CN110156815A - 12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓及其制备方法 - Google Patents
12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓及其制备方法 Download PDFInfo
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Abstract
本发明涉及有机合成化学领域,具体是涉及一种12a氢‑苯并[f]吡啶[1,2‑d][1,4]硫氮卓及其制备方法,分子中含有硫氮卓杂环骨架和二氢吡啶结构单元,并具有丰富的多种官能团取代。结构式为:
Description
技术领域
本发明涉及有机合成化学领域,具体是涉及一种12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓及其制备方法。
背景技术
含硫化合物以不同的存在形式服务于人类生活的各个方面。含硫有机化合物在药物分子中大量存在,例如噻吩、苯并噻吩等常见含硫杂环。本发明所涉及的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓类化合物为本发明首次合成,分子中含有硫氮卓杂环骨架和二氢吡啶结构单元,并具有丰富的多种官能团取代。因其结构新颖,包含常见的药效团,多个杂环稠和,可能使该类化合物具有潜在的生物活性,在生物医药等领域可能成为药物先导化合物。
发明内容
本发明的主要目的在于提供了一种12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓及其制备方法。该方法实现了由苯炔前体化合物与含硫内鎓盐,在氟化钾/18-冠-6作为催化剂的条件下,一步简洁高效合成12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓类化合物。
本发明所述的化合物是如Ⅰ所示的化合物—12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓(12aH-benzo[f]pyrido[1,2-d][1,4]thiazepine);
其中:
R1为氢、2,3-二甲基、苯环、2,3-二氧杂环、2,3-环戊烷、2,3-二氟;
R2为11-甲基或9,10苯环稠和取代;
R3为甲酯、乙酯、叔丁酯、三氟甲基、苯甲酰基;
R4为甲酯、乙酯、苯甲酰基、4-甲氧基苯甲酰基、4-甲基苯甲酰基、4-溴苯甲酰基、4-硝基苯甲酰基、呋喃甲酰基。
本发明的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓(12aH-benzo[f]pyrido[1,2-d][1,4]thiazepine)的合成方法如下所示:
即将通式Ⅱ所示化合物、通式Ⅲ所示化合物、氟化钾/18-冠-6在室温条件下溶解于乙腈溶剂中,反应物Ⅱ反应完全后,将反应混合物在减压条件下除去有机溶剂,柱层析洗脱得到目标化合物Ⅰ。其中:
R1为氢、2,3-二甲基、苯环、2,3-二氧杂环、2,3-环戊烷、2,3-二氟;
R2为11-甲基或9,10苯环稠和取代;
R3为甲酯、乙酯、叔丁酯、三氟甲基、苯甲酰基;
R4为甲酯、乙酯、苯甲酰基、4-甲氧基苯甲酰基、4-甲基苯甲酰基、4-溴苯甲酰基、4-硝基苯甲酰基、呋喃甲酰基。
本发明优选的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓的合成方法是,使用氟化钾作/18-冠-6作为催化剂,以乙腈作为溶剂。
进一步,反应时化合物Ⅱ、化合物Ⅲ、氟化钾/18-冠-6的最优摩尔比(即当量比)为Ⅱ:Ⅲ:氟化钾/18-冠-6=1.0:1.5:2.0,最优浓度为0.1M,即0.1摩尔每升。
更进一步,在硅胶柱层析时,所用的洗脱液为石油醚与乙酸乙酯的混合溶剂,且体积比V石油醚:V乙酸乙酯=10:1~5:1。
本发明涉及的方法,具有的技术效果:
