CN112142660A - Method for simply, conveniently and efficiently synthesizing 4-aryl butyric acid derivative - Google Patents

Method for simply, conveniently and efficiently synthesizing 4-aryl butyric acid derivative Download PDF

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CN112142660A
CN112142660A CN202011072220.7A CN202011072220A CN112142660A CN 112142660 A CN112142660 A CN 112142660A CN 202011072220 A CN202011072220 A CN 202011072220A CN 112142660 A CN112142660 A CN 112142660A
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aminoquinoline
reaction
fluoride
acid derivative
enamide
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CN112142660B (en
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卢明祝
罗海青
胡正松
邵长栋
阚玉和
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Lanzhou Yaben Fine Chemical Co ltd
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Huaiyin Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/40—Nitrogen atoms attached in position 8

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Abstract

The invention discloses a method for simply, conveniently and efficiently synthesizing 4-aryl butyric acid derivatives, which utilizes removable 8-aminoquinoline as a guide group to control the regioselectivity of reaction, uses non-activated 3-butenamide as a reaction raw material to react with cheap, easily obtained, stable and efficient aryl trimethoxy silane, and simply and efficiently prepares and synthesizes series of functionalized 4-aryl butyric acid derivatives. The method has the advantages of simple and convenient operation, simple and easily obtained reaction raw materials, easy separation and purification of the product, high product yield and good reaction area selectivity. The invention can provide related products for treating urea circulation disorder, novel anti-II type diabetes drugs, angiotensin converting enzyme inhibitors and the like, and has good market potential and application value.

Description

Method for simply, conveniently and efficiently synthesizing 4-aryl butyric acid derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a method for simply, conveniently and efficiently synthesizing a 4-aryl butyric acid derivative.
Background
The carboxylic acid and the derivatives thereof are widely existed in molecules such as medicines, pesticides, natural products and the like, and many carboxylic acids and the derivatives thereof are organic drug small molecules with specific physiological activity and are used for treating common diseases such as leukemia, hypertension, ovarian cancer, diabetes and the like. 4-aryl butyric acid and derivatives thereof are important, such as sodium phenylbutyrate (Buphenyl) is an important prodrug, and is used for treating urea circulation disorder, and can effectively reduce the content of blood ammonia and blood glutamic acid; chlorambucil (Chlorambucil) is used for treating Hodgkin's disease, various non-Hodgkin's lymphomas, chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and advanced ovarian adenocarcinoma, and has significant effects on part of breast cancer patients; for another example, sitagliptin (sitagliptin) is a novel anti-type II diabetes drug approved by FDA to be on the market, is the first dipeptidyl peptidase-IV inhibitor drug for treating type II diabetes, is different from the conventional oral hypoglycemic drugs, has the advantages of safe taking, good tolerance, less adverse reaction and the like, and has a huge market application prospect. In addition, 4-arylbutyric acid and its derivatives such as benazepril (benezepril), enalapril (enalapril), imidapril (imidapril), lisinopril (lisinopril), temocapril (temocapril) and the like are also widely used angiotensin converting enzyme inhibitors (ACE). Therefore, the development of a preparation method of the 4-aryl butyric acid derivative with simplicity, high efficiency, high selectivity and high yield is an important research content of synthetic chemistry, and has wide market application prospect. However, the catalytic synthesis systems reported so far have many disadvantages, such as: narrow substrate range, harsh reaction conditions, excessive additive amount, lengthy synthesis steps, relatively low yield, etc. Therefore, the development of better methods for synthesizing 4-aryl butyric acid and derivatives is the goal and continuous direction of effort pursued by researchers in the industry.
