CN110407791A - α-substituted isochroman derivatives and preparation method thereof - Google Patents
α-substituted isochroman derivatives and preparation method thereof Download PDFInfo
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- CN110407791A CN110407791A CN201910780001.5A CN201910780001A CN110407791A CN 110407791 A CN110407791 A CN 110407791A CN 201910780001 A CN201910780001 A CN 201910780001A CN 110407791 A CN110407791 A CN 110407791A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical class C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 125000004971 nitroalkyl group Chemical group 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- -1 p-tert-butylphenyl Chemical group 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 5
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical group CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000005504 styryl group Chemical group 0.000 claims description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 125000000552 p-cresyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1O*)C([H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 239000003814 drug Substances 0.000 abstract description 6
- 229930014626 natural product Natural products 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 5
- 239000007800 oxidant agent Substances 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- 238000012512 characterization method Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- HUUZDOOYRYHRIP-UHFFFAOYSA-N COC(C(OC)=C1)=CC(CCO)=C1C(C=CC=C1)=C1C(C1=CC=CC=C1)=O Chemical compound COC(C(OC)=C1)=CC(CCO)=C1C(C=CC=C1)=C1C(C1=CC=CC=C1)=O HUUZDOOYRYHRIP-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- LCFRULIWHIDZPL-UHFFFAOYSA-N COC(C=C(CCOC1(C[N+]([O-])=O)C2=CC=CC=C2)C1=C1)=C1OC Chemical compound COC(C=C(CCOC1(C[N+]([O-])=O)C2=CC=CC=C2)C1=C1)=C1OC LCFRULIWHIDZPL-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- NTKMSRLEYNMNLD-UHFFFAOYSA-N CC(C)CC(C[N+]([O-])=O)(C1=C2)OCCC1=CC(OC)=C2OC Chemical compound CC(C)CC(C[N+]([O-])=O)(C1=C2)OCCC1=CC(OC)=C2OC NTKMSRLEYNMNLD-UHFFFAOYSA-N 0.000 description 1
- JMLXRENDHBVPPY-UHFFFAOYSA-N COC(C=C(CCOC1(C[N+]([O-])=O)C(C=C2)=CC=C2[N+]([O-])=O)C1=C1)=C1OC Chemical compound COC(C=C(CCOC1(C[N+]([O-])=O)C(C=C2)=CC=C2[N+]([O-])=O)C1=C1)=C1OC JMLXRENDHBVPPY-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000002355 alkine group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种α‑取代异色满衍生物及其制备方法，该衍生物的结构式为： 将羟乙基取代的芳酮和硝基烷烃混合，室温至150℃反应0.5‑3天制备而成。本发明所用的方法无需催化剂、氧化剂和溶剂，反应一步高效完成，反应条件温和、高效，操作简单。本发明合成化合物可作为药物、活性的天然产物、有机合成的重要结构单元。An α-substituted isochroman derivative and a preparation method thereof, the structural formula of the derivative is: It is prepared by mixing hydroxyethyl-substituted aryl ketone and nitroalkane, and reacting at room temperature to 150°C for 0.5-3 days. The method used in the invention does not need a catalyst, an oxidizing agent and a solvent, and the reaction can be completed efficiently in one step, with mild and efficient reaction conditions and simple operation. The synthetic compound of the present invention can be used as medicine, active natural product and important structural unit of organic synthesis.
Description
技术领域technical field
本发明涉及α-取代异色满衍生物及其制备方法。The present invention relates to α-substituted isochroman derivatives and a preparation method thereof.
背景技术Background technique
异色满骨架存在于许多天然产物和合成药物中，具有广泛的生物活性，特别是在α位带有两个不同取代基的这种结构单元已经证明具有抗氧化，抗癌，抗菌，抗真菌，抗病毒和抗抑郁活性等药理活性。硝基是活性的天然产物和药物的重要合成子，硝基的引入将会引起药理活性的差异。截至目前在异色满的α位引入硝基的官能团化合物尚未报道。The heterochroman skeleton exists in many natural products and synthetic drugs, and has a wide range of biological activities, especially this structural unit with two different substituents at the α position has been proven to have antioxidant, anticancer, antibacterial, and antifungal properties , pharmacological activities such as antiviral and antidepressant activity. Nitro is an active natural product and an important synthon of drugs, and the introduction of nitro will cause differences in pharmacological activity. Up to now, the functional group compound that introduces a nitro group at the α position of isochroman has not been reported yet.
