An allyl aromatic amine compound, a preparation method thereof and applications thereof

Abstract

The present invention discloses an allyl arylamine compound, a preparation method and an application thereof. The structural general formula of the allyl arylamine compound is shown as structure (3), wherein R is selected from a hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, an alkylthio group, an acyloxy group, a hydroxyl group, an amino group, a phenyl group, a substituted phenyl group, a pyridyl group, and a vinyl group. Compared with the existing ones, the allyl arylamine compound of the present invention can be efficiently and conveniently synthesized under mild conditions by a cheap palladium catalyst, and the aryl allylamine derivative is used for the development and application of drugs.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to an allyl arylamine compound, a method for preparing an allyl arylamine compound, and the use of an allyl arylamine compound in the preparation of drugs. Background Art

[0002] Aryl allylamine compounds are an important chemical skeleton, which widely exist and are applied in the structures of bioactive molecules and natural products. Their synthesis methods have always been the focus of attention of chemists. Their structural feature is that one of the groups connected to both ends of the nitrogen atom is an aryl group and the other is an allyl group. Such a structural characteristic makes aryl allylamine an important platform compound, which can be subsequently transformed and modified to generate target compounds with more complex structures and higher added values, having huge development space. Therefore, the synthesis of aryl allylamine compounds has always received much attention.

[0003] In the past, the widely used synthesis method for aryl allylamination reaction used allyl chloride and hexamethylenetetramine as reaction raw materials and potassium iodide as a catalyst to synthesize allylamine. This method has strict requirements for the reaction system, the selection of solvents is relatively harsh, and the recovery of chloroform is also a major problem, with low product conversion rate. In addition, another common synthesis method is: using allyl chloride and liquid ammonia as raw materials and cuprous chloride as a catalyst to synthesize allylamine. However, since thioisopropyl isocyanate and hydrochloric acid generally need to be reacted in a reflux device in the reaction system, the reactants are concentrated and crystallized and then liquid alkali is added to distill out allylamine. The preparation process is relatively cumbersome, the operation is complex, the reaction time is long, and the formation of a large number of by-products will lead to a decrease in the selectivity and yield of the target product. With subsequent development, a new method of transition metal-catalyzed allyl substitution reaction has gradually emerged. Most of these reactions are convenient, applicable to many cross-coupling reactions of allyl electrophiles and various nucleophiles, and then complete the functionalization reaction of olefins, making them useful molecular motifs.

[0004] However, generally speaking, these methods all have some deficiencies, such as noble metal catalysts, which are costly and difficult to popularize.

[0005] Therefore, it is worthy of further research to develop inexpensive metal catalysts, reduce the reaction cost, and make them have the potential for large-scale preparation; in addition, known reactions often require high temperature and high pressure conditions, otherwise the reaction effect is not good. Therefore, it is also very meaningful to develop efficient catalysts to enable the reaction to proceed under milder conditions and reduce energy consumption; and many of the above methods have limited substrate scopes. Therefore, developing catalytic methods with a wider practical range of substrates is also an issue that needs to be considered in the research. Summary of the Invention

[0006] In view of the above deficiencies, the present invention provides an allyl arylamine compound, which can be efficiently and conveniently synthesized under mild conditions by a cheap palladium catalyst, and the aryl allylamine derivative is used for the development and application of drugs.

[0007] An allyl arylamine compound, the structural general formula of the allyl arylamine compound is shown in Structure (1):

[0008]

[0009] Among them, R is selected from a hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, an alkylthio group, an acyloxy group, a hydroxyl group, an amino group, a phenyl group, a substituted phenyl group, a pyridyl group, and a vinyl group.

[0010] The allyl arylamine compound is prepared by the following reaction equation:

[0011]

[0012] Among them, R is selected from a hydrogen atom, an alkyl group, a substituted alkyl group, an alkoxy group, an alkylthio group, an acyloxy group, a hydroxyl group, an amino group, a phenyl group, a substituted phenyl group, a pyridyl group, and a vinyl group.