Disclosure of Invention
The invention aims to provide a method for simply, conveniently and efficiently synthesizing a 4-aryl butyric acid derivative, which has the advantages of low reaction cost, simplicity, high efficiency, high selectivity and wide applicability.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for synthesizing 4-aryl butyric acid derivatives simply and efficiently uses non-activated 3-butenamide as a reaction raw material to react with cheap and easily available aryl trimethoxy silane under the catalysis condition, and prepares and synthesizes a series of functionalized 4-aryl butyric acid derivatives simply and efficiently; the method comprises the following specific steps: in an organic solvent system, taking substituted 3-butenamide shown in a formula (1) and substituted aryl trimethoxy silane shown in a formula (2) as raw materials, adding a proton source in the presence of a palladium catalyst and a silane activating agent, heating a reaction mixture to 80-120 ℃, stirring and refluxing for reaction, and tracking and detecting by TLC (thin layer chromatography) until the reaction is complete; finally, carrying out post-treatment to obtain a target compound, namely a 4-aryl butyric acid derivative shown in a formula (3); wherein the molar ratio of the substituted 3-butenamide to the substituted aryltrimethoxysilane to the palladium catalyst to the silane activator is 1: 2-3: 0.1: 2-3, wherein the molar ratio of the proton source to the substituted 3-butenamide is 1: 5-10.
The reaction equation is as follows:
Figure BDA0002715456800000021
AQ in the formula is a removable guide auxiliary group 8-aminoquinoline; r is any one of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, naphthyl and benzyl substituted propyl, wherein the substituent is phenyl or methoxy.
Preferably, the substituted 3-butenamide is N- (8-aminoquinoline) but-3-enamide, 2-methyl-N- (8-aminoquinoline) but-3-enamide, 2-ethyl-N- (8-aminoquinoline) but-3-enamide, 2-isopropyl-N- (8-aminoquinoline) but-3-enamide, 2-cyclopropyl-N- (8-aminoquinoline) but-3-enamide, 2- (3-methoxypropyl) -N- (8-aminoquinoline) but-3-enamide, 2-benzyl-N- (8-aminoquinoline) but-3-enamide, or mixtures thereof, Any one of 2-phenylpropyl-N- (8-aminoquinoline) but-3-enamide.
Preferably, the substituted aryltrimethoxysilane is phenyltrimethoxysilane, 4-methylphenyltrimethoxysilane, 4-fluorophenyltrimethoxysilane, 4-chlorophenyltrimethoxysilane, 4-isopropylphenyltrimethoxysilane, 4-butylphenyltrimethoxysilane, 4-tert-butylphenyl-trimethoxysilane, 4-biphenyltrimethoxysilane, 4-methoxyphenyltrimethoxysilane, 4-vinylphenyltrimethoxysilane, 4-trifluoromethylphenyltrimethoxysilane, 4-trifluoromethoxyphenyltrimethoxysilane, 3-methylphenyltrimethoxysilane, 3-fluorophenyltrimethoxysilane, 3-trifluoromethylphenyltrimethoxysilane, 3-methoxyphenyltrimethoxysilane, m-propyltrimethoxysilane, m-butyltrimethoxysilane, m-butylphenyltrimethoxysilane, m-butyltrimethoxysilane, 2-methylphenyltrimethoxysilane, 2-methoxyphenyltrimethoxysilane, 2-trifluoromethylphenyltrimethoxysilane, 1-naphthyltrimethoxysilane, 2, 3-dimethylphenyltrimethoxysilane, 2-methyl-3-fluorophenyltrimethoxysilane, 2-methoxy-4-fluorophenyltrimethoxysilane, 2, 4-dimethylphenyltrimethoxysilane, 2-methyl-4-methoxyphenyltrimethoxysilane, 2-methyl-5-fluorophenyltrimethoxysilane, 2, 5-dimethylphenyltrimethoxysilane, 3-methyl-4-fluorophenyltrimethoxysilane, 2-trifluoromethylphenyltrimethoxysilane, 2-phenyltrimethoxysilane, 2-, 3-methyl-4-chlorophenyltrimethoxysilane, 3-methyl-4-methoxyphenyl trimethoxysilane, 2, 4-dimethoxyphenyltrimethoxysilane, 3, 5-dimethylphenyltrimethoxysilane, 3-fluoro-5-methoxyphenyl trimethoxysilane, 2,4, 5-trimethylphenyltrimethoxysilane, 2,4, 6-trimethylphenyltrimethoxysilane, 3, 5-dimethoxy-4-methoxyphenyl trimethoxysilane.