在异色满骨架的α位引入两个不同取代基通常采用的方法有两种途径：一种是α位单取代异色满通过强氧化剂DDQ的自由基单电子转移反应，首先获得氧稳定的碳正离子，然后亲核试剂CN基团进攻正碳中心获得α位双取代异色满结构(Chinese Chemical Letters30(2019)1241–1243)；另一种是通过强碱性的金属有机试剂烷基锂亲核加成到异色满α位内酯化合物，进而获得氧稳定的碳正离子，再用亲核试剂炔官能团进攻而获得(Angew.Chem.Int.Ed.2015,54,14154–14158)。然而，现有的方法需要使用强氧化剂和对水敏感的金属有机试剂，且反应步骤较长，原子经济性差。There are two ways to introduce two different substituents at the α position of the isochroman skeleton: one is to obtain the oxygen-stabilized isochroman through the radical single electron transfer reaction of the strong oxidant DDQ Carbocation, and then the nucleophile CN group attacks the positive carbon center to obtain the α-position disubstituted isochroman structure (Chinese Chemical Letters 30 (2019) 1241–1243); the other is through a strongly basic metal organic reagent alkyl The nucleophilic addition of lithium to the α-position lactone compound of isochroman to obtain an oxygen-stabilized carbocation, which is then attacked by a nucleophile alkyne functional group (Angew.Chem.Int.Ed.2015,54,14154–14158 ). However, existing methods require the use of strong oxidizing agents and water-sensitive metal-organic reagents, with long reaction steps and poor atom economy.
发明内容Contents of the invention
本发明的目的在于提供一种α-取代异色满衍生物及其制备方法。The object of the present invention is to provide an α-substituted isochroman derivative and a preparation method thereof.
为实现上述目的，本发明所采用的技术方案是：To achieve the above object, the technical solution adopted in the present invention is:
一种α-取代异色满衍生物，该衍生物的结构式如下所示：An α-substituted isochroman derivative, the structural formula of which is as follows:
A＝Ar或R，Ar代表苯基、萘基、对甲苯基、邻甲苯基、间甲苯基、对叔丁基苯基、对氯苯基、对溴苯基、对氟苯基、对硝基苯基、对甲氧基苯基、对三氟甲基苯基、间氯苯基与间硝基苯基中的任意一种，R为C1～C6的烷基、苯乙烯基、对甲苯乙烯基、对氯苯乙烯基与对硝基苯乙烯基中的任意一种。A=Ar or R, Ar represents phenyl, naphthyl, p-tolyl, o-tolyl, m-tolyl, p-tert-butylphenyl, p-chlorophenyl, p-bromophenyl, p-fluorophenyl, p-nitrogen Any one of phenyl, p-methoxyphenyl, p-trifluoromethylphenyl, m-chlorophenyl and m-nitrophenyl, R is C1-C6 alkyl, styryl, p-toluene Any one of vinyl, p-chlorostyryl and p-nitrostyryl.
一种α-取代异色满衍生物的制备方法，将羟乙基取代的芳酮和硝基烷烃按摩尔比为1:1～10混合均匀，在20℃～150℃反应0.5～3天，得到α-取代异色满衍生物。A method for preparing α-substituted isochroman derivatives, comprising uniformly mixing hydroxyethyl-substituted aryl ketone and nitroalkane at a molar ratio of 1:1 to 10, and reacting at 20°C to 150°C for 0.5 to 3 days, α-substituted isochroman derivatives are obtained.