[0013] The present invention also provides a method for preparing the above allyl arylamine compound.

[0014] A method for preparing an allyl arylamine compound, the method for preparing the allyl arylamine compound uses palladium-catalyzed synthesis of aryl phenolic compounds and ethylene vinyl carbonate.

[0015] In one or more specific embodiments of the present invention, the method for preparing the allyl arylamine compound includes the following steps:

[0016] S1: Mix an arylamine compound, ethylene vinyl carbonate, a palladium catalyst, and an additive, then add an organic solvent, stir evenly and react, and obtain a mixed solution after the reaction;

[0017] S2: Concentrate and evaporate the mixed solution obtained in S1 to obtain a crude product;

[0018] S3: Extract, dry, filter, concentrate, and purify the crude product in S2 by column chromatography to obtain the product.

[0019] In one or more specific embodiments of the present invention, in S1, the reaction temperature is 70 °C and the reaction time is 15 h.

[0020] In one or more specific embodiments of the present invention, the molar ratio of the aryl phenolic compound to ethylene vinyl carbonate is 1:1.5.

[0021] In one or more specific embodiments of the present invention, the organic solvent is N,N-dimethylformamide.

[0022] In one or more specific embodiments of the present invention, the addition amount of the palladium catalyst is 5% of the molar amount of the arylphenol substrate.

[0023] In one or more specific embodiments of the present invention, the palladium catalyst is dichlorobis(diphenylphosphino)ferrocene palladium(II).

[0024] In one or more specific embodiments of the present invention, in S3, the extraction method for extraction is: adding a mixed solution of water and ethyl acetate to the crude product, stirring evenly and then standing until complete stratification, and then separating the organic layer and the water layer. The volume ratio of water to ethyl acetate in the mixed solution of water and ethyl acetate is 1-2:1.

[0025] In one or more specific embodiments of the present invention, in S3, the chromatography is column chromatography. The column used for column chromatography treatment is a silica gel column, and the chromatography solution is a mixed solution of petroleum ether and ethyl acetate mixed at a volume ratio of 10:1-5:1.

[0026] The present invention also provides an application of the above-mentioned allylarylamine compound.

[0027] The above-mentioned allylarylamine compound is applied to the preparation of drugs.

[0028] Principle and beneficial effects of the invention:

[0029] The present invention uses arylamine substrates with easily available raw materials and vinyl ethylene carbonate as reactants, inexpensive transition metal palladium as a catalyst, and anhydrous acetonitrile as a solvent. The reaction temperature is relatively mild, and the reaction by-product is only carbon dioxide, which is green and environmentally friendly.

[0030] The reaction conditions of the present invention are mild, the derivative range is wide, and the structural diversity of arylallylamine compounds is enriched. The synthesis method in the present invention solves problems such as harsh traditional reaction conditions, complex operations, substrate limitations, cumbersome steps, and poor functional group tolerance of substrates, and opens up a new path for the synthesis of arylallylamine compounds. Specific embodiments

[0031] The following further illustrates the present invention in conjunction with specific examples.

[0032] A method for preparing an allylarylamine compound, comprising the following steps:

[0033] S1: Add the following into a reaction tube: 0.20 mmol of arylamine substrate, 0.30 mmol of vinyl ethylene carbonate, 0.01 mmol of dichloropalladium(II) bis(diphenylphosphino)ferrocene, and 2 mL of anhydrous acetonitrile. Then react at 70 °C for 15 h to obtain a mixed solution containing the product.

[0034] S2: Concentrate and evaporate the mixed solution obtained in S1 to remove the solvent, and obtain the crude product.

[0035] S3: Extract the crude product obtained in S2 three times with water and ethyl acetate (volume ratio 1:1). Combine the organic layers, dry the organic layers with anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1 - 5 / 1) to obtain the product.