Preferably, the catalyst is any one of palladium acetate, palladium trifluoroacetate, palladium pivalate, palladium chloride, tetranitrile palladium tetrafluoroborate, allyl palladium (II) chloride dimer and tris (dibenzylideneacetone) dipalladium.
Preferably, the silane activating agent is any one of lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, iron fluoride, copper fluoride, magnesium fluoride, zinc fluoride and manganese fluoride.
Preferably, the proton source is any one of acetic acid, pivalic acid, water, methanol, ethanol and tert-butanol.
Preferably, the organic solvent is any one of dichloromethane, chloroform, acetone, acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, 1, 2-dichloroethane, dimethyl sulfoxide or N, N-dimethylformamide.
Preferably, the post-processing step is: after the reaction is finished, pouring the reaction liquid into saturated saline solution, extracting with dichloromethane, combining organic phases, drying through anhydrous sodium sulfate, filtering, distilling under reduced pressure, then separating through silica gel column chromatography, distilling the obtained eluent under reduced pressure, and drying to obtain the 4-aryl butyric acid derivative shown in the formula (3).
Compared with the prior art, the method has the advantages that the reaction area and chemical selectivity are controlled by designing 8-aminoquinoline as a guide group, the 4-aryl butyric acid derivative substituted by the double bond end is directly obtained by reacting with cheap and easily available aryl trimethoxy silane, and the problem of complicated steps in the synthesis process of the 4-aryl butyric acid derivative is effectively solved; meanwhile, the method has the characteristics of good reaction regioselectivity, high product yield, mild reaction conditions, simple and convenient reaction and post-treatment purification process operation and the like. The invention can provide related products for treating urea circulation disorder, novel anti-II type diabetes drugs, angiotensin converting enzyme inhibitors and the like, and has good market potential and application value.
Drawings
FIG. 1 is a diagram of 4-arylbutyric acid derivative 3a1Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is a diagram of 4-arylbutyric acid derivative 3a13Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 is a diagram of 4-arylbutyric acid derivative 3c1Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is a diagram of 4-arylbutyric acid derivative 3c13Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is a drawing showing the preparation of 4-arylbutyric acid derivative 3e1Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 is a drawing showing the preparation of 4-arylbutyric acid derivative 3e13Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 shows 3g of 4-arylbutyric acid derivative1Nuclear magnetic resonance spectrum of H-NMR;
FIG. 8 shows 3g of 4-arylbutyric acid derivative13Nuclear magnetic resonance spectrum of C-NMR;
FIG. 9 is a drawing showing the preparation of 4-arylbutyric acid derivative 3i1Nuclear magnetic resonance spectrum of H-NMR;
FIG. 10 shows 4-arylbutyric acid derivative 3iIs/are as follows13Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified, and the purity thereof is analytical or higher.
Example 1
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of phenyltrimethoxysilane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid, the desired product is passed over1H NMR、13The C NMR test showed 4-arylbutyric acid derivative 3a in 77% yield.1H NMR(400MHz,CDCl3)9.79(s,1H),8.81-8.77(m,2H),8.14(dd, J ═ 8.2,1.3Hz,1H),7.56-7.47(m,2H),7.44(dd, J ═ 8.2,4.2Hz,1H),7.32-7.27(m,2H),7.26-7.17(m,3H),2.77(t, J ═ 7.5Hz,2H),2.57(t, J ═ 7.5Hz,2H),2.21-2.11(m,2H) (fig. 1);13C NMR(100MHz,CDCl3)171.36,148.06,141.47,138.31,136.31,134.49,128.54,128.38,127.91,127.39,125.93,121.53,121.34,116.41,37.27,35.16,26.99 (FIG. 2).