本发明进一步的改进在于：羟乙基取代的芳酮为 The further improvement of the present invention is: the aryl ketone substituted by hydroxyethyl is
A＝Ar或R，Ar代表苯基、萘基、对甲苯基、邻甲苯基、间甲苯基、对叔丁基苯基、对氯苯基、对溴苯基、对氟苯基、对硝基苯基、对甲氧基苯基、对三氟甲基苯基、间氯苯基与间硝基苯基中的任意一种，R为C1～C6的烷基、苯乙烯基、对甲苯乙烯基、对氯苯乙烯基与对硝基苯乙烯基中的任意一种。A=Ar or R, Ar represents phenyl, naphthyl, p-tolyl, o-tolyl, m-tolyl, p-tert-butylphenyl, p-chlorophenyl, p-bromophenyl, p-fluorophenyl, p-nitrogen Any one of phenyl, p-methoxyphenyl, p-trifluoromethylphenyl, m-chlorophenyl and m-nitrophenyl, R is C1-C6 alkyl, styryl, p-toluene Any one of vinyl, p-chlorostyryl and p-nitrostyryl.
本发明进一步的改进在于：硝基烷烃为R1CH2NO2，R1代表H或C1～C6的烷基中的任意一种。The further improvement of the present invention is: the nitroalkane is R 1 CH 2 NO 2 , and R 1 represents any one of H or C1-C6 alkyl.
本发明在无溶剂无催化剂的条件下将羟乙基取代的芳酮和硝基烷烃直接混合反应由于羟乙基取代的芳酮发生了缩酮反应，形成缩酮产物，硝基烷烃作为亲核试剂取代缩酮中的羟基进而获得相应的产物。本发明所用的方法无需催化剂和溶剂，反应步骤短，反应条件温和、高效，操作简单，原子经济性高，高产率。本发明合成化合物可作为药物、活性的天然产物、有机合成的重要结构单元。制备得到的α-取代异色满衍生物在药物、活性的天然产物的制备中具有很大的应用潜力。In the present invention, the aryl ketone substituted by hydroxyethyl group and the nitroalkane are directly mixed and reacted under the condition of no solvent and no catalyst. Since the aryl ketone substituted by hydroxyethyl group undergoes a ketal reaction, a ketal product is formed, and the nitroalkane acts as a nucleophile. The reagent replaces the hydroxyl group in the ketal to obtain the corresponding product. The method used in the invention does not need catalyst and solvent, has short reaction steps, mild reaction conditions, high efficiency, simple operation, high atom economy and high yield. The synthetic compound of the present invention can be used as medicine, active natural product and important structural unit of organic synthesis. The prepared α-substituted isochroman derivatives have great application potential in the preparation of medicines and active natural products.
具体实施方式Detailed ways
下面结合实施例对本发明进一步详细说明，但本发明所要保护的范围不限于这些实施例。The present invention will be further described in detail below in conjunction with examples, but the scope of protection of the present invention is not limited to these examples.
将羟乙基取代的芳酮和硝基烷烃按摩尔比为1:1～10直接混合均匀，在无溶剂无催化剂的条件下，室温至150℃反应0.5～3天得到α-取代异色满衍生物。Mix the hydroxyethyl substituted aryl ketone and nitroalkane at a molar ratio of 1:1~10 and mix them evenly, and react at room temperature to 150°C for 0.5~3 days under the condition of solvent-free and catalyst-free to obtain α-substituted isochroman derivative.
上述的α-取代异色满衍生物，其特征在于它的结构式如下所示：The above-mentioned α-substituted isochroman derivative is characterized in that its structural formula is as follows:
其中Ar代表苯基、对甲苯基、对叔丁基苯基、对氯苯基、对溴苯基、对氟苯基、对硝基苯基、对甲氧基苯基、对三氟甲基苯基、间甲苯基、间氯苯基、间硝基苯基、邻甲苯基中的任意一种，R代表C1～C6的烷基中的任意一种。Where Ar represents phenyl, p-tolyl, p-tert-butylphenyl, p-chlorophenyl, p-bromophenyl, p-fluorophenyl, p-nitrophenyl, p-methoxyphenyl, p-trifluoromethyl Any one of phenyl, m-tolyl, m-chlorophenyl, m-nitrophenyl, ortho-tolyl, and R represents any one of C1-C6 alkyl groups.
