CN107033104B - 一种手性噻嗪类化合物的不对称合成方法 - Google Patents

一种手性噻嗪类化合物的不对称合成方法 Download PDF

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CN107033104B
CN107033104B CN201710344224.8A CN201710344224A CN107033104B CN 107033104 B CN107033104 B CN 107033104B CN 201710344224 A CN201710344224 A CN 201710344224A CN 107033104 B CN107033104 B CN 107033104B
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周海峰
隋月波
崔鹏
刘森生
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China Three Gorges University CTGU
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    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
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    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
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    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3

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Abstract

本发明涉及一种手性噻嗪类化合物的不对称合成方法。该方法以含环戊二烯骨架的手性布朗斯特酸为催化剂，以邻氨基苯磺酰胺和醛为反应物，经过缩合、不对称加成反应得到手性噻嗪类化合物。该方法在合成手性噻嗪类利尿药物方面具有重要的应用前景。

Description

一种手性噻嗪类化合物的不对称合成方法
技术领域
本发明属于不对称合成领域，具体涉及一种手性噻嗪类化合物的不对称合成方法。
背景技术
噻嗪类化合物是常用的中效利尿药物，该类药物主要作用为利尿与降压作用。Guidotti 研究组通过手性拆分的方法得到手性噻嗪类化合物，动物实验研究结果表明右旋对映异构体的活性高于左旋对映异构体(J.Pharm.Sci.1995,84,937)。但目前市场上的噻嗪类利尿药物如环戊噻二嗪,贝美噻二嗪，氟苄噻二嗪等近20种均为外消旋体。研究手性噻嗪类化合物的不对称合成，为合成手性噻嗪类药物提供适用的方法具有重要意义。
关于手性噻嗪类化合物的不对称合成，到目前为止只有两例子报道：(1)以手性磷酸为催化剂，邻氨基苯磺酰胺与相应的醛为反应物，在室温下反应7天，得到手性噻嗪类化合物，对映选择性可以达到92％(J.Am.Chem.Soc.2008,112,6104)。但该方法使用邻位带较大位阻的手性磷酸(BINOL-PA)为催化剂(合成繁琐，成本高)，而且反应时间长，不具有应用价值。(2)本研究小组报道以手性噁唑配体与三氟甲磺酸钪的络合物为催化剂，以邻氨基苯磺酰胺和醛为反应物，经过缩合、不对称加成反应得到手性噻嗪类化合物，对映选择性可以达到92％(Tetrahedron,2016,72,1573)。
发明内容
本发明的目的在于提供一种手性噻嗪类化合物的不对称合成新方法。本发明所述的手性噻嗪类化合物，结构式如下：
所述的X1、X2、X3、X4为氢、卤素、氨基、硝基、氰基、羟基、巯基、三氟甲基，酰胺基，C1—C6烷基、C1—C6卤代烷基、C3—C8环烷基、C1—C6烷基氧基、C1—C6烷基氨基、甲酸C1—C6烷基酯基中的任意一种。
R1、R2、R3基团为氢、C1～C40内的脂肪基团或C6～C60内的芳香基团。
所述的C1～C40内的脂肪基团包括甲基、乙基、丙基、异丙基、丁基、苄基或卤素取代的烷基基团；所述的C6～C60内的芳香基团包括苯基，各类取代的苯基，1-萘基，2-萘基，或烷氧基、磺酰基、磺酰胺基、羟基、硝基、氨基、氟、氯、溴、碘。
本发明还提供一种手性噻嗪类化合物的不对称的合成方法，该方法以含环戊二烯骨架的手性布朗斯特酸为催化剂，以邻氨基苯磺酰胺和醛为反应物，经过缩合、不对称加成得到手性噻嗪类化合物，具体反应方程式如下：
所述溶剂为硝基甲烷、甲苯、1,4-二氧六环、乙腈、二氯甲烷、三氯甲烷、1,2-二氯乙烷、乙醚、乙二醇二甲醚、甲基叔丁基醚、四氢呋喃、N,N-二甲基甲酰胺、二甲基亚砜、乙醇、异丙醇、水、乙酸乙酯、三氟甲苯、苯、甲醇、环己烷、正己烷的单一溶剂或者混合物。
所述的手性噻嗪类化合物的不对称合成方法，所述催化剂为含环戊二烯骨架手性布朗斯特酸为催化剂，其结构示例如下(不局限于下列的手性胺或手性醇)：