Example 2
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 4-methylphenyl trimethoxy silane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid, the expected compound is passed through1H NMR、13The C NMR test showed 4-arylbutyric acid derivative 3b in 73% yield.1H NMR(400MHz,CDCl3)9.78(s,1H),8.82-8.75(m,2H),8.14(dd,J＝8.3,1.7Hz,1H),7.56-7.47(m,2H),7.44(dd,J＝8.3,4.2Hz,1H),7.15-7.08(m,4H),2.73(t,J＝7.5Hz,2H),2.56(t,J＝7.5Hz,2H),2.31(s,3H),2.19-2.10(m,2H)；13C NMR(100MHz,CDCl3)171.46,148.06,138.37,138.33,136.32,135.38,134.52,129.07,128.43,127.92,127.41,121.53,121.33,116.42,37.31,34.73,27.10,20.96.
Example 3
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 4-fluorophenyl trimethoxy silane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR、13The C NMR test showed 4-arylbutyric acid derivative 3C in 82% yield.1H NMR(400MHz,CDCl3)9.78(s,1H),8.82-8.75(m,2H),8.15(dd,J＝8.3,1.6Hz,1H),7.56-7.47(m,2H),7.44(dd,J＝8.3,4.2Hz,1H),7.21-7.15(m,2H),7.00-6.93(m,2H),2.73(t, J ═ 7.6Hz,2H),2.56(t, J ═ 7.4Hz,2H),2.17-2.08(m,2H) (fig. 3);13C NMR(100MHz,CDCl3)171.22,161.33(d, J-242.0 Hz),148.08,138.29,137.07(d, J-3.1 Hz),136.34,134.43,129.84(d, J-7.7 Hz),127.92,127.39,121.48(d, J-15.4 Hz),116.42,115.20,114.99,37.10,34.31,27.10 (fig. 4);19F NMR(376MHz,CDCl3)-117.56.
example 4
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 4-trifluoromethoxyphenyl trimethoxy silane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13The C NMR test showed 4-arylbutyric acid derivative 3d in a yield of 70%.1H NMR(400MHz,CDCl3)9.82(s,1H),8.85-8.78(m,2H),8.18(dd,J＝8.3,1.6Hz,1H),7.60-7.50(m,2H),7.47(dd,J＝8.3,4.2Hz,1H),7.30-7.25(m,2H),7.19-7.13(m,2H),2.83-2.77(m,2H),2.60(t,J＝7.4Hz,2H),2.22-2.13(m,2H)；13C NMR(100MHz,CDCl3)171.10,148.10,147.52,140.23,138.32,136.37,134.43,129.76,127.95,127.41,121.58,121.45,120.93,120.51(d,J＝255.0Hz),116.46,37.09,34.44,26.89；19F NMR(376MHz,CDCl3)-57.91.
Example 5
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 3-trimethoxyphenyltrimethoxysilane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetateNo. 5:1) to give a colorless solid which was passed through1H NMR,13The C NMR test showed 4-arylbutyric acid derivative 3e in a yield of 78%.1H NMR(400MHz,CDCl3)9.79(s,1H),8.80-8.77(m,2H),8.14(dd, J ═ 8.3,1.6Hz,1H),7.56-7.46(m,2H),7.44(dd, J ═ 8.3,4.2Hz,1H),7.21(t, J ═ 7.8Hz,1H),6.86-6.78(m,2H),6.75(dd, J ═ 8.2,2.4Hz,1H),3.78(s,3H),2.75(t, J ═ 7.5Hz,2H),2.57(t, J ═ 7.5Hz,2H),2.20-2.10(m,2H) (fig. 5);13C NMR(100MHz,CDCl3)171.38,159.68,148.07,143.10,138.30,136.31,134.47,129.33,127.90,127.38,121.53,121.35,120.95,116.41,114.19,111.37,55.09,37.24,35.20,26.86 (fig. 6).
