CN107033136B - 手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法 - Google Patents
手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法 Download PDFInfo
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- -1 benzazolyl compounds Chemical class 0.000 claims abstract description 12
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- 239000002994 raw material Substances 0.000 claims abstract description 3
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- 150000001875 compounds Chemical class 0.000 claims description 10
- DLBPTOMGZXBZOX-UHFFFAOYSA-N 1,2-thiazole 1,1-dioxide Chemical class O=S1(=O)C=CC=N1 DLBPTOMGZXBZOX-UHFFFAOYSA-N 0.000 claims description 9
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- 229910052736 halogen Inorganic materials 0.000 claims description 4
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- 241000790917 Dioxys <bee> Species 0.000 claims 1
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- 239000011574 phosphorus Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
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- 150000003851 azoles Chemical class 0.000 description 1
- 108010079785 calpain inhibitors Proteins 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
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- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明公开了一种手性磷酸催化合成光学活性2,3‑二氢苯并[d]异噻唑1,1‑二氧化物衍生物的方法。它是以3‑甲氧羰基苯并[d]异噻唑1,1‑二氧化物和吲哚化合物为原料,以手性磷酸为催化剂,在有机溶剂中反应完全,制备得到光学活性2,3‑二氢苯并[d]异噻唑1,1‑二氧化物衍生物。本发明反应条件温和,工艺简单,操作便捷;所得产物有潜在的良好的生物活性,并可以作为有机合成中间体使用。
Description
技术领域
本发明属于药物合成技术领域,具体是涉及一种手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法。
背景技术
磺内酰胺衍生物是一种具有非常重要生物活性和药理活性的特殊化合物,在生物医药等领域有着广泛地应用,包括钙蛋白酶抑制剂(A)、凝血酶抑制剂(B)、金属蛋白酶抑制剂(C)及HIV-1抑制剂(D)等,是目前药物合成研究的热点之一。
更加值得注意的是,3-取代-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物因其广泛存在于多种重要的生物活性结构单元和药物结构的中间体中,一直备受关注,例如:5-HT2受体拮抗剂(E)、HCV(丙型肝炎病毒)NS5b抑制剂(F)、选择性CRTh2拮抗剂(G)等。此外,3-取代-2,3-二氢苯并[d]异噻唑1,1-二氧化物及其类似物在有机合成领域中也有着广泛的应用,通常作为保护基、手性辅剂以及金属化作用的导向基团等。
另外,含有吲哚环结构单元的化合物在自然界中广泛存在,是迄今为止所发现最多的一类生物碱,数量占所有生物碱的五分之一。由于吲哚类化合物所特有的生物特性,使其在有机合成、材料科学、农业化学与药物学等研究领域中有着极其广泛的应用。不仅如此,由于吲哚类衍生物的骨架和官能团的多样性,使其具有良好的药理活性功能,比如抗氧化、解毒和消炎止疼等。
一直以来,3-取代吲哚衍生物的合成是有机合成领域的研究热点之一,而含手性季碳的吲哚衍生物的合成更是热点领域中的前沿。因此,如何高效高对映选择性的合成2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的意义十分重大。
发明内容
本发明的目的是提供一种反应温和、操作简便、对映选择性高的手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法。
本发明的手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法,其步骤是:以3-甲氧羰基苯并[d]异噻唑1,1-二氧化物和吲哚化合物为原料,以手性磷酸为催化剂,在有机溶剂中于0-50℃反应5~24小时,制备得到结构式如式(4)所示的光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,3-甲氧羰基苯并[d]异噻唑1,1-二氧化物和吲哚化合物的摩尔比为1:1~1.2,手性磷酸催化剂和3-甲氧羰基苯并[d]异噻唑1,1-二氧化物的摩尔比为5:100;
所述的手性磷酸催化剂为具有结构式(1)的左旋或右旋的光学活性化合物:
所述3-甲氧羰基苯并[d]异噻唑1,1-二氧化物结构如式(2)所示:
所述吲哚化合物结构如式(3)所示:
所述2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的结构式如式(4)所示:
以上式(2)、(3)、(4)中:R1选自H、卤素、C1~C4的烷基或C1~C4的烷氧基;R2选自H、卤素、C1~C4的烷基或C1~C4的烷氧基。
本发明中,所述的3-甲氧羰基苯并[d]异噻唑1,1-二氧化物优选为下列化合物之一:
本发明中,所述的吲哚化合物优选为下列化合物之一:
本发明中,所述的有机溶剂选自二氯甲烷、1,2-二氯乙烷或三氯甲烷。
本发明的反应方程式如下:
与现有技术相比,本发明具有以下优点:
1)反应条件温和,无需金属催化,反应不需要苛刻的反应条件;
2)含有取代基的吲哚能直接作为反应底物,来源广泛,降低了最终产品的制备成本;
3)可以获得高光学活性的含非天然氨基酸酯季立体中心的3-甲氧羰基-3-(3-吲哚基)-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物。
综上所述,本发明拟利用不对称催化氮杂傅克烷基化反应方法合成光学活性含有非天然氨基酸酯季立体中心的3-甲氧羰基-3-(3-吲哚基)-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,反应条件温和,工艺简单,操作便捷,所得产物有潜在的良好的生物活性,这将对新药筛选有重要意义,同时得到的手性化合物可以作为药物合成的中间体使用。
具体实施方式
以下实施例将有助于理解本发明,但本发明不限于实施例。
实施例1
反应瓶中加入3-甲氧羰基苯并[d]异噻唑1,1-二氧化物(0.02mmol)、吲哚(0.024mmol)、如前述结构式(1)所示的(R)-联萘磷酸(0.001mmol)(cas:791616-56-3),注入1mL 1,2-二氯乙烷,室温反应16小时,反应完成后,直接用硅胶柱层析,洗脱剂为用乙酸乙酯/石油醚=1:2,得相应的光学活性3-甲氧羰基-3-(3-吲哚基)-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,产率95%;产物表征如下:
结构式:
性状:白色固体;
m.p.224.5-226.6℃;
光学纯度:93%ee;
HPLC分析条件:(菲罗门手性柱)00G-4459-E0(正己烷/i-PrOH=70/30,0.8mL/min,254nm),tR(minor)16.280min,tR(major)18.406min;
旋光度:[α]D 20=-103.0°(c=0.15,CH2Cl2);
1H NMR(400MHz,D6-DMSO):δ11.30(s,1H),9.09(s,1H),7.92-7.89(m,1H),7.69-7.67(m,2H),7.55-7.53(m,1H),7.39(d,J=8.1Hz,1H),7.29(d,J=2.5Hz,1H),7.10-7.04(m,2H),6.88(t,J=7.5Hz,1H),3.80(s,3H);
HRMS(GC-TOF):计算值C17H14N2O4S 342.0674,检测值342.0674.
实施例2
反应瓶中加入3-甲氧羰基-5-甲基苯并[d]异噻唑1,1-二氧化物(0.02mmol)、吲哚(0.024mmol)、如前述结构式(1)所示的(R)-联萘磷酸(0.001mmol)(cas:791616-56-3),注入1mL 1,2-二氯乙烷,室温反应16小时,反应完成后,直接用硅胶柱层析,洗脱剂为用乙酸乙酯/石油醚=1:2,得相应的光学活性3-甲氧羰基-3-(3-吲哚基)-5-甲基-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,产率93%;产物表征如下:
结构式:
性状:白色固体;
m.p.214.8-215.6℃;
光学纯度:93%ee;
HPLC分析条件:(菲罗门手性柱)00G-4459-E0(正己烷/i-PrOH=70/30,0.8mL/min,254nm),tR(minor)17.152min,tR(major)19.916min;
旋光度:[α]D 20=-43.0°(c=0.14,CH2Cl2);
1H NMR(400MHz,D6-DMSO):δ11.28(d,J=1.8Hz,1H),8.97(s,1H),7.78(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.39(d,J=8.1Hz,1H),7.32(s,1H),7.28(d,J=2.7Hz,1H),7.11-7.06(m,2H),6.90-6.86(m,1H),3.80(s,3H),2.35(s,3H);
HRMS(GC-TOF):计算值C18H16N2O4S 356.0831,检测值356.0830.
实施例3
反应瓶中加入3-甲氧羰基-5-氯苯并[d]异噻唑1,1-二氧化物(0.02mmol)、吲哚(0.024mmol)、如前述结构式(1)所示的(R)-联萘磷酸(0.001mmol)(cas:791616-56-3),注入1mL 1,2-二氯乙烷,室温反应16小时,反应完成后,直接用硅胶柱层析,洗脱剂为用乙酸乙酯/石油醚=1:2,得相应的光学活性3-甲氧羰基-3-(3-吲哚基)-5-氯-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,产率90%;产物表征如下:
结构式:
性状:白色固体;
m.p.216.1-217.7℃;
光学纯度:91%ee;
HPLC分析条件:(大赛璐手性柱)ChiralpakID-3(正己烷/i-PrOH=70/30,0.8mL/min,254nm),tR(minor)10.389min,tR(major)12.022min;
旋光度:[α]D 20=-73.0°(c=0.06,CH2Cl2);
1H NMR(400MHz,D6-DMSO):δ11.37(d,J=2.0Hz,1H),9.31(s,1H),7.99(d,J=8.3Hz,1H),7.76(dd,J=8.3,1.9Hz,1H),7.48(d,J=1.7Hz,1H),7.41(d,J=8.2Hz,1H),7.36(d,J=2.7Hz,1H),7.12-7.05(m,2H),6.93-6.89(m,1H),3.84(s,3H);
HRMS(GC-TOF):计算值C17H13ClN2O4S 376.0285,检测值376.0286.