本发明的羟乙基取代的芳酮优选The hydroxyethyl-substituted aryl ketones of the present invention are preferably
本发明的硝基烷烃优选R1CH2NO2，R1代表C1～C6的烷基中的任意一种。The nitroalkane of the present invention is preferably R 1 CH 2 NO 2 , and R 1 represents any one of C1-C6 alkyl groups.
实施例1Example 1
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-phenylisochroman as an example, the raw materials used and its preparation method are as follows:
将172mg(0.6mmol)(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮和321uL(6mmol)硝基甲烷置于反应瓶中，在150℃下搅拌反应0.5天，停止反应，向体系中加入2mL饱和碳酸氢钠水溶液，用10mL乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，抽滤，浓缩，粗产物进行柱层析分离(乙酸乙酯和正己烷)，得到白色固体产物，其产率为83％。所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据如下：1H NMR(600MHz,CDCl3)δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J＝12.1Hz,1H),4.89(d,J＝12.1Hz,1H),3.88(ddd,J＝11.6,6.1,2.0Hz,1H),3.81(s,3H),3.79(s,3H),3.52(td,J＝11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H)；13C NMR(151MHz,CDCl3)δ147.77,145.93,140.08,127.64,127.56,126.86,126.54,123.46,110.88,109.78,81.96,78.86,59.48,55.30,54.80,26.96.Put 172mg (0.6mmol) (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl) benzophenone and 321uL (6mmol) nitromethane in the reaction flask and stir at 150°C Reacted for 0.5 days, stopped the reaction, added 2mL saturated aqueous sodium bicarbonate solution to the system, extracted three times with 10mL ethyl acetate, combined the organic phases, dried with anhydrous sodium sulfate, suction filtered, concentrated, and the crude product was separated by column chromatography ( ethyl acetate and n-hexane) to obtain a white solid product with a yield of 83%. The obtained product was characterized by a Bruker Avance superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were as follows: 1 H NMR (600MHz, CDCl 3 ) δ7.40–7.39 (m, 2H), 7.36–7.32 (m, 3H), 6.64(s,1H),6.58(s,1H),5.06(d,J=12.1Hz,1H),4.89(d,J=12.1Hz,1H),3.88(ddd,J=11.6,6.1,2.0Hz ,1H),3.81(s,3H),3.79(s,3H),3.52(td,J＝11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H); 13 C NMR (151MHz, CDCl 3 ) δ147.77, 145.93, 140.08, 127.64, 127.56, 126.86, 126.54, 123.46, 110.88, 109.78, 81.96, 78.86, 59.48, 55.30, 54.80, 26.96.
实施例2Example 2
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-对氯苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-p-chlorophenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例2中，所用的(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮用等摩尔的(2-(2-羟基乙基)-4,5-二甲氧基苯基)对氯苯甲酮替换，其它步骤与实施例1相同，制备成淡黄色固体，其产率为82％，表征数据为：1H NMR(600MHz,CDCl3)δ7.30–7.24(m,4H),6.59(s,2H),5.02(d,J＝12.0Hz,1H),4.88(d,J＝12.0Hz,1H),3.96–3.86(m,1H),3.83(s,3H),3.80(s,3H),3.52(d,J＝3.6Hz,1H),3.01–2.93(m,1H),2.49–2.38(m,1H)；13C NMR(151MHz,CDCl3)δ147.96,146.11,138.65,133.77,127.99,127.74,126.80,123.10,110.98,109.49,81.69,78.39,59.57,55.34,54.83,26.90.In Example 2, the (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl)benzophenone used was equimolar with (2-(2-hydroxyethyl)-4, 5-dimethoxyphenyl) p-chlorobenzophenone was replaced, and the other steps were the same as in Example 1 to prepare a light yellow solid with a yield of 82%. The characterization data is: 1 H NMR (600MHz, CDCl 3 ) δ7.30–7.24(m,4H),6.59(s,2H),5.02(d,J=12.0Hz,1H),4.88(d,J=12.0Hz,1H),3.96–3.86(m,1H) ,3.83(s,3H),3.80(s,3H),3.52(d,J＝3.6Hz,1H),3.01–2.93(m,1H),2.49–2.38(m,1H); 13 C NMR (151MHz , CDCl 3 ) δ147.96, 146.11, 138.65, 133.77, 127.99, 127.74, 126.80, 123.10, 110.98, 109.49, 81.69, 78.39, 59.57, 55.34, 54.83, 26.90.