Example 6
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 2-trifluoromethylphenyltrimethoxysilane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13C NThe MR test showed 4-arylbutyric acid derivative 3f with a yield of 81%.1H NMR(400MHz,CDCl3)9.82(s,1H),8.83-8.76(m,2H),8.15(dd,J＝8.3,1.5Hz,1H),7.62(d,J＝7.9Hz,1H),7.56-7.41(m,5H),7.28(t,J＝7.6Hz,1H),2.97-2.91(m,2H),2.65(t,J＝7.5Hz,2H),2.22-2.12(m,2H)；13C NMR(100MHz,CDCl3)171.02,148.09,140.40,138.31,136.32,134.45,131.77,131.07,128.47(d,J＝29.5Hz),127.91,126.03,125.89(q,J＝5.7Hz),123.27,121.55,121.39,116.44,37.50,31.86,27.07；19F NMR(376MHz,CDCl3)-59.48.
Example 7
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 1-naphthyltrimethoxysilane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13The C NMR measurement confirmed 3g of the 4-arylbutyric acid derivative in a yield of 76%.1H NMR(400MHz,CDCl3)9.79(s,1H),8.84-8.74(m,2H),8.15-8.07(m,2H),7.86-7.81(m,1H),7.71(dt, J ═ 7.0,3.6Hz,1H),7.55-7.44(m,4H),7.44-7.35(m,3H),3.26-3.18(m,2H),2.64(t, J ═ 7.3Hz,2H),2.33-2.23(m,2H) (fig. 7);13C NMR(100MHz,CDCl3)171.30,148.05,138.30,137.62,136.29,134.48,133.90,131.87,128.69,127.90,127.38,126.76,126.21,125.83,125.46,125.44,123.84,121.51,121.35,116.45,37.52,32.33,26.28 (fig. 8).
Example 8
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 3-methyl-4-chlorphenyl trimethoxy silane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13C NMR measurement confirmed the 4-arylbutyric acid derivative for 3h, with a yield of 85%.1H NMR(400MHz,CDCl3)9.77(s,1H),8.82-8.74(m,2H),8.14(dd,J＝8.3,1.6Hz,1H),7.56-7.46(m,2H),7.44(dd,J＝8.3,4.2Hz,1H),7.23(d,J＝8.1Hz,1H),7.09(d,J＝1.6Hz,1H),6.99(dd,J＝8.1,2.0Hz,1H),2.69(t,J＝7.5Hz,2H),2.55(t,J＝7.4Hz,2H),2.32(s,3H),2.17-2.07(m,2H)；13C NMR(100MHz,CDCl3)171.21,148.07,139.96,138.29,136.33,135.78,134.43,131.81,131.16,128.90,127.91,127.38,127.27,121.54,121.40,116.42,113.82,37.09,34.41,26.87,19.93.
Example 9
(1) Adding 0.2mmol of N- (8-aminoquinoline) but-3-enamide, 0.4mmol of 2-methoxy-4-fluorophenyl trimethoxy silane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing in 100 deg.C oil bath, stirring vigorously, reacting for 24 hr, and performing TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13The C NMR test showed 3i, a 83% yield, of the 4-arylbutyric acid derivative.1H NMR(400MHz,CDCl3)9.78(s,1H),8.83-8.74(m,2H),8.14(dd, J ═ 8.3,1.6Hz,1H),7.56-7.46(m,2H),7.44(dd, J ═ 8.3,4.2Hz,1H),7.10(t, J ═ 7.4Hz,1H),6.62-6.53(m,2H),3.77(s,3H),2.71(t, J ═ 7.4Hz,2H),2.56(t, J ═ 7.5Hz,2H),2.15-2.04(m,2H) (fig. 9);13C NMR(100MHz,CDCl3)171.59,162.22(d, J-241.6 Hz),158.42(d, J-9.5 Hz),148.03,138.32,136.32,134.54,130.41(d, J-9.7 Hz),127.92,127.41,125.36(d, J-3.2 Hz),121.51,121.34,116.41,106.32(d, J-20.6 Hz),98.65(d, J-25.4 Hz),55.39,37.47,29.03,25.58 (fig. 10);19F NMR(376MHz,CDCl3)-114.46.