[0036] The following examples prepare allyl arylamine compounds according to the above S1 - S3 method.

[0037] Example 1

[0038] In this example, the structural formula of the arylamine substrate in S1 is:

[0039]

[0040] In this example, petroleum ether / ethyl acetate = 4:1.

[0041] In this example, the product obtained by separation and purification in S3 is (E)-4-(phenylamino)but-2-en-1-ol (English name: (E)-4-(phenylamino)but-2-en-1-ol), with a weight of 27 mg, a yield of 85%, and a purity of 99.5%. The structural formula and corresponding spectral data are as follows:

[0042]

[0043] 1 H NMR(600MHz,CDCl3)δ7.22–7.14(m,2H),6.72(t,J=7.5Hz,1H),6.62(d,J=7.8Hz,2H),5.92–5.82(m,2H),4.16(d,J=5.2Hz,2H),3.79(d,J=5.0Hz,2H). 13 C NMR(150MHz,CDCl3)δ142.11,134.66,128.20,126.65,118.73,116.85,116.61,111.61,63.89,56.43.ESI-HRMS(m / z):calcd for C 10 H 14 NO[M+H] +: 164.1075; found: 164.1078.

[0044] Example 2

[0045] In this example, the structural formula of the arylamine substrate of S1 is:

[0046]

[0047] In this example, petroleum ether / ethyl acetate = 2:1.

[0048] In this example, the product obtained by separating and purifying S3 is (E)-4-(m-tolylamino)but-2-en-1-ol (English name: (E)-4-(m-tolylamino)but-2-en-1-ol), with a weight of 28 mg, a yield of 79%, and a purity of 98.7%. The structural formula and corresponding spectral data are as follows:

[0049]

[0050] 1 H NMR (600 MHz, CDCl3) δ 7.08 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.4 Hz, 1H), 6.52–6.51 (m, 2H), 5.92–5.85 (m, 2H), 4.16–4.15 (m, 2H), 3.83–3.72 (m, 2H), 2.28 (s, 3H). 13 C NMR (150 MHz, CDCl3) δ 146.07, 138.12, 130.53, 128.15, 127.31, 118.37, 113.43, 109.80, 61.99, 45.05, 20.58. ESI-HRMS (m / z): calcd for C 11 H 16 NO[M+H] + : 178.1232; found: 178.1229.

[0051] Example 3

[0052] In this example, the structural formula of the arylamine substrate of S1 is:

[0053]

[0054] In this example, petroleum ether / ethyl acetate = 2:1.

[0055] In this example, the product obtained by separation and purification in S3 is (E)-4-([1,1'-biphenyl]-3-ylamino)but-2-en-1-ol, with a weight of 34 mg, a yield of 71%, and a purity of 98.5%. The structural formula and corresponding spectral data are as follows:

[0056]

[0057] 1 H NMR(600MHz,CDCl3)δ7.56–7.55(m,2H),7.41(t,J=7.7Hz,2H),7.35–7.30(m,1H),7.27–7.24(m,1H),6.99(d,J=7.6Hz,1H),6.90(s,1H),6.68(dd,J=7.1,0.9Hz,1H),6.03–5.86(m,2H),4.16–4.15(m,2H),3.89–3.78(m,2H). 13 C NMR(150MHz,CDCl3)δ146.31,141.46,140.45,130.78,128.65,127.62,127.02,126.23,126.13,116.62,111.72,111.51,61.94,45.14.ESI-HRMS(m / z):calcd for C 16 H 18 NO[M+H] + :240.1388;found:240.1387.

[0058] Example 4

[0059] In this example, the structural formula of the arylamine substrate in S1 is:

[0060]

[0061] In this example, petroleum ether / ethyl acetate = 2:1.

