CN111499657A - 一种异喹啉类噁唑烷的合成方法 - Google Patents
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- LXXQLPTWUJNVPY-UHFFFAOYSA-N isoquinoline 1,3-oxazolidine Chemical compound C1COCN1.c1ccc2cnccc2c1 LXXQLPTWUJNVPY-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims abstract description 18
- -1 diethyl pyruvate Chemical compound 0.000 claims abstract description 16
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical class O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims abstract description 11
- 229940117916 cinnamic aldehyde Drugs 0.000 claims abstract description 7
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 125000001424 substituent group Chemical group 0.000 claims abstract description 6
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 239000007858 starting material Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 10
- XZNLSDPNMNWCRE-UHFFFAOYSA-N 2,6-bis(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=C(C(F)(F)F)C=CC=C1C(F)(F)F XZNLSDPNMNWCRE-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ONOTYLMNTZNAQZ-UHFFFAOYSA-N 2,6-difluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1F ONOTYLMNTZNAQZ-UHFFFAOYSA-N 0.000 claims description 2
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 150000004982 aromatic amines Chemical class 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000000758 substrate Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000003814 drug Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000004983 proton decoupled 13C NMR spectroscopy Methods 0.000 description 3
- YSIYEWBILJZDQH-OWOJBTEDSA-N (e)-3-(4-fluorophenyl)prop-2-enal Chemical compound FC1=CC=C(\C=C\C=O)C=C1 YSIYEWBILJZDQH-OWOJBTEDSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000005311 nuclear magnetism Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 150000002917 oxazolidines Chemical class 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- BLRKQLICTKRDDZ-UHFFFAOYSA-N 7-chloro-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=CC(Cl)=CC=C21 BLRKQLICTKRDDZ-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical class N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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Abstract
一种异喹啉类噁唑烷的合成方法，包括以下步骤：以带有1,2,3,4取代基的四氢异喹啉（I）、芳香取代的肉桂醛(II)和丙酮二酸二乙酯为起始物料，在苯甲酸相似物的催化条件下，得到异喹啉类噁唑烷化合物(III)，本发明的合成方法，催化剂廉价且毒性小，反应直接且原子经济性高，底物来源广泛且稳定，适用范围广。在优化的反应条件之下，目标产品分离收率高达91%，非对映异构体比例高达20:1。