example 10
(1) Adding 0.2mmol of 2-methyl-N- (8-aminoquinoline) but-3-enamide, 0.4mmol of phenyltrimethoxysilane, 0.02mmol of palladium acetate, 0.4mmol of copper fluoride, 2.0mmol of acetic acid and 2.0mL of tetrahydrofuran into a reaction vessel under the condition of air, and uniformly mixing and stirring; the reaction vessel is a pressure-resistant sealing tube containing a magnetic stirrer;
(2) sealing the reaction vessel, placing the reaction vessel into an oil bath at 100 ℃ to be vigorously stirred for reaction for 24 hours, and carrying out TLC (developing solvent is V)Petroleum ether:VEthyl acetate9:1) end of the substrate disappearance reaction. The reaction mixture was poured into saturated brine (15mL), extracted with dichloromethane (3X 10mL), the combined organic phases were dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, etc., and subjected to silica gel column chromatography (eluent V)Petroleum ether:VEthyl acetate9:1) to give a colorless solid which is passed through1H NMR,13The C NMR test showed 4-arylbutyric acid derivative 3j in a yield of 77%.1H NMR(400MHz,CDCl3)9.87(s,1H),8.86-8.78(m,2H),8.16(dd,J＝8.3,1.6Hz,1H),7.57-7.48(m,2H),7.45(dd,J＝8.3,4.2Hz,1H),7.30-7.16(m,5H),2.82-2.67(m,2H),2.67-2.58(m,1H),2.27-2.16(m,1H),1.91-1.81(m,1H),1.36(d,J＝6.9Hz,3H)；13C NMR(100MHz,CDCl3)174.95,148.10,141.72,138.47,136.32,134.53,128.47,128.36,127.93,127.42,125.85,121.55,121.37,116.50,42.25,36.00,33.60,18.20.
The following table shows the structural formulae and yields of the products 3a to 3j obtained in examples 1 to 10:
Figure BDA0002715456800000101
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the compounds 3a to 3j prepared in the above examples can confirm that: the target product 4-aryl butyric acid derivative prepared by the invention meets the quality requirement, has enough selection space in the component raw material proportion and the structure diversification of the target product, and brings different changes to the yield of the target product only by the feed ratio among the component raw materials, the slight difference of reaction conditions and the change of the electrical property and position of a substituent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (8)

1. A method for synthesizing a 4-aryl butyric acid derivative simply, conveniently and efficiently is characterized in that in an organic solvent system, substituted 3-butenamide shown in a formula (1) and substituted aryl trimethoxy silane shown in a formula (2) are used as raw materials, a proton source is added under the condition that a palladium catalyst and a silane activating agent exist, a reaction mixture is heated to 80-120 ℃, stirred and refluxed for reaction, and tracking and detection are carried out by TLC until the reaction is complete; finally, carrying out post-treatment to obtain a target compound, namely a 4-aryl butyric acid derivative shown in a formula (3); wherein the molar ratio of the substituted 3-butenamide to the substituted aryltrimethoxysilane to the palladium catalyst to the silane activator is 1: 2-3: 0.1: 2-3, wherein the molar ratio of the proton source to the substituted 3-butenamide is 1: 5-10;
Figure FDA0002715456790000011
AQ in the formula is a removable guide auxiliary group 8-aminoquinoline; r is any one of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, phenyl, naphthyl and benzyl substituted propyl, wherein the substituent is phenyl or methoxy.
2. The method of claim 1, wherein the substituted 3-butenamide is N- (8-aminoquinoline) but-3-enamide, 2-methyl-N- (8-aminoquinoline) but-3-enamide, 2-ethyl-N- (8-aminoquinoline) but-3-enamide, 2-isopropyl-N- (8-aminoquinoline) but-3-enamide, 2-cyclopropyl-N- (8-aminoquinoline) but-3-enamide, 2- (3-methoxypropyl) -N- (8-aminoquinoline) but-3-enamide, or a mixture thereof, Any one of 2-benzyl-N- (8-aminoquinoline) but-3-enamide and 2-phenylpropyl-N- (8-aminoquinoline) but-3-enamide.