一方面使用含硫内鎓盐作为12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓化合物中硫原子的引入试剂,另一方面该类内鎓盐中吡啶也可以作为活性单元参与反应,这不仅极大的提高了该类内鎓盐的原子经济性,同时也使产物中引入二氢吡啶结构单元。12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓类化合物的骨架结构本发明属于首次合成。该类化合物结构新颖,具有潜在的生物活性,从而让其具有进一步研究和应用的价值。
具体实施方式
本发明以下结合具体实施例进行解说。
以下是本发明制备化合物的最佳实施例。在以下所有实施例中,核磁谱检测通过Varian 300,Bruker400,JEOL400and Varian 600MHz仪器在CDCl3、(CD3)2CO或d6-DMSO中获得。δ值为内标相对值(CDCl3定标δ7.26 1H NMR和77.0013C NMR;(CD3)2CO定标δ2.05 1H NMR和29.84 13C NMR;d6-DMSOδ2.501H NMR和39.5213C NMR)。高分辨质谱(HRMS)通过4Gquadrupole time-of-flight(QTof)质谱仪器得到。
实施例1
实施例1的反应式,具体使用的化合物Ⅱ-1和化合物Ⅲ-1以及产物Ⅰ-1结构如下所示。实验表明本发明优选的氟源/18-冠-6作为催化剂,优选的有机溶剂为乙腈,最优的原料摩尔比为化合物Ⅱ:化合物Ⅲ:氟化钾/18-冠-6=1.0:1.5:2.0,最优浓度为0.1M。
具体实验步骤是:将90mg(0.30mmol,1.0当量)的化合物Ⅱ-1和114mg(0.450mmol,1.5当量)的化合物Ⅲ-1溶于3mL的乙腈中,加入35mg(0.60mmol,2.0当量)的氟化钾和159mg(0.60mmol,2.0当量)的18-冠-6,于室温下反应。薄层色谱监测反应物Ⅱ-1反应完全,将反应混合物在水泵减压下旋转蒸发除去溶剂乙腈。残留物以200-300目硅胶,洗脱液(体积比V石油醚:V乙酸乙酯=10:1~5:1)柱层析得到Ⅰ-1所示化合物58mg,其产物经过核磁(氢谱、碳谱)、高分辨质谱鉴定。
产物Ⅰ-1为黄色固体,产率为59%;熔点:59-60℃.1H NMR(400MHz,CDCl3)δ7.46–7.41(m,1H),7.35–7.31(m,1H),7.31–7.26(m,2H),6.73(d,J=6.0Hz,1H),6.27(dd,J=9.6,5.6Hz,1H),5.77(d,J=7.6Hz,1H),5.48(dd,J=9.6,6.4Hz,1H),5.26–5.20(m,1H),3.81(s,3H),3.78(s,3H);13C NMR(100MHz,CDCl3)δ165.4,165.0,145.3,141.6,135.1,132.0,128.6,128.2,127.6,126.6,124.3,116.6,105.6,103.5,55.8,53.0,52.7;ESI-HRMSm/z calcd for C17H15NO4S+H+330.0795,found 330.0797.
实施例2-18
制备本发明的其它化合物(化合物Ⅰ-2至化合物Ⅰ-18)的实施例所用的方法与实施例1相同,反应条件如下:化合物Ⅱ(0.3mmol)、化合物Ⅲ(1.5当量)溶于3mL的乙腈中,加入氟化钾量为35mg(0.60mmol,2.0当量)、18-冠-6量为159mg(0.60mmol,2.0当量),室温下反应。
所得产物表征如下:
产物Ⅰ-2为黄色固体,产率为48%;熔点:68-69℃.1H NMR(400MHz,CDCl3)δ7.48–7.42(m,1H),7.36–7.32(m,1H),7.30–7.26(m,2H),6.69(d,J=6.0Hz,1H),6.27(dd,J=9.6,5.6Hz,1H),5.80(d,J=7.2Hz,1H),5.49(dd,J=9.6,6.0Hz,1H),5.24–5.19(m,1H),4.33–4.20(m,4H),1.33(t,J=7.2Hz,3H),1.30(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ165.0,164.6,145.2,141.8,135.5,132.1,128.6,128.1,127.7,127.0,124.5,116.5,105.3,104.6,62.3,61.8,56.0,14.1,13.8;ESI-HRMS m/z calcd for C19H19NO4S+H+358.1108,found 358.1111.
