本发明涉及有机合成领域。具体涉及一种5-磺酰氧基-8-酰胺基喹啉衍生物的制备方法，尤其涉及以8-乙酰氨基喹啉为原料制备5-磺酰氧基-8-乙酰氨基喹啉的方法。
背景技术：
喹啉环是多种天然产物的母核结构，其衍生物具有多种生物活性。文献(j.med.chem.2010,53,8228–8240和bioorg.med.chem.lett.2010,20,7092–7096)报道了其作为重要中间体用于制备5-ht1受体拮抗剂类活性分子，文献(j.med.chem.2011,54,2127–2142)也报道了其作为合成c-met抑制剂的关键中间体。
文献报道的5-磺酰氧基喹啉衍生物的合成均采用5-羟基喹啉衍生物为起始原料。如文献(bioorg.med.chem.2008,16,6707–6723)和(jmedchem,2011,54,2127-2142)均以5-羟基喹啉为原料，在三乙胺存在下分别与苯磺酸酐或苯磺酰氯反应制得5-苯磺酰氧基喹啉化合物。但起始原料5-羟基喹啉衍生物的价格昂贵且不易得。文献(bioorg.andmed.chem.lett.2016,26,3307-3312)以5-氨基喹啉原料，经过重氮化-水解制得5-羟基喹啉，该反应的原料5-氨基喹啉价格较贵，反应不易控制，收率较低(56％)；文献(angew.chem.2017,129,4549-4553)以5-溴喹啉为原料，在c44h62no4ppds催化下反应而得，其中5-溴喹啉的原料价格较贵，催化剂无商品供应；文献(heterocycles,2001,54,105-108)3-氨基苯酚为原料，经过磺酰基保护、迈克尔加成和环合、脱保护获得5-羟基喹啉，虽然3-氨基苯酚价廉易得，但反应步骤多，总收率不足10％，“三废”较多，不利于环境保护。
技术实现要素：
本发明公开了一种5-磺酰氧基-8-酰胺基喹啉衍生物(i)的制备方法，该方法以8-酰胺基喹啉及其衍生物为原料，利用8-乙酰氨基为导向基团，选择性地在喹啉5位直接引入磺酰氧基。具体包括：
其中r1、r2为c1～c6烷基、
r3、r4为h、f、cl、br、ch3或och3。
其中氧化剂优选三氟醋酸碘苯或醋酸碘苯。更优选的氧化剂为三氟醋酸碘苯。
反应溶剂优选自甲苯、氯苯、四氢呋喃、1,4-二氧六环、乙二醇二甲醚中的一种或两种的混合溶剂。更优选的反应溶剂为四氢呋喃、氯苯或1,4-二氧六环。
反应式中ii、iii、氧化剂的投料摩尔比优选为1:1～2:2～6。
ii、iii、氧化剂更优选的投料摩尔比为1:1～1.1:3～3.3。
本发明的制备方法，其中反应温度优选0℃～130℃；更优选为20℃～80℃。
本发明的制备方法与文献相比，具有原料价廉易得、底物适应范围广、产率高等优点。
具体实施方式
实施例1
5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制备
250ml四口烧瓶中加入四氢呋喃(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺酰基)肼(iii-1)(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)，室温搅拌反应1小时，过滤，用二氯甲烷洗涤滤饼，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体2.78g，产率78％，m.p.163-167℃。1hnmr(300mhz,cdcl3)δ(ppm):9.78(s,1h),8.85(d,j＝2.8hz,1h),8.65(d,j＝8.6hz,1h),8.44(d,j＝8.4hz,1h),7.79(d,j＝8.1hz,2h),7.53(dd,j＝8.4,4.2hz,1h),7.36(d,j＝7.9hz,2h),7.01(d,j＝8.6hz,1h),2.49(s,3h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.27,148.29,145.29,138.95,133.31,131.67,130.84,129.44,128.14,126.77,122.41,121.60,119.31,114.62,24.52,21.20。
实施例2
5-(4-叔丁基苯磺酰氧基)-8-乙酰胺基喹啉(i-2)的制备
250ml四口烧瓶中加入四氢呋喃(100ml)、ii-1(1.86,0.01mol)、n,n’-二(4-叔丁基苯磺酰基)肼(iii-2)(4.66g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)，室温搅拌反应1小时，过滤，用二氯甲烷洗涤滤饼，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体2.71g，产率68％，m.p.142-145℃。1hnmr(300mhz,cdcl3)δ(ppm):9.74(s,1h),8.81(s,1h),8.66(d,j＝8.4hz,1h),8.33(d,j＝8.5hz,1h),7.81(d,j＝7.1hz,2h),7.55(d,j＝7.1hz,2h),7.47(s,1h),7.08(d,j＝7.5hz,1h),2.37(s,3h),1.36(s,9h)；13cnmr(75mhz,cdcl3)δ(ppm):168.26,158.30,148.20,138.91,137.83,133.30,131.59,130.74,127.95,125.82,122.38,121.49,119.46,114.70,34.87,30.48,24.52。
实施例3
5-苯磺酰氧基-8-乙酰胺基喹啉(i-3)的制备