[0062] In this example, the product obtained by separation and purification in S3 is (E)-4-((4-fluorophenyl)amino)but-2-en-1-ol, with a weight of 29 mg, a yield of 81%, and a purity of 98.7%. The structural formula and corresponding spectral data are as follows:

[0063]

[0064] 1 1H NMR (600 MHz, CDCl3) δ 7.01 (t, J = 8.0 Hz, 1H), 6.84–6.82 (m, 1H), 6.76–6.75 (m, 1H), 6.55–6.53 (m, 1H), 5.92–5.76 (m, 2H), 4.19–4.11 (m, 2H), 3.77–3.73 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 147.86, 130.51, 129.48, 126.78, 122.23, 119.55, 114.64, 110.91, 61.89, 44.29. ESI-HRMS (m / z): calcd for C 10 H 13 NOF [M + H] + : 182.0981; found: 182.0984.

[0065] Example 5

[0066] In this example, the structural formula of the arylamine substrate of S1 is as follows:

[0067]

[0068] In this example, petroleum ether / ethyl acetate = 2:1.

[0069] In this example, the product obtained by separating and purifying S3 is (E)-4-((4-bromophenyl)amino)but-2-en-1-ol (English name: (E)-4-((4-bromophenyl)amino)but-2-en-1-ol), with a weight of 33 mg, a yield of 70%, and a purity of 99.1%. The structural formula and corresponding spectral data are as follows:

[0070]

[0071] 1 1H NMR (600 MHz, CDCl3) δ 7.27–7.25 (m, 2H), 6.60–6.49 (m, 2H), 5.93–5.75 (m, 2H), 4.15 (dd, J = 5.1, 1.2 Hz, 2H), 3.75 (dd, J = 5.3, 1.2 Hz, 2H).

[0072] 1313C NMR (150 MHz, CDCl3) δ 145.11, 130.97, 130.76, 126.64, 115.82, 114.10, 108.96, 61.87, 44.84. ESI-HRMS (m / z): calcd for C 10 H 13 NOBr [M+H] + : 242.0181; found: 242.0183.

[0073] Example 6

[0074] In this example, the structural formula of the arylamine substrate of S1 is:

[0075]

[0076] In this example, petroleum ether / ethyl acetate = 2:1.

[0077] In this example, the product obtained by separating and purifying S3 is (E)-4-((3-bromophenyl)amino)but-2-en-1-ol (English name: (E)-4-((3-bromophenyl)amino)but-2-en-1-ol), with a weight of 37 mg, a yield of 78%, and a purity of 99.1%. The structural formula and corresponding spectral data are respectively:

[0078]

[0079] 1 1H NMR (600 MHz, CDCl3) δ 7.01 (t, J = 8.0 Hz, 1H), 6.83–6.81 (m, 1H), 6.75–6.74 (m, 1H), 6.53–6.51 (m, 1H), 5.87–5.78 (m, 2H), 4.17–4.10 (m, 2H), 3.75–3.73 (m, 2H). 13 13C NMR (150 MHz, CDCl3) δ 147.97, 130.43, 129.47, 126.84, 122.21, 119.43, 114.56, 110.83, 61.87, 44.21. ESI-HRMS (m / z): calcd for C 10 H 13 NOBr [M+H] + : 242.0181; found: 242.0179.

[0080] Example 7

[0081] In this example, the structural formula of the arylamine substrate of S1 is:

[0082]

[0083] In this example, petroleum ether / ethyl acetate = 2:1.

[0084] In this example, the product obtained by separation and purification in S3 is (E)-2-((4-hydroxybut-2-en-1-yl)amino)benzonitrile (English name: (E)-2-((4-hydroxybut-2-en-1-yl)amino)benzonitrile), with a weight of 26 mg, a yield of 71%, and a purity of 98.3%. The structural formula and corresponding spectral data are as follows:

[0085]

[0086] 1 H NMR(600MHz,CDCl3)δ7.44–7.33(m,2H),6.74–6.64(m,2H),5.98–5.76(m,2H),4.18(d,J=4.4Hz,2H),3.88(d,J=4.9Hz,2H).

