本發明涉及有機合成領域。具體涉及一種5-磺酰氧基-8-酰胺基喹啉衍生物的制備方法，尤其涉及以8-乙酰氨基喹啉為原料制備5-磺酰氧基-8-乙酰氨基喹啉的方法。

背景技術：

喹啉環是多種天然產物的母核結構，其衍生物具有多種生物活性。文獻(j.med.chem.2010,53,8228–8240和bioorg.med.chem.lett.2010,20,7092–7096)報道了其作為重要中間體用于制備5-ht1受體拮抗劑類活性分子，文獻(j.med.chem.2011,54,2127–2142)也報道了其作為合成c-met抑制劑的關鍵中間體。

文獻報道的5-磺酰氧基喹啉衍生物的合成均采用5-羥基喹啉衍生物為起始原料。如文獻(bioorg.med.chem.2008,16,6707–6723)和(jmedchem,2011,54,2127-2142)均以5-羥基喹啉為原料，在三乙胺存在下分別與苯磺酸酐或苯磺酰氯反應制得5-苯磺酰氧基喹啉化合物。但起始原料5-羥基喹啉衍生物的價格昂貴且不易得。文獻(bioorg.andmed.chem.lett.2016,26,3307-3312)以5-氨基喹啉原料，經過重氮化-水解制得5-羥基喹啉，該反應的原料5-氨基喹啉價格較貴，反應不易控制，收率較低(56％)；文獻(angew.chem.2017,129,4549-4553)以5-溴喹啉為原料，在c44h62no4ppds催化下反應而得，其中5-溴喹啉的原料價格較貴，催化劑無商品供應；文獻(heterocycles,2001,54,105-108)3-氨基苯酚為原料，經過磺酰基保護、邁克爾加成和環合、脫保護獲得5-羥基喹啉，雖然3-氨基苯酚價廉易得，但反應步驟多，總收率不足10％，“三廢”較多，不利于環境保護。

技術實現要素：

本發明公開了一種5-磺酰氧基-8-酰胺基喹啉衍生物(i)的制備方法，該方法以8-酰胺基喹啉及其衍生物為原料，利用8-乙酰氨基為導向基團，選擇性地在喹啉5位直接引入磺酰氧基。具體包括：

其中r¹、r²為c1～c6烷基、r⁵為h、f、cl、br、ch3、cf3、och3、no2或cn。

r³、r⁴為h、f、cl、br、ch3或och3。

其中氧化劑優選三氟醋酸碘苯或醋酸碘苯。更優選的氧化劑為三氟醋酸碘苯。

反應溶劑優選自甲苯、氯苯、四氫呋喃、1,4-二氧六環、乙二醇二甲醚中的一種或兩種的混合溶劑。更優選的反應溶劑為四氫呋喃、氯苯或1,4-二氧六環。

反應式中ii、iii、氧化劑的投料摩爾比優選為1:1～2:2～6。

ii、iii、氧化劑更優選的投料摩爾比為1:1～1.1:3～3.3。

本發明的制備方法，其中反應溫度優選0℃～130℃；更優選為20℃～80℃。

本發明的制備方法與文獻相比，具有原料價廉易得、底物適應范圍廣、產率高等優點。

具體實施方式

實施例1

5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制備

250ml四口燒瓶中加入四氫呋喃(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺?；?肼(iii-1)(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)，室溫攪拌反應1小時，過濾，用二氯甲烷洗滌濾餅，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體2.78g，產率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。

實施例2

5-(4-叔丁基苯磺酰氧基)-8-乙酰胺基喹啉(i-2)的制備

250ml四口燒瓶中加入四氫呋喃(100ml)、ii-1(1.86,0.01mol)、n,n’-二(4-叔丁基苯磺?；?肼(iii-2)(4.66g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)，室溫攪拌反應1小時，過濾，用二氯甲烷洗滌濾餅，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體2.71g，產率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。

實施例3

5-苯磺酰氧基-8-乙酰胺基喹啉(i-3)的制備

以ii-1(1.86g,0.01mol)、n,n’-二苯磺?；?iii-3)(3.43g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)為原料。操作同實施例1，得白色固體2.46g，產率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。