产物Ⅰ-3为黄色固体,产率为54%;熔点:74-75℃.1H NMR(400MHz,CDCl3)δ8.00–7.94(m,2H),7.94–7.85(m,2H),7.56–7.31(m,10H),7.10(d,J=6.0Hz,1H),6.23(dd,J=9.2,5.6Hz,1H),5.61(d,J=7.2Hz,1H),5.58–5.52(m,1H),5.01–4.94(m,1H);13C NMR(100MHz,CDCl3)δ192.3,191.8,148.2,142.8,137.4,136.1,135.9,133.4,132.6,131.6,129.9,129.0,128.7,128.6(2C),128.4,128.2,128.0,125.4,119.2,115.6,104.6,55.8;ESI-HRMS m/z calcd for C27H19NO2S+H+422.1209,found 422.1212.
产物Ⅰ-4为黄色固体,产率为58%;熔点:>200℃.1H NMR(400MHz,CDCl3)δ8.00–7.92(m,2H),7.59–7.54(m,1H),7.50–7.42(m,3H),7.41–7.37(m,1H),7.36–7.27(m,2H),6.58(d,J=6.0Hz,1H),6.37(dd,J=9.6,5.6Hz,1H),5.80(d,J=7.2Hz,1H),5.55–5.48(m,1H),5.24–5.18(m,1H),3.43(s,3H);13C NMR(75MHz,CDCl3)δ191.2,164.3,142.3,138.1,136.7,134.9,133.0,131.3,130.0,129.5,128.6,128.4,128.3,128.2,125.4,124.1,114.6,103.5,56.3,52.5;ESI-HRMS m/z calcd for C22H17NO3S+H+376.1002,found376.1004.
产物Ⅰ-5为黄色固体,产率为57%;熔点:122-123℃.1H NMR(400MHz,CDCl3)δ8.01–7.95(m,2H),7.43(dd,J=7.2,2.0Hz,1H),7.38(dd,J=7.2,1.6Hz,1H),7.33–7.26(m,2H),6.98–6.93(m,2H),6.48(d,J=6.0Hz,1H),6.36(dd,J=9.2,5.2Hz,1H),5.81(d,J=6.8Hz,1H),5.52–5.46(m,1H),5.22–5.16(m,1H),3.88(s,3H),3.44(s,3H);13C NMR(100MHz,CDCl3)δ189.8,164.3,163.6,142.4,136.9,134.8,132.0,131.2,130.4,129.4,128.5,128.3,128.1,125.6,125.5,114.1,113.7,103.0,56.4,55.4,52.4;ESI-HRMS m/z calcdfor C23H19NO4S+H+406.1008,found 406.1008.
产物Ⅰ-6为黄色固体,产率为57%;熔点:131-132℃.1H NMR(400MHz,CDCl3)δ7.88(d,J=7.6Hz,2H),7.43(d,J=7.2Hz,1H),7.38(d,J=7.2Hz,1H),7.33–7.24(m,4H),6.52(d,J=6.0Hz,1H),6.36(dd,J=9.2,5.6Hz,1H),5.80(d,J=7.6Hz,1H),5.54–5.46(m,1H),5.23–5.16(m,1H),3.43(s,3H),2.42(s,3H);13C NMR(100MHz,CDCl3)δ190.8,164.3,143.9,142.4,137.4,134.8,134.0,131.2,130.2,129.7,129.1,128.5,128.3,128.1,125.4,125.0,114.3,103.2,56.4,52.4,21.7;ESI-HRMS m/z calcd for C23H19NO3S+H+390.1158,found 390.1161.
产物Ⅰ-7为红色固体,产率为37%;熔点:148-149℃.1H NMR(400MHz,CDCl3)δ7.82(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),7.44(dd,J=7.6,1.6Hz,1H),7.40–7.27(m,3H),6.63(d,J=6.0Hz,1H),6.36(dd,J=9.2,5.6Hz,1H),5.77(d,J=7.6Hz,1H),5.56–5.47(m,1H),5.26–5.18(m,1H),3.50(s,3H);13C NMR(100MHz,CDCl3)δ190.2,164.4,142.4,138.5,135.5,134.8,131.7,131.4,131.1,129.8,128.7,128.5,128.4,128.0,125.4,122.8,114.9,103.8,56.1,52.7;ESI-HRMS m/z calcd for C22H16BrNO3S+H+454.0107,found454.0112.