[0087] 13 C NMR(150MHz,CDCl3)δ148.91,133.23,131.73,130.92,125.80,116.85,115.78,109.89,94.87,61.80,43.60.ESI-HRMS(m / z):calcd for C 11 H 13 N2O[M+H] + :189.1028;found:189.1031.

[0088] Example 8

[0089] In this example, the structural formula of the arylamine substrate in S1 is:

[0090]

[0091] In this example, petroleum ether / ethyl acetate = 5:4.

[0092] In this example, the product obtained by separation and purification in S3 is (E)-4-((4-hydroxybut-2-en-1-yl)amino)benzonitrile (English name: (E)-4-((4-hydroxybut-2-en-1-yl)amino)benzonitrile), with a weight of 23 mg, a yield of 62%, and a purity of 98.6%. The structural formula and corresponding spectral data are as follows:

[0093]

[0094] : The crude product was purified via flash chromatography, eluting with petroleum ether / ethyl acetate () to give a colorless oil (mg, %). 1 1H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 5.97–5.71 (m, 2H), 4.17 (dd, J = 4.8, 1.1 Hz, 2H), 3.83 (dd, J = 5.4, 1.1 Hz, 2H). 13 13C NMR (150 MHz, CDCl3) δ 149.40, 132.72, 131.24, 125.51, 119.19, 111.94, 98.73, 61.70, 44.02. ESI-HRMS (m / z): calcd for C 11 H 13 N2O [M + H] + : 189.1028; found: 189.1030.

[0095] Example 9

[0096] In this example, the arylamine substrate structure of S1 is:

[0097]

[0098] In this example, petroleum ether / ethyl acetate = 1:1.

[0099] In this example, the product obtained by separating and purifying S3 is (E)-5-((4-hydroxybut-2-en-1-yl)amino)-2-methylbenzonitrile (English name: (E)-5-((4-hydroxybut-2-en-1-yl)amino)-2-methylbenzonitrile), with a weight of 32 mg, a yield of 80%, and a purity of 98.8%. The structural formula and corresponding spectral data are as follows:

[0100]

[0101] 11H NMR (600 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 1H), 6.81–6.80 (m, 1H), 6.76 (dd, J = 8.4, 2.6 Hz, 1H), 5.92–5.77 (m, 2H), 4.16–6.15 (m, 2H), 3.76 (dd, J = 5.3, 1.2 Hz, 2H), 2.40 (s, 3H). 13 13C NMR (150 MHz, CDCl3) δ 144.46, 130.78, 129.97, 129.77, 126.35, 117.62, 117.30, 114.65, ESI-HRMS (m / z): calcd for C 12 H 15 N2O [M + H] + : 203.1184; found: 203.1182.

[0102] Example 10

[0103] In this example, the structural formula of the arylamine substrate of S1 is as follows:

[0104]

[0105] In this example, petroleum ether / ethyl acetate = 3:1.

[0106] In this example, the product obtained by separating and purifying S3 is (E)-4-((2-bromo-4-methylphenyl)amino)but-2-en-1-ol (English name: (E)-4-((2-bromo-4-methylphenyl)amino)but-2-en-1-ol), with a weight of 43 mg, a yield of 86%, and a purity of 98.9%. The structural formula and corresponding spectral data are as follows:

[0107]

[0108] 1 1H NMR (600 MHz, CDCl3) δ 7.26–7.25 (m, 1H), 6.98–6.96 (m, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.87–5.84 (m, 2H), 4.16–4.15 (m, 2H), 3.81 (dd, J = 5.0, 1.2 Hz, 2H), 2.22 (s, 3H).

[0109] 1313C NMR (150 MHz, CDCl3) δ 141.23, 131.75, 130.18, 127.94, 127.08, 126.67, 110.74, 108.74, 61.94, 44.44, 18.99. ESI-HRMS (m / z): calcd for C 11 H 15 NOBr [M+H] + : 256.0337; found: 256.0340.