实施例3Example 3
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-对甲苯基异苯并二氢吡喃酮为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-p-tolylisochromanone as an example, the raw materials used and its preparation method are as follows:
在实施例3中，所用的(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮用等摩尔的(2-(2-羟基乙基)-4,5-二甲氧基苯基)对甲苯甲酮替换，其它步骤与实施例1相同，制备成白色固体，其产率为81％，表征数据为：1H NMR(600MHz,CDCl3)δ7.21–7.16(m,2H),7.08(d,J＝8.3Hz,2H),6.62(s,2H),6.58(s,1H),5.05(d,J＝11.9Hz,1H),4.87(d,J＝11.9Hz,1H),3.86(ddd,J＝11.4,6.0,1.8Hz,1H),3.81(s,3H),3.79(s,3H),3.51(td,J＝11.4,3.5Hz,1H),3.01–2.92(m,1H),2.44–2.37(m,1H),2.26(s,3H)；13C NMR(151MHz,CDCl3)δ147.71,145.89,137.58,137.10,128.22,126.87,126.53,123.64,110.83,109.75,82.07,78.76,59.35,55.27,54.79,26.98,19.97.In Example 3, the (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl)benzophenone used was equimolar with (2-(2-hydroxyethyl)-4, 5-dimethoxyphenyl) p-toluene was replaced, and the other steps were the same as in Example 1 to prepare a white solid with a yield of 81%. The characterization data was: 1 H NMR (600MHz, CDCl 3 ) δ7. 21–7.16(m,2H),7.08(d,J=8.3Hz,2H),6.62(s,2H),6.58(s,1H),5.05(d,J=11.9Hz,1H),4.87(d ,J=11.9Hz,1H),3.86(ddd,J=11.4,6.0,1.8Hz,1H),3.81(s,3H),3.79(s,3H),3.51(td,J=11.4,3.5Hz, 1H),3.01–2.92(m,1H),2.44–2.37(m,1H),2.26(s,3H); 13 C NMR(151MHz,CDCl 3 )δ147.71,145.89,137.58,137.10,128.22,126.87,126.53 ,123.64,110.83,109.75,82.07,78.76,59.35,55.27,54.79,26.98,19.97.
实施例4Example 4
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-对硝基苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-p-nitrophenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例4中，所用的(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮用等摩尔的(2-(2-羟基乙基)-4,5-二甲氧基苯基)对硝基苯甲酮替换，其它步骤与实施例1相同，制备成黄色固体，其产率为90％，表征数据为：1H NMR(600MHz,CDCl3)δ8.13(d,J＝8.6Hz,2H),7.59(d,J＝8.8Hz,2H),6.60(d,J＝3.9Hz,2H),5.07(d,J＝12.1Hz,1H),4.93(d,J＝12.1Hz,1H),3.82(s,3H),4.01–3.94(m,1H),3.79(s,3H),3.62–3.55(m,1H),2.96(ddd,J＝15.8,9.8,5.6Hz,1H),2.54(d,J＝16.1Hz,1H)；13C NMR(151MHz,CDCl3)δ150.27,148.31,129.31,128.52,125.46,123.47,114.34,112.02,81.49,79.20,60.99,56.12,55.67,27.80.In Example 4, the (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl)benzophenone used was equimolar with (2-(2-hydroxyethyl)-4, 5-dimethoxyphenyl) p-nitrobenzophenone was replaced, and the other steps were the same as in Example 1 to prepare a yellow solid with a yield of 90%. The characterization data is: 1 H NMR (600MHz, CDCl 3 ) δ8.13(d, J=8.6Hz, 2H), 7.59(d, J=8.8Hz, 2H), 6.60(d, J=3.9Hz, 2H), 5.07(d, J=12.1Hz, 1H), 4.93(d,J=12.1Hz,1H),3.82(s,3H),4.01–3.94(m,1H),3.79(s,3H),3.62–3.55(m,1H),2.96(ddd,J= 15.8,9.8,5.6Hz,1H),2.54(d,J=16.1Hz,1H); 13 C NMR(151MHz,CDCl 3 )δ150.27,148.31,129.31,128.52,125.46,123.47,114.34,112.02,81.49,79.20 ,60.99,56.12,55.67,27.80.