本发明所提供的手性噻嗪类化合物不对称合成反应条件为：邻氨基苯磺酰胺：醛：催化剂的摩尔比为：10-100:10-100:1，反应物浓度：0.1-2.0mol/L，反应温度-78～20℃，反应时间 1-72小时。
本发明为手性噻嗪类化合物的不对称合成提供一种新方法。与已报到的手性磷酸催化剂体系相比，具有如下优点：催化剂廉价易得，可规模化生产，反应时间短，更适合工业化的应用，在手性噻嗪类利尿药物的合成中具有应用前景。
具体实施方法
下面结合具体实施例，对本发明作进一步说明，但本发明并不限于以下实施例。
3-异丁基-3,4-二氢-2H-1,2,4-苯并噻二嗪-1,1-二氧化物的不对称合成(实施例1-3)
实施例1：
在氮气保护下，往Schlenk试管中依次加入PCCP 1(3.9mg,0.004mmol)，邻氨基苯磺酰胺(34.4mg,0.2mmol)，异戊醛(20.7mg,0.24mmol)，70mg分子筛和1ml Tol，-20℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物46.6mg，产率97％，ee值98％。1HNMR(400MHz,DMSO)δ＝7.46(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.40(d,J＝11.2Hz,1H), 7.31-7.27(m,1H),6.97(s,1H),6.82(d,J＝8.0Hz,1H),6.71(dt,J1＝8.0Hz,J2＝0.4Hz,1H),4.71(s,1H),1.92-1.85(m,1H),1.73-1.66(m,1H),1.62-1.55(m,1H),0.96-0.93(m,6H)；13CNMR(100MHz,DMSO)δ＝144.25,133.16,124.20,121.77,116.74,116.45,64.55,42.54,23.91, 23.18,22.34.
实施例2：
在氮气保护下，往Schlenk试管中依次加入PCCP 2(3.5mg,0.004mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，异戊醛(20.7mg,0.24mmol)，70mg分子筛和1ml Tol，-20℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物45.1mg，产率94％，ee值96％。
实施例3：
在氮气保护下，往Schlenk试管中依次加入PCCP3(3.2mg,0.004mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，异戊醛(20.7mg,0.24mmol)，70mg分子筛和1ml Tol，-20℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物43.2mg，产率90％，ee值89％。
实施例4：3-异丙基-3,4-二氢-2H-1,2,4-苯并噻二嗪-1,1-二氧化物的不对称合成
在氮气保护下，往Schlenk试管中依次加入PCCP 1(3.9mg,0.004mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，异丁醛(17.3mg,0.24mmol)，70mg分子筛和1ml Tol，-20℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物41mg，产率91％，ee值93％。1H NMR(400MHz,CDCl3)δ＝7.66(d,J＝7.2Hz,1H),7.32-7.28(m,1H),6.88-6.84(m,1H), 6.70(d,J＝8.4Hz,1H),4.78(dd,J1＝13.6Hz,J2＝5.2Hz,1H),4.41(s,1H),4.23(d,J＝13.2Hz,1H),2.06-1.98(m,1H),1.12(t,J＝7.6Hz,6H)；13C NMR(100MHz,CDCl3)δ＝142.62,133.31,124.88,122.68,118.96,116.19,70.55,32.11,17.64,16.63.
实施例5：3-新戊基-3,4-二氢-2H-1,2,4-苯并噻二嗪-1,1-二氧化物的不对称合成
在氮气保护下，往Schlenk试管中依次加入PCCP 1(3.9mg,0.004mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，3,3-二甲基丁醛(24mg,0.24mmol)，70mg分子筛和1ml Tol，-20℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物33mg，产率65％，ee值94％。1H NMR(400MHz,DMSO)δ＝7.45(s,1H),7.42(d,J＝3.2Hz,1H),7.29-7.25(m,1H),6.93(s,1H),6.77(d,J＝8.4Hz,1H),6.69(t,J＝7.2Hz,1H),4.75(t,J＝9.6Hz,1H),1.75(dd,J1＝14.4Hz,J2＝9.2Hz,1H),1.6(dd,J1＝14Hz,J1＝2.0Hz,1H),0.97(s,9H)；13C NMR(100MHz, DMSO)δ＝144.17,133.18,124.21,121.45,116.72,116.43,64.09,46.89,30.24,30.20.