Description
技术领域
本发明涉及一种异喹啉类噁唑烷的合成方法。
背景技术
噁唑烷类化合物是重要的有机中间体，广泛的应用于生物和医药领域，表现出独特的消炎、抗肿瘤、抗精神类等特性。合成此类物质的方法已经引起了广泛的关注，并取得了一些进展。
Tetrahedron Lett.1987,28,6077-6080文献中，作者报道了1,2,3,4-四氢异喹啉-1-羧酸和两倍当量的2-吡啶甲醛，最终以中等收的得到产物，文献中只提到了这一个底物，底物适用范围很窄。反应方程式如下：
Tetrahedron 1990，46,6449-6466中报道了四氢异喹啉和两倍当量的2-吡啶甲醛反应，以70％的收率得到异喹啉类噁唑烷类化合物，文章中只涉及到这一个底物，范围比较窄。反应方程式如下：
RSC Adv.2015,5,61664-61670报道中，作者以苯甲酸为催化剂，可以高效的催化四氢喹啉系列物和芳香醛反应，得到四氢喹啉类噁唑烷类化合物。反应使用了两倍当量的芳香醛，收率中等，后期的衍生化不太理想。反应方程式如下：
目前所公开报道的合成方法存在底物适用范围窄，非对映异构体选择性差等特点。
发明内容
本发明所要解决的技术问题是提供一种异喹啉类噁唑烷的合成方法，采用一锅法、高效的得到异喹啉类噁唑烷化合物，底物和催化剂来源广泛、官能团相容性好，催化剂价廉且毒性小，目标产物收率高，适用范围广。
为解决上述技术问题，本发明提供了一种异喹啉类噁唑烷的合成方法，包括以下步骤：以带有1,2,3,4取代基的四氢异喹啉(I)、芳香取代的肉桂醛(II)和丙酮二酸二乙酯为起始物料，在苯甲酸相似物的催化条件下，得到异喹啉类噁唑烷化合物(III)，反应通式表示如下：
上述反应通式中：
R1～R9任意选自：C1～C12直链或支链的烷基或胺基烷基、C1～C12直链或支链的烷氧基、C1～C12直链或支链的全氟取代烷基、C3～C12的环烷基、无取代基的芳基或芳氧基、无取代基的杂芳基或杂芳基氧基、无取代基的胺基或芳胺基或杂芳基胺基、氟、氯、溴、碘、羟基、氨基、羰基、磺酸基、磺酸醋基、磷酸醋基、硝基；
R7或R8与相邻取代基相连成5～6元环；
催化剂为苯甲酸、2,6-硝基苯甲酸、2,6-二氟苯甲酸、2,6-二(三氟甲基)苯甲酸中的一种；
反应溶剂为四氢呋喃、乙酸乙酯、甲苯、苯、1,2-二氯乙烷，1,4-二氧六环中的一种；
反应温度为0～50℃。
本发明的优点：在苯甲酸类似物的催化条件下，以带有1,2,3,4取代基的四氢异喹啉(I)、芳香取代的肉桂醛(II)和丙酮二酸二乙酯为起始物料的三组份、一锅法制备噁唑烷的新方法，该方法催化剂廉价且毒性小:反应直接且原子经济性高，反应无需配体且活性好，底物来源广泛且稳定，底物官能团相容性好且底物的适用范围广。所述的方法简单易行，在优化的反应条件之下，目标产品分离后收率高达91％，非对映异构体比例高达20:1，是一种高效、环境友好的合成噁唑烷的方法。另外本发明方法制备的噁唑烷具有独特的生物、药理活性和功能，可以作为药物中间体、活性药物分子、小分子探针和荧光材料。
作为优选的，所述的反应溶剂为四氢呋喃。
作为优选的，所述的反应温度为25℃。
作为优选的，所述反应的最优催化剂为2,6-二(三氟甲基)苯甲酸。
具体实施方式
实施例一：
邻氨基苯硫酚(III)的制备，反应方程式如下：
称取53.2g四氢异喹啉(0.40mmol,2.0eq)，26.4mg肉桂醛(0.20mmol,1.0eq)，38.3mg丙酮二酸二乙酯(0.22mmol,1.1eq.)置于干燥的玻璃瓶中，然后再加入酸性催化剂苯甲酸(0.04mmol，0.2eq)，150mg
分子筛和2.0ml四氢呋喃。该体系在25℃条件下搅拌72h,TLC检测反应结束。40℃减压蒸馏得到产物粗产物，然后柱层析(淋洗相为石油醚：乙酸乙酯＝1:30)得到白色固体53.0mg。收率63％。熔点93-96℃，Dr:10:1.1H NMR(600MHz,CDCl3)δ7.58–7.54(m,1H),7.34(d,J＝7.2Hz,2H),7.32–7.26(m,4H),7.23(t,J＝7.3Hz,1H),7.17(d,J＝6.9Hz,1H),6.73(d,J＝15.7Hz,1H),6.18(dd,J＝15.8,8.1Hz,1H),5.92(s,1H),4.94(dd,J＝8.1,1.0Hz,1H),4.35(dq,J＝10.8,7.1Hz,1H),4.19(ddd,J＝14.3,8.9,5.4Hz,1H),4.12(dq,J＝10.8,7.1Hz,1H),4.09–4.02(m,1H),3.11–3.04(m,1H),2.99(ddd,J＝10.6,5.1,2.2Hz,1H),2.92(ddd,J＝12.6,10.8,3.1Hz,1H),2.77(d,J＝16.0Hz,1H),1.25(t,J＝7.1Hz,3H),1.14(t,J＝7.1Hz,3H).13C{1H}NMR(151MHz,CDCl3)δ168.54,168.17,136.32,135.18,133.00,130.45,129.52,128.80,128.53,128.06,127.85,126.47,126.39,123.92,93.31,87.39,73.82,62.42,61.81,45.94,29.47,14.15,13.88.HRMS(ESI)m/z(M+H)+calculated for C25H28NO5:422.1962,observed:422.1963.