实施例5Example 5
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-对三氟甲基苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-p-trifluoromethylphenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例5中，所用的(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮用等摩尔的(2-(2-羟基乙基)-4,5-二甲氧基苯基)对三氟甲基苯甲酮替换，其它步骤与实施例1相同，制备成黄色固体，其产率为86％，表征数据为：1H NMR(600MHz,CDCl3)δ7.62(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),6.68(s,2H),5.13(d,J＝12.1Hz,1H),4.98(d,J＝12.1Hz,1H),4.00(ddd,J＝11.4,5.8,2.6Hz,1H),3.90(s,3H),3.87(s,3H),3.61(td,J＝11.1,3.8Hz,1H),3.05(ddd,J＝16.3,10.6,5.9Hz,1H),2.56(dt,J＝16.1,3.1Hz,1H)；13C NMR(151MHz,CDCl3)δ149.11,147.27,145.21,127.99,127.98,127.79,125.60,125.62,123.90,112.08,110.44,82.47,79.45,60.86,56.38,55.88,27.91.In Example 5, the (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl)benzophenone used was equimolar with (2-(2-hydroxyethyl)-4, 5-dimethoxyphenyl) p-trifluoromethyl benzophenone was replaced, and the other steps were the same as in Example 1 to prepare a yellow solid with a yield of 86%, and the characterization data were: 1 H NMR (600MHz, CDCl 3 ) δ7.62(d, J=8.4Hz, 2H), 7.57(d, J=8.4Hz, 2H), 6.68(s, 2H), 5.13(d, J=12.1Hz, 1H), 4.98(d ,J=12.1Hz,1H),4.00(ddd,J=11.4,5.8,2.6Hz,1H),3.90(s,3H),3.87(s,3H),3.61(td,J=11.1,3.8Hz, 1H), 3.05 (ddd, J＝16.3, 10.6, 5.9Hz, 1H), 2.56 (dt, J＝16.1, 3.1Hz, 1H); 13 C NMR (151MHz, CDCl 3 ) δ149.11, 147.27, 145.21, 127.99, 127.98, 127.79, 125.60, 125.62, 123.90, 112.08, 110.44, 82.47, 79.45, 60.86, 56.38, 55.88, 27.91.
实施例6Example 6
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-异丁基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-isobutylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例6中，所用的(2-(β-羟乙基)-4,5-二甲氧基苯基)苯甲酮用等摩尔的(2-(2-羟基乙基)-4,5-二甲氧基苯基)异戊酮替换，其它步骤与实施例1相同，制备成白色固体，其产率为69％，表征数据为：1H NMR(600MHz,CDCl3)δ6.65(s,1H),6.58(s,1H),4.92(d,J＝12.1Hz,1H),4.68(d,J＝12.1Hz,1H),3.85-3.88(m,1H),3.79(s,3H),3.76(s,3H),3.48-3.55(m,1H),2.92-3.05(m,1H),2.42-2.35(m,1H),1.62-1.65(m,1H),1.78-1.85(m,2H),0.90-0.93(m,6H)；13C NMR(151MHz,CDCl3)δ146.11,145.90,127.99,127.51,111.48,108.41,80.37,76.92,60.05,56.21,55.80,47.20,29.2,23.91,22.60.In Example 6, the (2-(β-hydroxyethyl)-4,5-dimethoxyphenyl)benzophenone used was equimolar with (2-(2-hydroxyethyl)-4, 5-Dimethoxyphenyl) isoamylone was replaced, and the other steps were the same as in Example 1 to prepare a white solid with a yield of 69%. The characterization data was: 1 H NMR (600MHz, CDCl 3 ) δ6.65 (s,1H),6.58(s,1H),4.92(d,J=12.1Hz,1H),4.68(d,J=12.1Hz,1H),3.85-3.88(m,1H),3.79(s, 3H),3.76(s,3H),3.48-3.55(m,1H),2.92-3.05(m,1H),2.42-2.35(m,1H),1.62-1.65(m,1H),1.78-1.85( m,2H),0.90-0.93(m,6H); 13 C NMR(151MHz,CDCl 3 )δ146.11,145.90,127.99,127.51,111.48,108.41,80.37,76.92,60.05,56.21,55.80,47.20,29.1,23. ,22.60.