实施例4
反应瓶中加入3-甲氧羰基苯并[d]异噻唑1,1-二氧化物(0.02mmol)、5-甲基吲哚(0.024mmol)、如前述结构式(1)所示的(R)-联萘磷酸(0.001mmol)(cas:791616-56-3),注入1mL 1,2-二氯乙烷,室温反应16小时,反应完成后,直接用硅胶柱层析,洗脱剂为用乙酸乙酯/石油醚=1:2,得相应的光学活性3-甲氧羰基-3-(5-甲基-3-吲哚基)-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,产率97%;产物表征如下:
结构式:
性状:白色固体;
m.p.183.6-186.4℃;
光学纯度:91%ee;
HPLC分析条件:(菲罗门手性柱)00G-4459-E0(正己烷/i-PrOH=70/30,0.8mL/min,254nm),tR(minor)15.125min,tR(major)17.556min;
旋光度:[α]D 20=-169.0°(c=0.03,CH2Cl2);
1H NMR(400MHz,D6-DMSO):δ11.16(d,J=1.9Hz,1H),9.04(s,1H),7.91-7.89(m,1H),7.71-7.66(m,2H),7.57-7.54(m,1H),7.27(d,J=8.2Hz,1H),7.19(d,J=2.7Hz,1H),6.92-6.88(m,2H),3.79(s,3H),2.23(s,3H);
HRMS(GC-TOF):计算值C18H16N2O4S 356.0831,检测值356.0827.
实施例5
反应瓶中加入3-甲氧羰基-5-甲基苯并[d]异噻唑1,1-二氧化物(0.02mmol)、2-甲基吲哚(0.024mmol)、如前述结构式(1)所示的(R)-联萘磷酸(0.001mmol)(cas:791616-56-3),注入1mL 1,2-二氯乙烷,室温反应24小时,反应完成后,直接用硅胶柱层析,洗脱剂为用乙酸乙酯/石油醚=1:2,得相应的光学活性3-甲氧羰基-3-(2-甲基-3-吲哚基)-5-甲基-2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,产率98%;产物表征如下:
结构式:
性状:白色固体;
m.p.210.6-212.5℃;
光学纯度:97%ee;
HPLC分析条件:(菲罗门手性柱)00G-4459-E0(正己烷/i-PrOH=60/40,0.8mL/min,220nm),tR(minor)10.612min,tR(major)18.293min;
旋光度:[α]D 20=-113.0°(c=0.06,CH2Cl2);
1H NMR(400MHz,D6-DMSO):δ11.21(s,1H),8.83(s,1H),7.79(d,J=8.0Hz,1H),7.51(d,J=7.9Hz,1H),7.33(s,1H),7.27(d,J=8.1Hz,1H),6.97(t,J=7.3Hz,1H),6.77(t,J=7.4Hz,1H),6.49(d,J=8.1Hz,1H),3.79(s,3H),2.35(s,3H),2.06(s,3H);
HRMS(GC-TOF):计算值C19H18N2O4S 370.0987,检测值370.0985。
Claims (4)
1.一种手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法,其步骤是:以3-甲氧羰基苯并[d]异噻唑1,1-二氧化物和吲哚化合物为原料,以手性磷酸为催化剂,在有机溶剂中于0-50℃反应5~24小时,得到结构式如式(4)所示的光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物,3-甲氧羰基苯并[d]异噻唑1,1-二氧化物和吲哚化合物的摩尔比为1:1~1.2,手性磷酸催化剂和3-甲氧羰基苯并[d]异噻唑1,1-二氧化物的摩尔比为5:100;
所述的手性磷酸催化剂为具有结构式(1)的光学活性化合物:
所述的3-甲氧羰基苯并[d]异噻唑1,1-二氧化物结构如式(2)所示:
所述的吲哚化合物结构如式(3)所示:
所述的2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的结构式如式(4)所示:
以上式(2)、(3)、(4)中:R1选自H、卤素、C1~C4的烷基或C1~C4的烷氧基;R2选自H、卤素、C1~C4的烷基或C1~C4的烷氧基。
2.根据权利要求1所述的手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法,其特征在于所述的3-甲氧羰基苯并[d]异噻唑1,1-二氧化物为下列化合物之一:
3.根据权利要求1所述的手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法,其特征在于所述的吲哚化合物为下列化合物之一:
4.根据权利要求1所述的手性磷酸催化合成光学活性2,3-二氢苯并[d]异噻唑1,1-二氧化物衍生物的方法,其特征在于所述的有机溶剂选自二氯甲烷、1,2-二氯乙烷或三氯甲烷。
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