产物Ⅰ-8为红色固体,产率为35%;熔点:140-141℃.1H NMR(400MHz,CDCl3)δ8.30(d,J=8.8Hz,2H),8.06(d,J=8.8Hz,2H),7.46(d,J=7.6Hz,1H),7.40–7.30(m,3H),6.82(d,J=6.0Hz,1H),6.35(dd,J=9.2,5.6Hz,1H),5.76(d,J=7.2Hz,1H),5.57–5.51(m,1H),5.28–5.23(m,1H),3.56(s,3H);13C NMR(100MHz,CDCl3)δ189.6,164.4,149.9,142.3,142.2,140.5,135.1,131.4,130.4,129.0(2C),128.9,128.4,125.2,123.6,119.6,115.9,104.8,55.9,52.9;ESI-HRMS m/z calcd for C22H16N2O5S+H+421.0853,found 421.0855.
产物Ⅰ-9为红色固体,产率为55%;熔点:120-121℃.1H NMR(400MHz,CDCl3)δ7.63(d,J=0.8Hz,1H),7.45–7.39(m,2H),7.37(d,J=3.2Hz,1H),7.33–7.27(m,2H),6.55(dd,J=3.6,1.6Hz,1H),6.51(d,J=6.0Hz,1H),6.35(dd,J=9.6,5.6Hz,1H),5.77(d,J=7.2Hz,1H),5.56–5.49(m,1H),5.26–5.18(m,1H),3.50(s,3H);13C NMR(100MHz,CDCl3)δ178.2,164.4,151.9,147.2,141.8,138.9,134.6,131.4,129.8,128.7,128.2,125.4,122.3,119.6,114.9,112.2,103.9,56.3,52.7,(1C missing);ESI-HRMS m/z calcd forC20H15NO4S+H+366.0795,found 366.0798.
产物Ⅰ-10为黄色固体,产率为51%;熔点:64-65℃.1H NMR(400MHz,CDCl3)δ8.05–8.00(m,2H),7.58–7.54(m,1H),7.51–7.46(m,2H),7.45–7.42(m,1H),7.39–7.24(m,3H),6.56(d,J=6.4Hz,1H),6.36(dd,J=9.6,5.6Hz,1H),5.82(d,J=7.6Hz,1H),5.52–5.44(m,1H),5.23–5.16(m,1H),1.12(s,9H);13C NMR(100MHz,CDCl3)δ191.0,162.5,142.7,138.9,136.6,135.2,133.1,131.2,130.4,130.0,128.5,128.4,128.3,128.2,125.4,122.8,114.3,102.8,83.8,56.3,27.1;ESI-HRMS m/z calcd for C25H23NO3S+H+418.1471,found418.1472.
产物Ⅰ-11为黄色固体,产率为40%;熔点:85-86℃.1H NMR(400MHz,CDCl3)δ7.38–7.31(m,2H),7.28–7.22(m,2H),6.36(dd,J=9.2,5.6Hz,1H),5.99(d,J=6.4Hz,1H),5.93(d,J=6.4Hz,1H),5.52–5.46(m,1H),5.30–5.25(m,1H),4.31(q,J=7.2Hz,2H),1.36(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ164.1,142.0,132.1,130.7,129.9(q,J=32.4Hz),129.1(d,J=1.9Hz),128.5,128.3,127.8,125.5,121.4(d,J=2.7Hz),120.5(q,J=276.7Hz),113.4,104.5,62.9,57.0,13.8;ESI-HRMS m/z calcd for C17H14F3NO2S+H+354.0770,found 354.0774.
