本发明属于有机合成技术领域,具体涉及一种苯并噻嗪类化合物的制备方法。
背景技术
苯并噻嗪作为杂环化合物中重要的一类化合物具有一定的生理活性,经研究表明,此类杂环化合物及其衍生物可以作为抗结核药物(j.med.chem.2012,55,7940)、抗肿瘤药物(j.med.chem.2015,58,6678)以及hiv抑制剂(bioorg.med.chem.lett.2016,26,1738),鉴于苯并噻嗪类化合物的广泛生物活性和应用价值,发展一种实用有效地合成苯并噻嗪类化合物的新方法具有重要意义。
苯并噻嗪类化合物的制备方法有:
1)以邻碘苄胺、苯甲醛为原料
2)以酰胺为原料
fodor课题组以酰胺为原料,在三氯氧磷作用下加热,以中等收率制备得到苯并噻嗪类化合物(tetrahedron2012,68,851)。
利用上述方法在实验室中合成苯并噻嗪类化合物,具有明显的缺点和不足:1)需要氮气保护;2)需要金属或强酸催化;3)反应时间长。
技术实现要素:
为了克服上述现有技术的不足,本发明提供了一种苯并噻嗪类化合物的制备方法。
一种苯并噻嗪类化合物的制备方法,所述苯并噻嗪类化合物具有式ⅰ所示的结构:
式ⅰ中,其中r1选自氢、甲基、3,4-二甲氧基;r2选自2-噻吩基、二苯基膦酰基、三氟甲基、苯基、取代苯基,取代基为氯、三氟甲基,甲氧基、3,4-二甲氧基;r3选自苯基、甲基;其特征在于,向反应器中加入摩尔比为1:1的硫代酰胺与羟基甲苯磺酰碘苯,加入甲醇、乙醇、三氟乙醇、六氟异丙醇之一的溶剂,室温下搅拌反应,反应方程式如式ii:
本发明的有益效果为:本发明提供的苯并噻嗪类化合物的合成方法科学合理,提供了一种合成多种取代基苯并噻嗪类化合物的新途径;而且还具有原料易得、操作简单、反应条件温和、反应时间短等特点。
附图说明
图1为实施例1制备的化合物3a的nmr图谱;
图2为实施例7制备的化合物3g的nmr图谱;
图3为实施例10制备的化合物3j的nmr图谱。
具体实施方式
下面结合附图和具体的实施例对本发明进一步详细的说明:
下述实施例中所述试验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1
化合物3a的制备
将n-苄基苯并硫代酰胺(0.4mmol,91mg),羟基甲苯磺酰碘苯(0.4mmol,157mg),4.0ml六氟异丙醇加入到15ml厚壁耐压管中,室温下搅拌10分钟。反应完毕后,经柱层析分离(200-300目硅胶)(石油醚/乙酸乙酯=30/1)得到2-苯基-4,5-二氢-1,3-苯并噻嗪3a,分离产率74%。
谱图解析数据3a:
1hnmr(500mhz,cdcl3):δ8.00(d,j=7.3hz,2h),7.47-7.37(m,4h),7.33-7.27(m,3h),4.78(s,2h).13cnmr(125mhz,cdcl3):δ161.6(s,1c),136.9(s,1c),131.3(s,1c),131.1(s,1c),130.9(s,1c),128.5(s,2c),127.7(s,2c),127.5(s,2c),126.8(s,1c),126.6(s,1c),56.7(s,1c).
实施例2
用1b代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3b:
1hnmr(500mhz,cdcl3):δ7.95(d,j=8.5hz,2h),7.41-7.38(m,3h),7.34-7.29(m,3h),4.79(s,2h).13cnmr(125mhz,cdcl3):δ160.5(s,1c),137.3(s,1c),135.4(s,1c),131.2(s,1c),130.6(s,1c),129.0(s,2c),128.8(s,2c),127.6(s,2c),126.9(s,1c),126.6(s,1c),56.8(s,1c).hrms(esi-tof,[m+h]+):calcdforc14h11nscl,260.0301,found260.0307.