实施例7Example 7
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-phenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例7中，所用的反应温度替换为20℃，反应时间替换为2天，其它步骤与实施例1相同，制备成白色固体，其产率为29％，所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据如下：1H NMR(600MHz,CDCl3)δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J＝12.1Hz,1H),4.89(d,J＝12.1Hz,1H),3.88(ddd,J＝11.6,6.1,2.0Hz,1H),3.81(s,3H),3.79(s,3H),3.52(td,J＝11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H)；13C NMR(151MHz,CDCl3)δ147.77,145.93,140.08,127.64,127.56,126.86,126.54,123.46,110.88,109.78,81.96,78.86,59.48,55.30,54.80,26.96.In Example 7, the reaction temperature used was replaced by 20°C, and the reaction time was replaced by 2 days. The other steps were the same as in Example 1, and a white solid was prepared with a yield of 29%. Characterized by Fourier digital nuclear magnetic resonance spectrometer, the characterization data are as follows: 1 H NMR (600MHz, CDCl 3 ) δ7.40–7.39 (m, 2H), 7.36–7.32 (m, 3H), 6.64 (s, 1H), 6.58 (s,1H),5.06(d,J=12.1Hz,1H),4.89(d,J=12.1Hz,1H),3.88(ddd,J=11.6,6.1,2.0Hz,1H),3.81(s, 3H), 3.79(s, 3H), 3.52(td, J=11.4, 3.7Hz, 1H), 3.05–2.89(m, 1H), 2.52–2.33(m, 1H); 13 C NMR (151MHz, CDCl 3 )δ147.77, 145.93, 140.08, 127.64, 127.56, 126.86, 126.54, 123.46, 110.88, 109.78, 81.96, 78.86, 59.48, 55.30, 54.80, 26.96.
实施例8Example 8
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-phenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例8中，所用的(2-(2-羟基乙基)-4,5-二甲氧基苯基)苯甲酮172mg(0.6mmol)和硝基烷烃32uL(0.6mmol)混合均匀，反应时间替换为3天，其它步骤与实施例1相同，制备成白色固体，其产率为58％，所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据如下：1H NMR(600MHz,CDCl3)δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J＝12.1Hz,1H),4.89(d,J＝12.1Hz,1H),3.88(ddd,J＝11.6,6.1,2.0Hz,1H),3.81(s,3H),3.79(s,3H),3.52(td,J＝11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H)；13C NMR(151MHz,CDCl3)δ147.77,145.93,140.08,127.64,127.56,126.86,126.54,123.46,110.88,109.78,81.96,78.86,59.48,55.30,54.80,26.96.In Example 8, 172 mg (0.6 mmol) of (2-(2-hydroxyethyl)-4,5-dimethoxyphenyl) benzophenone and 32 uL (0.6 mmol) of nitroalkane were mixed uniformly, The reaction time was replaced by 3 days, and other steps were the same as in Example 1, and a white solid was prepared with a yield of 58%. The resulting product was characterized by a Bruker Avance type superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were as follows: 1 H NMR(600MHz, CDCl 3 )δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J=12.1Hz, 1H), 4.89(d, J=12.1Hz, 1H), 3.88(ddd, J=11.6, 6.1, 2.0Hz, 1H), 3.81(s, 3H), 3.79(s, 3H), 3.52(td, J =11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H); 13 C NMR(151MHz,CDCl 3 )δ147.77,145.93,140.08,127.64,127.56,126.86,126.54, 123.46, 110.88, 109.78, 81.96, 78.86, 59.48, 55.30, 54.80, 26.96.