产物Ⅰ-12为黄色固体,产率为39%;熔点:79-80℃.1H NMR(400MHz,CDCl3)δ7.46–7.42(m,1H),7.28–7.26(m,3H),6.69(d,J=6.0Hz,1H),5.74(d,J=7.6Hz,1H),5.23–5.19(m,1H),5.15–5.09(m,1H),3.81(s,3H),3.79(s,3H),1.91(s,3H);13C NMR(100MHz,CDCl3)δ165.6,165.3,145.4,142.4,135.4,132.8,132.1,128.7,128.2,127.7,126.2,112.2,109.2,103.1,56.2,53.1,52.7,20.4;ESI-HRMS m/z calcd for C18H17NO4S+H+344.0951,found 344.0956.
产物Ⅰ-13为黄色固体,产率为48%;熔点:75-76℃.1H NMR(400MHz,CDCl3)δ7.35(d,J=7.6Hz,1H),7.19–7.14(m,1H),7.13–7.05(m,3H),6.99–6.93(m,1H),6.91–6.83(m,2H),6.56(d,J=8.0Hz,1H),6.27(d,J=6.0Hz,1H),6.12–6.05(m,1H),3.83(s,3H),3.60(s,3H);13C NMR(100MHz,CDCl3)δ165.3,165.1,141.8,141.1,137.7,133.2,131.0,128.8,128.4,127.9,127.7,127.1,127.1,125.2,122.7,122.6,118.0,116.7,58.8,53.0,52.7;ESI-HRMS m/z calcd for C21H17NO4S+H+380.0951,found 380.0957.
产物Ⅰ-14为黄色固体,产率为42%;熔点:92-93℃.1H NMR(400MHz,CDCl3)δ7.23(s,1H),7.07(s,1H),6.72(d,J=6.0Hz,1H),6.24(dd,J=9.6,5.6Hz,1H),5.75(d,J=7.2Hz,1H),5.50–5.43(m,1H),5.24–5.18(m,1H),3.80(s,3H),3.78(s,3H),2.25(s,3H),2.23(s,3H);13C NMR(100MHz,CDCl3)δ165.6,165.3,145.2,139.2,137.4,136.9,133.2,131.5,128.9,126.8,124.2,116.9,105.5,103.9,55.8,53.0,52.7,19.7,19.3;ESI-HRMSm/z calcd for C19H19NO4S+H+358.1108,found 358.1110.
产物Ⅰ-15为黄色固体,产率为35%;熔点:130-131℃.1H NMR(400MHz,CDCl3)δ7.30(dd,J=9.6,7.6Hz,1H),7.15(dd,J=10.4,8.0Hz,1H),6.67(d,J=6.0Hz,1H),6.29(dd,J=9.5,5.6Hz,1H),5.78(d,J=7.6Hz,1H),5.52–5.42(m,1H),5.28–5.22(m,1H),3.82(s,3H),3.78(s,3H);13C NMR(100MHz,CDCl3)δ165.2,164.8,149.8(dd,J=251.3,4.2Hz),148.5(dd,J=251.4,4.9Hz),145.4,139.1(t,J=4.1Hz),130.9(dd,J=6.2,4.2Hz),126.8,125.0,121.5(d,J=18.8Hz),117.4(d,J=19.1Hz),116.2,105.8,103.3,55.1,53.2,52.9;ESI-HRMS m/z calcd for C17H13F2NO4S+H+366.0606,found 366.0609.
产物Ⅰ-16为黄色固体,产率为48%;熔点:91-92℃.1H NMR(400MHz,CDCl3)δ6.94(s,1H),6.88(s,1H),6.80(d,J=6.0Hz,1H),6.24(dd,J=9.6,5.6Hz,1H),6.00–5.93(m,2H),5.78–5.73(m,1H),5.48–5.41(m,1H),5.23–5.17(m,1H),3.80(s,3H),3.77(s,3H);13CNMR(100MHz,CDCl3)δ165.4,165.1,148.0,147.1,145.3,136.8,126.8,126.5,124.5,117.0,112.8,108.6,105.5,103.4,101.5,55.4,53.1,52.7;ESI-HRMS m/z calcd forC18H15NO6S+H+374.0693,found 374.0695.