3. The method of claim 1, wherein the substituted aryltrimethoxysilane is selected from the group consisting of phenyltrimethoxysilane, 4-methylphenyltrimethoxysilane, 4-fluorophenyltrimethoxysilane, 4-chlorophenyltrimethoxysilane, 4-isopropylphenyltrimethoxysilane, 4-butylphenyltrimethoxysilane, 4-tert-butylphenyl trimethoxysilane, 4-biphenyltrimethoxysilane, 4-methoxyphenyl trimethoxysilane, 4-vinylphenyltrimethoxysilane, 4-trifluoromethylphenyltrimethoxysilane, 4-trifluoromethoxyphenyl trimethoxysilane, 3-methylphenyltrimethoxysilane, 3-fluorophenyltrimethoxysilane, 4-fluorophenyltrimethoxysilane, and the like, 3-trifluoromethylphenyltrimethoxysilane, 3-methoxyphenyltrimethoxysilane, 2-methylphenyltrimethoxysilane, 2-methoxyphenyltrimethoxysilane, 2-trifluoromethylphenyltrimethoxysilane, 2-trifluoromethoxyphenyltrimethoxysilane, 1-naphthyltrimethoxysilane, 2, 3-dimethylphenyltrimethoxysilane, 2-methyl-3-fluorophenyltrimethoxysilane, 2-methoxy-4-fluorophenyltrimethoxysilane, 2, 4-dimethylphenyltrimethoxysilane, 2-methyl-4-methoxyphenyltrimethoxysilane, 2-methyl-5-fluorophenyltrimethoxysilane, 2, 5-dimethylphenyltrimethoxysilane, 3-methyl-4-fluorophenyltrimethoxysilane, 3-methyl-4-chlorophenyltrimethoxysilane, 3-methyl-4-methoxyphenyltrimethoxysilane, 2, 4-dimethoxyphenyltrimethoxysilane, 3, 5-dimethylphenyltrimethoxysilane, 3-fluoro-5-methoxyphenyltrimethoxysilane, 2,4, 5-trimethylphenyltrimethoxysilane, 2,4, 6-trimethylphenyltrimethoxysilane, 3, 5-dimethoxy-4-methoxyphenyltrimethoxysilane.
4. The method of claim 1, wherein the catalyst is any one of palladium acetate, palladium trifluoroacetate, palladium pivalate, palladium chloride, tetraacetonitrile palladium tetrafluoroborate, allylpalladium (II) chloride dimer, and tris (dibenzylideneacetone) dipalladium.
5. The method of claim 1, wherein the silane activator is any one of lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, silver fluoride, iron fluoride, copper fluoride, magnesium fluoride, zinc fluoride, and manganese fluoride.
6. The method for synthesizing a 4-arylbutyric acid derivative according to claim 1, wherein the proton source is any one of acetic acid, pivalic acid, water, methanol, ethanol and tert-butanol.
7. The method for synthesizing a 4-arylbutyric acid derivative according to claim 1, wherein the organic solvent is any one of dichloromethane, chloroform, acetone, acetonitrile, diethyl ether, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, 1, 2-dichloroethane, dimethyl sulfoxide, or N, N-dimethylformamide.
8. The method for synthesizing 4-aryl butyric acid derivative according to claim 1, wherein the post-treatment comprises the following steps: after the reaction is finished, pouring the reaction liquid into saturated saline solution, extracting with dichloromethane, combining organic phases, drying through anhydrous sodium sulfate, filtering, distilling under reduced pressure, then separating through silica gel column chromatography, distilling the obtained eluent under reduced pressure, and drying to obtain the 4-aryl butyric acid derivative shown in the formula (3).
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