实施例9Example 9
以制备下式化合物1-硝基甲基-6,7-二甲氧基-1-苯基异苯并二氢吡喃为例，所用原料及其制备方法如下：Taking the preparation of the compound of the following formula 1-nitromethyl-6,7-dimethoxy-1-phenylisochroman as an example, the raw materials used and its preparation method are as follows:
在实施例9中，所用的(2-(2-羟基乙基)-4,5-二甲氧基苯基)苯甲酮172mg(0.6mmol)和硝基烷烃160uL(3mmol)混合均匀，反应温度替换120℃，其它步骤与实施例1相同，制备成白色固体，其产率为80％，所得产物用Bruker Avance型超导傅立叶数字化核磁共振谱仪进行表征，表征数据如下：1H NMR(600MHz,CDCl3)δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J＝12.1Hz,1H),4.89(d,J＝12.1Hz,1H),3.88(ddd,J＝11.6,6.1,2.0Hz,1H),3.81(s,3H),3.79(s,3H),3.52(td,J＝11.4,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H)；13C NMR(151MHz,CDCl3)δ147.77,145.93,140.08,127.64,127.56,126.86,126.54,123.46,110.88,109.78,81.96,78.86,59.48,55.30,54.80,26.96.In Example 9, 172 mg (0.6 mmol) of (2-(2-hydroxyethyl)-4,5-dimethoxyphenyl) benzophenone and 160 uL (3 mmol) of nitroalkane were mixed uniformly, and the reaction The temperature was replaced by 120° C., and the other steps were the same as in Example 1 to prepare a white solid with a yield of 80%. The resulting product was characterized by a Bruker Avance type superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were as follows: 1 H NMR ( 600MHz, CDCl 3 )δ7.40–7.39(m,2H),7.36–7.32(m,3H),6.64(s,1H),6.58(s,1H),5.06(d,J＝12.1Hz,1H) ,4.89(d,J=12.1Hz,1H),3.88(ddd,J=11.6,6.1,2.0Hz,1H),3.81(s,3H),3.79(s,3H),3.52(td,J=11.4 ,3.7Hz,1H),3.05–2.89(m,1H),2.52–2.33(m,1H); 13 C NMR(151MHz,CDCl 3 )δ147.77,145.93,140.08,127.64,127.56,126.86,126.54,123.46, 110.88, 109.78, 81.96, 78.86, 59.48, 55.30, 54.80, 26.96.
该方法在无溶剂无催化剂的条件下将羟乙基取代的芳酮和硝基烷烃直接混合，利用羟乙基的邻基参与效应直接反应得到高产率的α位双取代的异色满。本发明所用的方法无需催化剂和溶剂，原子经济性高，反应条件温和、高效，反应步骤短，操作简单，制备得到的α-取代异色满衍生物在药物、活性的天然产物的制备中具有很大的应用潜力。In the method, the aryl ketone substituted by hydroxyethyl group and nitroalkane are directly mixed under the condition of no solvent and no catalyst, and the adjacent group of hydroxyethyl group is used to participate in the direct reaction to obtain the α-position disubstituted isochroman with high yield. The method used in the present invention does not need catalysts and solvents, has high atom economy, mild and efficient reaction conditions, short reaction steps, and simple operation, and the prepared α-substituted isochroman derivatives are useful in the preparation of medicines and active natural products. Great application potential.
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| CN112321556B (en) * | 2020-11-10 | 2022-10-11 | 西安石油大学 | A three-component method for preparing α,α-disubstituted isochroman derivatives |
| CN112321402B (en) * | 2020-11-10 | 2022-11-29 | 西安石油大学 | A kind of method that two-component coupling prepares 2-hydroxyethyl phenyl ketone |
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