實施例4

5-(4-氯苯磺酰氧基)-8-乙酰胺基喹啉(i-4)的制備

以ii-1(1.86g,0.01mol)、n,n’-二(4-氯苯磺?；?肼(iii-4)(4.19g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mmol)為原料，操作同實施例1，得白色固體2.45g，產率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。

實施例5

5-(4-氟苯磺酰氧基)-8-乙酰胺基喹啉(i-5)的制備

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)為原料。操作同實施例1，得白色固體2.27g，產率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。

實施例6

5-(4-硝基苯磺酰氧基)-8-乙酰胺基喹啉(i-6)的制備

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)為原料，操作同實施例1，得淡黃色固體1.51g，產率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)。

實施例7

5-(3-硝基苯磺酰氧基)-8-乙酰胺基喹啉(i-7)的制備

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)為原料，操作同實施例1，得白色固體1.74g，產率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。

實施例8

5-(3-三氟甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-8)的制備

以ii-1(1.86g,0.01mol)、n,n’-二(3-三氟甲基苯磺?；?肼(iii-8)(4.93g,0.011mmol)和三氟醋酸碘苯(14.2g,0.033mol)為原料，操作同實施例1，得白色固體2.79g，產率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。

實施例9

5-乙磺酰氧基-8-乙酰胺基喹啉(i-9)的制備

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)為原料，操作同實施例1，得淺棕色固體1.71g，產率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。

實施例10

5-[(萘-2-基)磺酰氧基]-8-乙酰胺基喹啉(i-10)的制備

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)為原料，操作同實施例1，得類白色固體2.55g，產率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。

實施例11

5-[(噻吩-2-基)磺酰氧基]-8-乙酰胺基喹啉(i-11)的制備

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)為原料，操作同實施例1，得白色固體1.92g，產率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。

實施例12

5-(4-甲基苯磺酰氧基)-8-丁酰胺基喹啉(i-12)的制備

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)為原料，操作同實施例1，得類白色固體2.73g，產率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。

實施例13

5-(4-甲基苯磺酰氧基)-8-異戊酰胺基喹啉(i-13)的制備

以8-異戊酰胺基喹啉(ii-3)(2.42g,0.01mol)、iii-1(3.70g,0.011mol)和三氟醋酸碘苯(14.2g,0.033mol)為原料，操作同實施例1，得類白色固體2.68g，產率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。

實施例14

5-(4-甲基苯磺酰氧基)-8-苯甲酰胺基喹啉(i-14)的制備

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)為原料，操作同實施例1，得類白色色固體2.17g，產率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)。

實施例15

4-甲基-5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-15)的制備

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)為原料，操作同實施例1，得類白色固體2.67g，產率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。

實施例16

5-(4-甲基苯磺酰氧基)-6-甲氧基-8-乙酰胺基喹啉(i-16)的制備

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)為原料，操作同實施例1，得類白色固體3.17g，產率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。

實施例17

5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制備

250ml四口燒瓶中加入四氫呋喃(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺?；?肼(iii-1)(3.70g,0.011mol)和醋酸碘苯(10.63g,0.033mol)，室溫攪拌反應3小時，過濾，用二氯甲烷洗滌濾餅，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體1.50g，產率42％，m.p.164-167℃。

實施例18

5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制備

250ml四口燒瓶中加入氯苯(100ml)、8-乙酰胺基喹啉(ii-1)(1.86g,0.01mol)、n,n’-二(4-甲基苯磺?；?肼(iii-1)(3.70g,0.011mol)和三氟醋酸碘苯(10.63g,0.033mol)，回流反應3小時，過濾，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體1.25g，產率35％，m.p.163-167℃。

實施例19

5-乙磺酰氧基-8-乙酰胺基喹啉(i-9)的制備

250ml四口燒瓶中加入1,4-二氧六環(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)，室溫反應3小時，過濾，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體2.49g，產率70％，m.p.163-167℃。

實施例20

5-(4-甲基苯磺酰氧基)-8-乙酰胺基喹啉(i-1)的制備

250ml四口燒瓶中加入四氫呋喃(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)，室溫攪拌反應3小時，過濾，減壓除去溶劑得粗品，柱層析(石油醚/乙酸乙酯為淋洗劑，梯度洗脫)得白色固體1.89g，產率53％，m.p.164-167℃。