实施例3
用1c代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3c:
1hnmr(500mhz,cdcl3):δ8.12(d,j=8.2hz,2h),7.69(d,j=8.2hz,2h),7.41-7.39(m,1h),7.35-7.30(m,3h),4.83(s,2h).13cnmr(125mhz,cdcl3):δ160.4(s,1c),140.1(s,1c),132.7(q,j=32.6hz,1c),130.8(s,1c),130.3(s,1c),128.0(s,2c),127.8(s,1c),127.7(s,1c),126.9(s,1c),126.6(s,1c),125.5(s,2c),123.8(q,j=270.3hz,1c),56.9(s,1c).hrms(esi-tof,[m+h]+):calcdforc15h11f3ns,294.0564,found294.0571.
实施例4
用1d代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3d:
1hnmr(500mhz,cdcl3):δ7.98(d,j=8.6hz,2h),7.40-7.39(m,1h),7.34-7.28(m,3h),6.94(d,j=8.6hz,2h),4.76(s,2h),3.85(s,3h).13cnmr(125mhz,cdcl3):δ162.1(s,1c),161.0(s,1c),131.8(s,1c),131.2(s,1c),129.7(s,1c),129.4(s,2c),127.5(s,1c),127.4(s,1c),126.8(s,1c),126.6(s,1c),113.8(s,2c),56.6(s,1c),55.4(s,1c).hrms(esi-tof,[m+h]+):calcdforc15h14nos,256.0796,found256.0800.
实施例5
用1e代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3e:
1hnmr(500mhz,cdcl3):δ7.63(d,j=8.4hz,1h),7.59(s,1h),7.40-7.39(m,1h),7.32-7.28(m,3h),6.89(d,j=8.4hz,1h),4.76(s,2h),3.94(d,j=16.9hz,6h).13cnmr(125mhz,cdcl3):δ161.1(s,1c),151.7(s,1c),148.9(s,1c),131.8(s,1c),131.1(s,1c),129.8(s,1c),127.4(s,2c),126.8(s,1c),126.6(s,1c),121.4(s,1c),110.3(s,1c),110.0(s,1c),56.6(s,1c),55.9(s,2c).hrms(esi-tof,[m+h]+):calcdforc16h16no2s,286.0902,found286.0905.
实施例6
用1f代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3f:
1hnmr(500mhz,cdcl3):δ7.69(d,j=3.3hz,1h),7.45(d,j=4.7hz,1h),7.39-7.37(m,1h),7.32-7.28(m,3h),7.09-7.07(m,1h),4.74(s,2h).13cnmr(125mhz,cdcl3):δ155.4(s,1c),141.8(s,1c),132.0(s,1c),130.5(s,1c),129.8(s,1c),129.2(s,1c),128.3(s,1c),127.5(s,2c),127.0(s,1c),126.6(s,1c),56.2(s,1c).hrms(esi-tof,[m+h]+):calcdforc12h10ns2,232.0255,found232.0258.
实施例7
用1g代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3g:
1hnmr(500mhz,cdcl3):δ7.82-7.78(m,4h),7.57-7.53(m,2h),7.47-7.43(m,4h),7.34-7.30(m,1h),7.28-7.26(m,3h),4.78(d,j=2.8hz,2h).13cnmr(125mhz,cdcl3):δ165.2(d,j=128.7hz,1c),132.5(s,2c),132.0(s,2c),131.9(s,2c),130.1(d,j=105.7hz,2c),129.8(s,1c),129.2(s,1c),128.5(s,2c),128.4(s,2c),128.1(s,1c),127.9(s,1c),127.0(s,1c),126.5(s,1c),58.0(d,j=17.5hz,1c).hrms(esi-tof,[m+h]+):calcdforc20h17nops,350.0768,found350.0772.
