hz); MS(EI)m/z(%): 681 (M+), 532, 439, 306, 241, 135(100); Anal. Calcd for C39H31N5O5S: C 68.71, H 4.58, N 10.27 ; Found: C 68.68, H 4.59, N 10.27.

2 結(jié)果與討論

2.1 化合物的合成

根據(jù)文獻(xiàn) [21]，α,β-不飽和酮(查爾酮)是由芳香醛和苯乙酮通過(guò)Claisen-Schmidt縮合反應(yīng)得到的，查爾酮與和等量的鄰氨基硫酚在酸化的乙醇中回流得到起始原料[1,5]苯并硫雜卓衍生物1a-l.

在合成1a-l的的過(guò)程中，反應(yīng)分兩步進(jìn)行:第一步,由于—SH的親核性大于—NH2，鄰氨基硫酚中的—SH負(fù)電子進(jìn)攻查爾酮類(lèi)似物共軛雙鍵中得β碳原子發(fā)生1,4-邁克爾加成;第二步,—NH2與C=O脫水縮合得到[1,5]苯并硫氮雜卓衍生物1a-l.

[1,5]苯并硫氮雜卓衍生物1a-1是以二氯甲烷為溶劑在室溫下攪拌48 h以上得到的，但是吡唑甲醛氯肟4和三乙胺都應(yīng)稍微過(guò)量.最終產(chǎn)物的結(jié)構(gòu)是由IR，1H NMR，MS和元素分析確證的.

2.2 目標(biāo)化合物的譜圖表征

IR：最終產(chǎn)物3a-l在1 650～1 631 cm-1、1 488～1 477cm-1及764～761 cm-1范圍內(nèi)分別出現(xiàn)了C=N，C=C和C—S—C的振動(dòng)吸收峰.在3 076～3 029 cm-1范圍內(nèi)表現(xiàn)出Ar—H伸縮振動(dòng)吸收峰.

1HNMR：最終產(chǎn)物3a-l在δ:7.72～6.43 ppm處出現(xiàn)的多重峰為芳環(huán)上的氫質(zhì)子峰，在δ:2.58～2.55 ppm處出現(xiàn)的單峰為甲基上的氫質(zhì)子峰，雜卓七元環(huán)上的3個(gè)飽和氫質(zhì)子Hx、Hb、Ha出現(xiàn)在δ:3.33～2.37 ppm.例如在化合物3c中，在δ:3.78 ppm和δ:2.58 ppm處出現(xiàn)的單峰分別為甲氧基和甲基上的氫質(zhì)子峰.雜卓七元環(huán)上的3個(gè)飽和氫質(zhì)子中的Hx在δ:3.27處出現(xiàn)三重峰，雜卓七元環(huán)上的3個(gè)飽和氫質(zhì)子中的Ha和Hb分別在δ:2.67和δ:2.48處出現(xiàn)雙重峰，這樣的分裂是由于卓環(huán)3位上的兩個(gè)不等價(jià)的氫質(zhì)子鄰位耦合造成的.同時(shí)在δ:7.67～6.63 ppm處出現(xiàn)芳環(huán)上氫質(zhì)子的多重峰.

MS： 此類(lèi)化合物的分子離子峰都相對(duì)較弱，以化合物3e為例，MS(EI)m/z(%): 640 (M+), 536, 443, 304, 245, 139(100).

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SynthesisandCharacterizationofNovel[1,2,4]Oxadiazolo-[5,4-d][1,5]benzothiazepineDerivativesContainingPyrazoleMoietyby1,3-DipolarCycloaddition

FANG Qinghua1, FEI Tinghong2, ZHOU Yinglei2, LIU Fangming2

(1. School of Health Management, Hangzhou Normal University, Hangzhou 310036, China;2. College of Materials，Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China)

A series of new substituted-[1,2,4]oxadiazolo-[5,4-d][1,5]benzothiazepine derivatives containing a pyrazole ring 3a-lwere synthesized from substituted-[1,5]benzothiazepines 1a-land pyrazolohydroximinoyl chloride 4 through the 1,3-dipolar cycloaddition reaction. The structures of the compounds were represented by1H NMR, MS, IR and elemental analysis.

[1,5]benzothiazepine; 1,3-dipolar cycloaddition; [1,2,4]oxadiazole; pyrazole

2012-10-19

劉方明(1966—)，男，教授，博士，主要從事雜環(huán)化學(xué)研究.E-mail：fmliu859@sohu.com

10.3969/j.issn.1674-232X.2013.01.006

O626.5

A

1674-232X(2013)01-0030-05