以ii-1(1.86g,0.01mol)、n,n’-二苯磺酰基肼(iii-3)(3.43g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)为原料。操作同实施例1，得白色固体2.46g，产率72％，m.p.165-168℃。1hnmr(300mhz,cdcl3)δ(ppm):9.77(s,1h),8.85(d,j＝4.3hz,1h),8.67(d,j＝8.6hz,1h),8.39(d,j＝8.4hz,1h),7.92(d,j＝7.3hz,2h),7.72(t,j＝7.4hz,1h),7.60–7.48(m,3h),7.04(d,j＝8.6hz,1h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.33,148.33,138.34,137.61,134.49,134.07,130.67,128.86,128.10,122.29,121.67,119.40,119.30,114.59,24.58。
实施例4
5-(4-氯苯磺酰氧基)-8-乙酰胺基喹啉(i-4)的制备
以ii-1(1.86g,0.01mol)、n,n’-二(4-氯苯磺酰基)肼(iii-4)(4.19g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)为原料，操作同实施例1，得白色固体2.45g，产率65％，m.p.151-154℃。1hnmr(300mhz,cdcl3)δ(ppm):9.77(s,1h),8.87(d,j＝4.2hz,1h),8.68(d,j＝8.6hz,1h),8.38(d,j＝8.5hz,1h),7.85(d,j＝8.6hz,2h),7.54(dd,j＝8.5,4.2hz,3h),7.07(d,j＝8.6hz,1h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.35,148.39,140.95,138.64,137.80,133.55,133.06,130.65,129.50,129.24,122.22,121.78,119.37,114.67,24.57。
实施例5
5-(4-氟苯磺酰氧基)-8-乙酰胺基喹啉(i-5)的制备
以ii-1(1.86g,0.01mol)、n,n’-二(4-氟苯磺酰基)肼(iii-5)(3.83g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料。操作同实施例1，得白色固体2.27g，产率63％，m.p.120-122℃。1hnmr(300mhz,cdcl3)δ(ppm):9.76(s,1h),8.85(d,j＝3.5hz,1h),8.68(d,j＝8.6hz,1h),8.36(d,j＝8.4hz,1h),7.93(dd,j＝8.4,5.0hz,2h),7.52(dd,j＝8.4,4.2hz,1h),7.24(t,j＝8.4hz,2h),7.08(d,j＝8.6hz,1h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.26,148.37,138.69,133.55,132.83,131.06,130.93,130.57,122.21,121.70,119.37,116.41,116.11,114.62,24.51。
实施例6
5-(4-硝基苯磺酰氧基)-8-乙酰胺基喹啉(i-6)的制备
以ii-1(1.86g,0.01mol)、n,n’-二(4-硝基苯磺酰基)肼(iii-6)(4.42g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得淡黄色固体1.51g，产率39％，m.p.143-147℃。1hnmr(300mhz,cdcl3)δ(ppm):9.80(s,1h),8.88(dd,j＝4.2,1.5hz,1h),8.86–8.80(m,1h),8.71(d,j＝8.7hz,1h),8.58(d,j＝8.3hz,1h),8.41(dd,j＝8.5,1.5hz,1h),8.23(d,j＝7.8hz,1h),7.81(t,j＝8.1hz,1h),7.57(dd,j＝8.5,4.3hz,1h),7.12(d,j＝8.7hz,1h),2.39(s,3h)。
实施例7
5-(3-硝基苯磺酰氧基)-8-乙酰胺基喹啉(i-7)的制备
以ii-1(1.86g,0.01mol)、n,n’-二(3-硝基苯磺酰基)肼(iii-7)(4.42g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得白色固体1.74g，产率45％，m.p.139-140℃。1hnmr(300mhz,cdcl3)δ(ppm):9.76(s,1h),8.94–8.85(m,1h),8.82(s,1h),8.69(d,j＝8.6hz,1h),8.57(d,j＝8.2hz,1h),8.39(dd,j＝8.5,1.2hz,1h),8.22(d,j＝8.0hz,1h),7.81(t,j＝8.1hz,1h),7.56(dd,j＝8.5,4.3hz,1h),7.12(d,j＝8.6hz,1h),2.37(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.38,148.47,137.74,136.88,133.77,133.37,132.67,130.55,130.33,128.39,127.87,123.23,122.53,121.92,119.38,114.84,24.48。
实施例8
5-(3-三氟甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-8)的制备
以ii-1(1.86g,0.01mol)、n,n’-二(3-三氟甲基苯磺酰基)肼(iii-8)(4.93g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得白色固体2.79g，产率68％，m.p.150-152℃。1hnmr(300mhz,cdcl3)δ(ppm):9.75(s,1h),8.92–8.79(m,1h),8.69(d,j＝8.6hz,1h),8.32(d,j＝8.5hz,1h),8.22(s,1h),8.07(d,j＝7.9hz,1h),7.97(d,j＝7.9hz,1h),7.71(t,j＝7.9hz,1h),7.50(dd,j＝8.5,4.2hz,1h),7.11(d,j＝8.6hz,1h),2.37(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.29,148.41,138.38,137.81,133.75,131.26,130.60,130.55,130.30,129.69,125.09,125.04,122.00,121.75,119.41,114.57,24.49。