实施例二：
称取53.2g四氢异喹啉(0.40mmol,2.0eq)，26.4mg肉桂醛(0.20mmol,1.0eq)，38.3mg丙酮二酸二乙酯(0.22mmol,1.1eq.)置于干燥的玻璃瓶中，然后再加入醋酸铜(0.04mmol，0.2eq)，150mg
分子筛和2.0ml四氢呋喃。该体系在25℃条件下搅拌72h,TLC检测反应结束。40℃减压蒸馏得到产物粗产物，然后柱层析(淋洗相为石油醚：乙酸乙酯＝1:30)得到白色固体43.7mg。收率52％。
为更简洁的说明，实施例三至实施例十二以表格的形式给出，参见表1，实施例三到实施例十二的具体操作步骤参考实施例一，反应通式如下：
表1
备注：反应条件为：4a(0.4mmol),5a(0.2mmol),6(0.22mmol),acid(0.04mmol)and
MS(150mg)加入到2.0ml溶剂中，25℃条件下搅拌72h；
通过条件筛选，得到最优反应条件，即以20％的2,6-双(三氟甲基)苯甲酸为催化剂，三个底物在四氢呋喃中，25℃搅拌条件下反应72h。并在此条件下进行了底物的适应性验证，具体实施案例如下：
称取53.2g的四氢异喹啉(0.40mmol,2.0eq)，30.0mg 4-氟肉桂醛(0.20mmol,1.0eq)，38.3mg丙酮二酸二乙酯(0.22mmol,1.1eq)置于干燥的玻璃瓶中，然后再加入10.3mg 2,6-双(三氟甲基)苯甲酸(0.04mmol，0.2eq)，150mg
分子筛和2.0ml四氢呋喃。该体系在25℃条件下搅拌72h，TLC检测反应结束。40℃减压蒸馏得到产物粗产物，然后柱层析(淋洗相为石油醚：乙酸乙酯＝1:30)得到白色固体7ab 57.0mg。收率66％。熔点112-115℃.Dr:15:1.1H NMR(600MHz,CDCl3)δ7.57–7.54(m,1H),7.33–7.25(m,4H),7.17(d,J＝7.0Hz,1H),6.98(t,J＝8.7Hz,2H),6.69(d,J＝15.7Hz,1H),6.10(dd,J＝15.8,8.1Hz,1H),5.90(s,1H),4.92(dd,J＝8.1,0.9Hz,1H),4.37–4.31(m,1H),4.19(dq,J＝10.8,7.1Hz,1H),4.15–4.09(m,1H),4.06(dq,J＝10.8,7.3Hz,1H),3.10–3.02(m,1H),2.98(ddd,J＝10.6,5.1,2.2Hz,1H),2.95–2.89(m,1H),2.76(d,J＝16.0Hz,1H),1.25(t,J＝7.1Hz,3H),1.14(t,J＝7.1Hz,3H).19F NMR(564MHz,CDCl3)δ-109.65.13C{1H}NMR(151MHz,CDCl3)δ168.53,168.12,162.44(d,J＝247.3Hz),135.14,132.50(d,J＝3.3Hz),131.75,130.38,129.50,128.82,128.06,127.96,126.40,123.73,115.51(d,J＝21.6Hz),93.31,87.37,73.75,62.45,61.80,45.95,29.46,14.16,13.87.HRMS(ESI)m/z(M+H)+calculated forC25H27FNO5:440.1868,observed:440.1865.