实施例6：3-环己基-3,4-二氢-2H-1,2,4-苯并噻二嗪-1,1-二氧化物的不对称合成
在氮气保护下，往Schlenk试管中依次加入PCCP1(3.9mg,0.004mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，环己基甲醛(66mg,0.5mmol)，70mg分子筛和1ml Tol，-40℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物49.5mg，产率93％，ee值87％。1HNMR(400MHz,CDCl3)δ＝7.68(d,J＝7.6Hz,1H),7.46-7.31(m,1H),6.91-6.87(m,1H), 6.72(d,J＝8.0Hz,1H),4.80(dd,J1＝13.2Hz,J2＝5.2Hz,1H),4.51(s,1H),4.33(d,J＝13.2Hz,1H),1.91-1.74(m,6H),1.38-1.15(m,5H)；13C NMR(100MHz,CDCl3)δ＝142.69,133.32,124.89,122.73,118.91,116.27,70.09,41.70,28.16,27.31,26.08,25.71,25.68.
实施例7：3-苯乙基-3,4-二氢-2H-1,2,4-苯并噻二嗪-1,1-二氧化物的不对称合成
在氮气保护下，往Schlenk试管中依次加入PCCP 1(9.8mg,0.01mmol),邻氨基苯磺酰胺(34.4mg,0.2mmol)，苯丙醛(68.6mg,0.5mmol)，70mg分子筛和1ml Tol，-40℃下反应24小时，经硅胶柱层析分离，得白色固体目标化合物37.5mg，产率65％，ee值93％。1HNMR(400MHz,CDCl3)δ＝7.65(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.45-7.38(m,3H), 7.34-7.26(m,3H),6.87(dt,J1＝8.0Hz,J2＝0.8Hz,1H),6.63(d,J＝8.4Hz,1H),5.28-5.23(m, 1H),4.52(d,J＝12.8Hz,2H),3.31(dd,J1＝14.0Hz,J2＝4.0Hz,1H),2.99(dd,J1＝14.0Hz,J2＝8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝142.38,133.88,133.36,129.56,129.32,127.94,124.73,122.43,119.11,116.42,66.05,40.90.
实施例8:利尿降压药异丁噻嗪的不对称合成
在氮气保护下，往Schlenk试管中依次加入PCCP 1(9.8mg,0.01mmol),4-氨基-6-氯 -1,3-苯二磺酰胺(57mg,0.2mmol)，异戊醛(43mg,0.5mmol)，70mg分子筛和1ml Tol，20℃下反应70小时，经硅胶柱层析分离，得白色固体目标化合物46.6mg，产率72％，ee值93％。1H NMR(400MHz,CD3OD)δ＝7.86(s,1H),7.75(s,1H),7.70(d,J＝12.0Hz,1H),7.39(s,1H),6.90(s,1H),4.73-4.67(m,1H),4.24(d,J＝13Hz,1H),1.83-1.74(m,1H),1.67-1.62(m,1H), 1.54-1.49(m,1H),0.86(t,J＝6.3Hz,6H)；13C NMR(100MHz,CD3OD)δ＝146.8,134.2,128.3, 125.7,118.5,117.3,117.1,64.8,64.7,42.0,23.8,23.0,22.1。

Claims (1)

1.一种手性噻嗪类化合物的不对称的合成方法，其特征在于，具体方法为在氮气保护下，先将催化剂加入到反应瓶中，然后加入邻氨基苯磺酰胺、醛类化合物和溶剂甲苯，在-78～20℃下反应1-72小时，反应结束后将溶剂抽干，采用硅胶柱层析分离，洗脱剂为V石油醚：V乙酸乙酯＝4：1，得到手性噻嗪类化合物；
邻氨基苯磺酰胺：醛类化合物：催化剂的摩尔比为：10-100：10-100：1；
具体反应方程式如下：
X1、X2、X3、X4、R1、R2为H；
所述的催化剂为含环戊二烯骨架的手性布朗斯特酸，结构示例如下：
中的任意一种；
所述的醛类化合物为异戊醛、异丁醛、3,3-二甲基丁醛、环己基甲醛、苯丙醛中的任意一种。
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