实施例9
5-乙磺酰氧基-8-乙酰胺基喹啉(i-9)的制备
以ii-1(1.86g,0.01mol)、n,n’-二乙磺酰氧基肼(iii-9)(2.61g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得浅棕色固体1.71g，产率58％，m.p.85-88℃。1hnmr(300mhz,cdcl3)δ(ppm):9.81(s,1h),8.91(d,j＝2.8hz,1h),8.82(d,j＝8.6hz,1h),8.58(d,j＝8.5hz,1h),7.63(dd,j＝8.5,4.2hz,1h),7.52(d,j＝8.6hz,1h),3.49(q,j＝7.4hz,2h),2.40(s,3h),1.67(t,j＝7.4hz,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.39,148.44,138.14,137.96,133.42,130.85,122.43,121.93,119.27,114.94,45.15,24.61,7.91。
实施例10
5-[(萘-2-基)磺酰氧基]-8-乙酰胺基喹啉(i-10)的制备
以ii-1(1.86g,0.01mol)、n,n’-二[(萘-2-基)磺酰基]肼(iii-10)(4.53g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色固体2.55g，产率65％，m.p.154-157℃。1hnmr(300mhz,cdcl3)δ(ppm):9.72(s,1h),8.81(d,j＝3.1hz,1h),8.60(d,j＝8.6hz,1h),8.44(d,j＝8.7hz,2h),8.05–7.89(m,4h),7.81–7.64(m,2h),7.46(dd,j＝8.5,4.2hz,1h),7.02(d,j＝8.6hz,1h),2.35(s,3h).13cnmr(75mhz,cdcl3)δ(ppm):168.22,148.26,138.88,137.81,135.02,134.12,133.37,131.51,131.31,130.83,130.76,130.16,129.32,129.24,128.97,127.53,122.31,121.62,119.32,114.68,24.51。
实施例11
5-[(噻吩-2-基)磺酰氧基]-8-乙酰胺基喹啉(i-11)的制备
以ii-1(1.86g,0.01mol)、n,n’-二[(噻吩-2-基)磺酰基]肼(iii-11)(3.56g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得白色固体1.92g，产率55％，m.p.184-187℃。1hnmr(300mhz,cdcl3)δ(ppm):9.77(s,1h),8.85(d,j＝1.9hz,1h),8.70(d,j＝8.5hz,1h),8.39(d,j＝8.1hz,1h),7.75(d,j＝4.9hz,1h),7.65(d,j＝1.6hz,1h),7.51(dd,j＝7.6,3.4hz,1h),7.22–7.07(m,2h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.26,148.32,135.29,134.47,133.58,130.52,130.43,129.99,128.20,127.24,122.12,121.69,119.52,119.39,114.66,24.52。
实施例12
5-(4-甲基苯磺酰氧基)-8-丁酰胺基喹啉(i-12)的制备
以8-丁酰胺基喹啉(ii-2)(2.14g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色固体2.73g，产率71％，m.p.120-122℃。1hnmr(300mhz,cdcl3)δ(ppm):9.77(s,1h),8.85(d,j＝2.7hz,1h),8.67(d,j＝8.6hz,1h),8.48–8.32(m,1h),7.79(d,j＝8.2hz,2h),7.51(dd,j＝8.5,4.2hz,1h),7.35(d,j＝8.0hz,2h),7.00(d,j＝8.5hz,1h),2.57(t,j＝7.4hz,2h),2.49(s,3h),1.88(dd,j＝14.7,7.3hz,2h),1.09(t,j＝7.3hz,3h)；13cnmr(75mhz,cdcl3)δ(ppm):171.40,148.29,145.31,138.83,137.93,133.33,131.56,130.78,129.45,128.14,127.34,121.61,119.36,114.58,39.59,21.23,18.57,13.28。
实施例13
5-(4-甲基苯磺酰氧基)-8-异戊酰胺基喹啉(i-13)的制备
以8-异戊酰胺基喹啉(ii-3)(2.42g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色固体2.68g，产率65％，m.p.98-101℃。1hnmr(300mhz,cdcl3)δ(ppm):9.75(s,1h),8.84(d,j＝3.0hz,1h),8.66(d,j＝8.7hz,1h),8.38(d,j＝7.5hz,1h),7.92(d,j＝7.6hz,2h),7.71(t,j＝7.4hz,1h),7.61–7.46(m,3h),7.04(t,j＝4.2hz,1h),2.37(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):171.62,148.27,145.29,138.82,137.91,133.37,131.58,130.88,129.45,128.16,122.43,121.60,119.38,114.60,35.71,33.87,27.30,21.86,21.24。