产物Ⅰ-17为黄色固体,产率为51%;熔点:68-69℃.1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.20(s,1H),6.79(d,J=6.0Hz,1H),6.24(dd,J=9.6,5.6Hz,1H),5.75(d,J=7.6Hz,1H),5.50–5.43(m,1H),5.24–5.19(m,1H),3.80(s,3H),3.78(s,3H),2.95–2.83(m,4H),2.12–2.02(m,2H);13C NMR(100MHz,CDCl3)δ165.6,165.3,145.2,145.0,144.8,139.5,132.1,128.3,126.7,124.2,123.7,117.1,105.5,103.7,55.8,53.0,52.7,32.8,32.6,25.3;ESI-HRMS m/z calcd for C20H19NO4S+H+370.1108,found 370.1111.
产物Ⅰ-18为黄色固体,产率为43%;熔点:121-122℃.1H NMR(400MHz,CDCl3)δ7.99(s,1H),7.84–7.80(m,1H),7.78–7.75(m,1H),7.73(s,1H),7.54–7.47(m,2H),6.86(d,J=5.6Hz,1H),6.36(dd,J=9.2,5.6Hz,1H),5.75–5.70(m,1H),5.62–5.55(m,1H),5.31–5.25(m,1H),3.82(s,3H),3.82(s,3H);13C NMR(100MHz,CDCl3)δ165.5,165.2,145.1,136.2,133.1,132.9,132.8,131.8,128.1,127.5,127.4,127.1,126.9,126.5,124.7,116.8,106.2,104.7,55.9,53.1,52.8;ESI-HRMS m/z calcd for C21H17NO4S+H+380.0951,found380.0957.
最后应说明的是:以上所述仅为本发明的优选实施例而已,并不用于限制本发明,尽管参照前述实施例对本发明进行了详细的说明,对于本领域的技术人员来说,其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换。凡在本发明的内容和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (4)
1.12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓,其特征在于,结构式如Ⅰ所示,七元环含有氮硫两个杂原子的同时,还含有多个不同种类的取代基;
其中:R1为氢、2,3-二甲基、苯环、2,3-二氧杂环、2,3-环戊烷、2,3-二氟;
R2为11-甲基或9,10苯环稠和取代;
R3为甲酯、乙酯、叔丁酯、三氟甲基、苯甲酰基;
R4为甲酯、乙酯、苯甲酰基、4-甲氧基苯甲酰基、4-甲基苯甲酰基、4-溴苯甲酰基、4-硝基苯甲酰基、呋喃甲酰基。
2.根据权利要求1所述的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓的制备方法,其特征在于,如下所示:
目标化合物Ⅰ的制备方法:将通式Ⅱ所示化合物、通式Ⅲ所示化合物、氟化钾和18-冠-6在室温条件下溶解于乙腈溶剂中,反应物Ⅱ反应完全后,将反应混合物在减压条件下除去有机溶剂,柱层析洗脱得到目标化合物Ⅰ;
反应物Ⅱ中:R1为氢、2,3-二甲基、苯环、2,3-二氧杂环、2,3-环戊烷、2,3-二氟;
反应物Ⅲ中:R2为11-甲基或9,10苯环稠和取代;R3为甲酯、乙酯、叔丁酯、三氟甲基、苯甲酰基;R4为甲酯、乙酯、苯甲酰基、4-甲氧基苯甲酰基、4-甲基苯甲酰基、4-溴苯甲酰基、4-硝基苯甲酰基、呋喃甲酰基。
3.根据权利要求2所述的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓的制备方法,其特征在于,化合物Ⅱ、化合物Ⅲ、氟化钾和18-冠-6的摩尔比1.0:1.5:2.0:2.0,乙腈溶液浓度为0.1M。
4.根据权利要求2所述的12a氢-苯并[f]吡啶[1,2-d][1,4]硫氮卓的制备方法,其特征在于,柱层析洗脱的硅胶柱层析,所用的洗脱液为石油醚与乙酸乙酯的混合溶剂,且体积比V石油醚:V乙酸乙酯=10:1~5:1。
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