为更简洁的说明，实施例十四至实施例二十八以反应产物结构式表示，实施例十四到实施例二十八的具体操作步骤参考实施例十三，反应通式如下：
备注：反应条件为：4a(0.4mmol),5a-r(0.2mmol),6(0.22mmol),2,6-三氟苯甲酸(0.04mmol)and
MS(150mg)加入到2.0ml四氢呋喃中，25℃条件下搅拌72h；非对映异构体(Dr)通过核磁鉴定，(所有产物的Dr>10/1)；
本发明中又对四氢异喹啉的系列底物进行了验证，均表现出不错的结果，实施例如下：
实施二十九：
称取67.4g(0.40mmol,2.0eq)的7-氯四氢异喹啉，26.4mg肉桂醛(0.20mmol,1.0eq)，38.3mg丙酮二酸二乙酯(0.22mmol,1.1eq)置于干燥的玻璃瓶中，然后再加入10.3mg 2,6-双(三氟甲基)苯甲酸(0.04mmol，0.2eq)，150mg
分子筛和2.0ml四氢呋喃。该体系在25℃条件下搅拌72小时,TLC检测反应结束。40℃减压蒸馏得到产物粗产物，然后柱层析(淋洗相为石油醚：乙酸乙酯＝1:30)得到白色固体7ba 58.0mg。收率64％。熔点52-55℃.Dr:10:1.1H NMR(600MHz,CDCl3)δ7.56(d,J＝1.8Hz,1H),7.34(d,J＝7.5Hz,2H),7.29(t,J＝7.5Hz,2H),7.24(dt,J＝16.2,5.3Hz,2H),7.10(d,J＝8.2Hz,1H),6.72(d,J＝15.8Hz,1H),6.15(dd,J＝15.8,8.1Hz,1H),5.85(s,1H),4.92(d,J＝8.0Hz,1H),4.36(dq,J＝10.8,7.1Hz,1H),4.22–4.17(m,1H),4.14(ddd,J＝14.2,10.9,7.2Hz,1H),4.07(dq,J＝10.8,7.1Hz,1H),3.04–2.96(m,2H),2.89(dd,J＝18.1,8.1Hz,1H),2.76–2.71(m,1H),1.26(t,J＝7.1Hz,3H),1.14(t,J＝7.2Hz,3H).13C{1H}NMR(151MHz,CDCl3)δ168.29,168.00,136.21,133.63,133.17,132.17,132.06,129.43,129.32,128.99,128.56,127.93,126.47,123.63,92.52,87.39,73.60,62.53,61.91,45.72,28.88,14.15,13.88.HRMS(ESI)m/z(M+H)+calculated for C25H27ClNO5:456.1573,observed:456.1576.
为更简洁的说明，实施例三十至实施例三十六以反应产物结构式表示，实施例三十到实施例三十六的具体操作步骤参考实施例二十九，反应通式如下：
备注：反应条件为：4b-i(0.4mmol),5a(0.2mmol),6(0.22mmol),2,6-双(三氟甲基)苯甲酸(0.04mmol)and
MS(150mg)加入到2.0ml四氢呋喃中，25℃条件下搅拌72h；非对映异构体(Dr)通过核磁鉴定。
以上各实施例所制备的噁唑烷类化合物均可作为药物中间体、有活性的药物分子、小分子探针或荧光材料使用。
以上所述，仅是本发明的较佳实施例而己，并非对本发明作任何形式上的限制，虽然本发明己以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专业的技术人员不难理解，在不脱离本发明技术方案范围内，当可进行变动或修饰得到相应的实施例，例如对于所述的四氢喹啉芳香环上的取代基以及肉桂醛芳香取代基可在本发明范围内进行替换、改变或修饰，均可以实现本发明方法。但凡是未脱离本发明技术方案的宗旨，依据本发明的对以上实施例所作的任何修改、修饰或等同与等效的变化，均仍属于本发明技术方案的范围内。
Claims (4)
1.一种异喹啉类噁唑烷的合成方法，其特征在于，包括以下步骤：以带有1,2,3,4取代基的四氢异喹啉(I)、芳香取代的肉桂醛(II)和丙酮二酸二乙酯为起始物料，在苯甲酸相似物的催化条件下，得到异喹啉类噁唑烷化合物(III)，反应通式表示如下：
上述反应通式中：
R1～R9任意选自：C1～C12直链或支链的烷基或胺基烷基、C1～C12直链或支链的烷氧基、C1～C12直链或支链的全氟取代烷基、C3～C12的环烷基、无取代基的芳基或芳氧基、无取代基的杂芳基或杂芳基氧基、无取代基的胺基或芳胺基或杂芳基胺基、氟、氯、溴、碘、羟基、氨基、羰基、磺酸基、磺酸醋基、磷酸醋基、硝基；
R7或R8与相邻取代基相连成5～6元环；
催化剂为苯甲酸、2,6-硝基苯甲酸、2,6-二氟苯甲酸、2,6-二(三氟甲基)苯甲酸中的一种；
反应溶剂为四氢呋喃、乙酸乙酯、甲苯、苯、1,2-二氯乙烷，1,4-二氧六环中的一种；
反应温度为0～50℃。
2.根据权利要求1所述的一种异喹啉类噁唑烷的合成方法，其特征在于：所述的反应溶剂为四氢呋喃。
3.根据权利要求1所述的一种异喹啉类噁唑烷的合成方法，其特征在于：所述的反应温度为25℃。
4.根据权利要求1所述的一种异喹啉类噁唑烷的合成方法，其特征在于：所述反应的最优催化剂为2,6-二(三氟甲基)苯甲酸。
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