[0110] Example 11

[0111] In this example, the structural formula of the arylamine substrate of S1 is:

[0112]

[0113] In this example, petroleum ether / ethyl acetate = 2:1.

[0114] In this example, the product obtained by separating and purifying S3 is (E)-4-((3,5-dibromophenyl)amino)but-2-en-1-ol (English name: (E)-4-((3,5-dibromophenyl)amino)but-2-en-1-ol), with a weight of 49 mg, a yield of 77%, and a purity of 98.7%. The structural formula and the corresponding spectral data are respectively:

[0115]

[0116] 1 1H NMR (600 MHz, CDCl3) δ 6.99–6.98 (m, 1H), 6.69–6.68 (m, 2H), 5.90–5.77 (m, 2H), 4.20–4.13 (m, 2H), 3.74 (dd, J = 5.4, 0.8 Hz, 2H). 13 13C NMR (150 MHz, CDCl3) δ 148.29, 131.05, 125.82, 122.44, 122.08, 113.77, 61.77, 44.32. ESI-HRMS (m / z): calcd for C 10 H 12 NOBr2 [M+H] + : 319.9286; found: 319.9283.

[0117] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any equivalent changes and modifications made according to the scope of the patent application of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing allyl aromatic amine compounds, characterized in that, The method for preparing allyl arylamine compounds is carried out by palladium-catalyzed synthesis of arylamine compounds and ethylene vinyl carbonate, and the method for preparing allyl arylamine compounds is prepared by the following reaction equation: The method for preparing allyl arylamine compounds includes the following steps: S1: Mix arylamine compounds, ethylene vinyl carbonate, and a palladium catalyst, then add an organic solvent, stir evenly and react, and obtain a mixed solution after the reaction; S2: Concentrate and evaporate the mixed solution obtained in S1 to obtain a crude product; S3: Extract, dry, filter, concentrate, and purify the crude product in S2 by column chromatography to obtain the product; The products are: (E)-4-(phenylamino)but-2-en-1-ol, (E)-4-(m-tolylamino)but-2-en-1-ol, (E)-4-([1,1'-biphenyl]-3-ylamino)but-2-en-1-ol, (E)-4-((4-fluorophenyl)amino)but-2-en-1-ol, (E)-4-((4-bromophenyl)amino)but-2-en-1-ol, (E)-4-((3-bromophenyl)amino)but-2-en-1-ol, (E)-2-((4-hydroxybut-2-en-1-yl)amino)benzonitrile, (E)-4-((4-hydroxybut-2-en-1-yl)amino)benzonitrile, (E)-5-((4-hydroxybut-2-en-1-yl)amino)-2-methylbenzonitrile, (E)-4-((2-bromo-4-methylphenyl)amino)but-2-en-1-ol or (E)-4-((3,5-dibromophenyl)amino)but-2-en-1-ol.

2. The method for preparing allyl arylamine compounds according to claim 1, characterized in that, The molar ratio of the arylamine compounds to ethylene vinyl carbonate is 1:1.

5.

3. The method for preparing allyl aromatic amine compounds according to claim 1 or 2, characterized in that, The organic solvent is anhydrous acetonitrile; and / or The addition amount of the palladium catalyst is 5% of the molar amount of the arylamine substrate; and / or The palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride.

4. The method for preparing allyl aromatic amine compounds according to claim 3, characterized in that, In S3, the extraction method for extraction is: add a mixed solution of water and ethyl acetate to the crude product, stir evenly and let it stand until completely separated into layers, then separate the organic layer and the water layer, and the volume ratio of water to ethyl acetate in the mixed solution of water and ethyl acetate is 1-2:1; and / or In S3, the chromatography is column chromatography, the column used for column chromatography treatment is a silica gel column, and the chromatography solution is a mixed solution of petroleum ether and ethyl acetate mixed at a volume ratio of 10:1-5:1.

Images