实施例14
5-(4-甲基苯磺酰氧基)-8-苯甲酰胺基喹啉(i-14)的制备
以8-苯甲酰胺基喹啉(ii-4)(2.47g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色色固体2.17g，产率52％，m.p.176-179℃。1hnmr(300mhz,cdcl3)δ(ppm):10.69(s,1h),8.90(d,j＝3.5hz,1h),8.83(d,j＝8.6hz,1h),8.45(d,j＝8.4hz,1h),8.09(d,j＝6.9hz,2h),7.81(d,j＝8.0hz,2h),7.65–7.51(m,4h),7.37(d,j＝8.0hz,2h),7.07(d,j＝8.6hz,1h),2.50(s,3h)。
实施例15
4-甲基-5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-15)的制备
以4-甲基-8-乙酰胺基喹啉(ii-5)(2.00g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色固体2.67g，产率72％，m.p.188-190℃。1hnmr(300mhz,cdcl3)δ(ppm):9.94(s,1h),8.65(d,j＝4.4hz,1h),8.57(d,j＝8.7hz,1h),7.80(d,j＝8.3hz,2h),7.39(d,j＝8.1hz,2h),7.31(d,j＝4.8hz,1h),6.83(d,j＝8.6hz,1h),2.99(s,3h),2.51(s,3h),2.35(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.31,147.56,145.31,144.30,139.93,138.59,133.77,132.33,129.52,128.24,124.86,122.52,119.54,114.19,24.65,23.12,21.26。
实施例16
5-(4-甲基苯磺酰氧基)-6-甲氧基-8-乙酰胺基喹啉(i-16)的制备
以6-甲氧基-8-乙酰胺基喹啉(ii-6)(2.16g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)为原料，操作同实施例1，得类白色固体3.17g，产率82％，m.p.160-163℃。1hnmr(300mhz,cdcl3)δ9.85(s,1h),8.70(s,2h),8.45(d,j＝8.4hz,1h),7.86(d,j＝8.2hz,2h),7.50(dd,j＝8.5,4.2hz,1h),7.38(d,j＝8.0hz,2h),3.65(s,3h),2.51(s,3h),2.38(s,3h)；13cnmr(75mhz,cdcl3)δ(ppm):168.56,149.13,145.80,144.70,134.27,133.21,130.32,129.11,128.91,128.35,128.16,123.80,122.19,103.60,55.55,24.68,21.23。
实施例17
5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制备
250ml四口烧瓶中加入四氢呋喃(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺酰基)肼(iii-1)(3.70g,0.011mol)和醋酸碘苯(10.63g,0.033mol)，室温搅拌反应3小时，过滤，用二氯甲烷洗涤滤饼，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体1.50g，产率42％，m.p.164-167℃。
实施例18
5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制备
250ml四口烧瓶中加入氯苯(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺酰基)肼(iii-1)(3.70g,0.011mol)和三氟醋酸碘苯(10.63g,0.033mol)，回流反应3小时，过滤，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体1.25g，产率35％，m.p.163-167℃。
实施例19
5-乙磺酰氧基-8-乙酰胺基喹啉(i-9)的制备
250ml四口烧瓶中加入1,4-二氧六环(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二乙磺酰氧基肼(iii-9)(2.61g,0.011mmol)和三氟醋酸碘苯(10.63g,0.033mol)，室温反应3小时，过滤，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体2.49g，产率70％，m.p.163-167℃。
实施例20
5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制备
250ml四口烧瓶中加入四氢呋喃(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺酰基)肼(iii-1)(1.85g,0.005mol)和三氟醋酸碘苯(5.32g,0.017mol)，室温搅拌反应3小时，过滤，减压除去溶剂得粗品，柱层析(石油醚/乙酸乙酯为淋洗剂，梯度洗脱)得白色固体1.89g，产率53％，m.p.164-167℃。