实施例8
用1h代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3h:
1hnmr(500mhz,cdcl3):δ7.81-7.77(m,4h),7.55-7.53(m,2h),7.46-7.42(m,4h),7.16-7.12(m,1h),7.10-7.08(m,2h),4.74(d,j=2.5hz,2h),2.34(s,3h).13cnmr(125mhz,cdcl3):δ164.5(d,j=128.9hz,1c),138.2(s,2c),132.4(s,2c),132.0(s,2c),131.9(s,2c),130.2(d,j=105.5hz,1c),129.1(s,1c),128.7(s,1c),128.5(s,2c),128.4(s,2c),127.2(d,j=118.8hz,1c),126.2(s,2c),58.0(d,j=17.3hz,1c),21.0(s,1c).hrms(esi-tof,[m+h]+):calcdforc21h19nops,364.0925,found364.0923.
实施例9
用1i代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3i:
1hnmr(500mhz,cdcl3):δ7.78(dd,j=11.8,7.9hz,4h),7.54-7.52(m,2h),7.45-7.43(m,4h),6.74(d,j=8.6hz,2h),4.71(s,2h),3.84(d,j=25.2hz,6h).13cnmr(125mhz,cdcl3):δ165.5(d,j=128.9hz,1c),149.4(s,1c),148.9(s,1c),132.5(s,2c),132.0(s,2c),131.9(s,2c),130.3(d,j=105.7hz,2c),128.6(s,2c),128.5(s,2c),121.2(s,1c),120.8(s,1c),110.1(s,1c),109.2(s,1c),57.9(d,j=17.7hz,1c),56.1(s,2c).hrms(esi-tof,[m+na]+):calcdforc22h20no3psna,432.0799,found432.0794.
实施例10
用1j代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3j:
1hnmr(500mhz,cdcl3):δ7.38-7.30(m,4h),4.78(s,2h).13cnmr(125mhz,cdcl3):δ153.6(q,j=38.4hz,1c),129.0(s,1c),128.5(s,1c),128.2(s,1c),127.8(s,1c),127.4(s,1c),126.7(s,1c),118.9(q,j=277.4hz,1c),55.9(s,1c).hrms(esi-tof,[m+h]+):calcdforc9h7f3ns,218.0251,found218.0251.
实施例11
用1k代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3k:
1hnmr(500mhz,cdcl3):δ7.89(dd,j=11.7,7.8hz,2h),7.74(dd,j=12.0,7.7hz,2h),7.52(dd,j=17.1,8.1hz,2h),7.46-7.43(m,2h),7.41-7.35(m,6h),7.33-7.31(m,2h),7.29-7.23(m,2h),6.82(d,j=7.5hz,1h),5.41(d,j=3.1hz,1h).13cnmr(125mhz,cdcl3):δ164.6(d,j=127.5hz,1c),139.2(s,2c),132.4(s,1c),132.3(s,1c),132.2(s,1c),132.1(s,1c),132.0(s,1c),131.9(s,1c),130.6(d,j=105.5,1c),130.1(d,j=100.7,1c),128.5(s,6c),128.1(s,2c),127.6(s,2c),127.3(s,2c),126.5(s,2c),69.8(d,j=16.6hz,1c).hrms(esi-tof,[m+na]+):calcdforc26h20nopsna,448.0901,found448.0899.
实施例12
用1l代替实例1中的1a,其他条件同实例1,实验结果见表1。
谱图解析数据3l:
1hnmr(500mhz,cdcl3):7.87-7.78(m,4h),7.56-7.52(m,2h),7.47-7.42(m,4h),7.35-7.32(m,1h),7.28-7.23(m,3h),4.75-4.71(m,1h),1.64(d,j=6.9hz,3h).13cnmr(125mhz,cdcl3):162.7(d,j=130.2hz,1c),132.9(s,1c),132.4(s,2c),132.0(s,4c),130.6(d,j=105.3,1c),130.2(d,j=105.1,1c),129.0(s,1c),128.5(s,2c),128.4(s,2c),128.2(s,1c),127.4(s,1c),126.6(s,1c),125.7(s,1c),61.5(d,j=16.6hz,1c),18.0(s,1c).hrms(esi-tof,[m+h]+):calcdforc21h19nops,364.0925,found364.0927.
表1