A method for preparing an imide derivative

Abstract

The present invention relates to a method for preparing imide compounds. Specifically, it is prepared by a one-pot method from amines, ethylene, and carbon monoxide under palladium catalysis. Starting from simple and readily available raw materials and catalysts, the present invention obtains a series of imide compounds through a carbonylation reaction.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing imide derivative compounds. Background Art

[0002] Imide compounds are important organic groups widely used in natural products, detergents, pharmaceutical intermediates, and pesticides. For example, in detergents with a scale of over 10,000 tons, tetraacetylethylenediamine (TAED) is used as a bleach activator, diacetylazole (Dermagan) stimulates wound healing, and cycloheximide is an antifungal antibiotic.

[0003] Compared with the conventional methods for synthesizing imides, the present invention directly constructs imide compounds through the dicarbonylation reaction of amines with ethylene gas and carbon monoxide gas.

[0004] In summary, a method for preparing imide derivatives by an efficient, highly atom - economical, and one - step direct dicarbonylation reaction with simple raw materials is described herein. Summary of the Invention

[0005] The object of the present invention is to provide a method for synthesizing imide derivatives.

[0006]

[0007] Reaction Equation 1: Synthesis of Imide Derivatives

[0008] The specific operation steps are as follows (Reaction Equation 1):

[0009] The reaction is carried out in a reaction kettle. First, a catalyst, a ligand, an acid, amine 1, and a solvent are added. Then, carbon monoxide gas is flushed and discharged three times, and then 5 bar of carbon monoxide gas is charged. Subsequently, 10 bar of ethylene gas is charged. The reaction is carried out at 50 - 120 °C, preferably 100 °C. The reaction time is 5 - 24 hours, preferably 15 hours. After the reaction is completed, the imide derivative is separated.

[0010] The dosage ratio of amine 1 is 0.2 - 100 mmol, preferably 1.0 mmol.

[0011] The catalyst is one or more of palladium chloride, palladium acetylacetonate, palladium acetate, and tetrakis(triphenylphosphine)palladium, preferably tetrakis(triphenylphosphine)palladium; the dosage of the catalyst is 1 mol% - 10 mol% of the dosage of amine 1, preferably 5 mol%.

[0012] The ligand is one or more of triphenylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)ferrocene, 1,1'-binaphthalene-2,2'-bis(di(3,5-dimethylphenyl)phosphine), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene; the dosage of the ligand is 1 mol% - 10 mol% of the dosage of amine 1, preferably 5 mol%.

[0013] The acid is one or more of benzeneboronic acid, benzoic acid, acetic acid, p-toluenesulfonic acid, camphorsulfonic acid, preferably p-toluenesulfonic acid; the dosage of the acid is 1 mol% - 50 mol% of the dosage of amine 1, preferably 10 mol%.

[0014] The solvent is one or more of n-hexane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dichloroethane, preferably 1,2-dichloroethane; the dosage of the solvent is 0.1 - 5.0 mL of the solvent per millimole of amine 1, preferably 2.0 mL.

[0015] The present invention has the following advantages:

[0016] The present invention starts from simple and readily available raw materials and catalysts, and a series of imide compounds are obtained through a carbonylation reaction.

[0017] First, the reaction has simple and readily available raw materials, and they are bulk chemicals with low prices. Second, the reaction is direct and efficient, with 100% atom economy. Finally, the functional group compatibility of this reaction system is good, and various functional groups such as various halides, amides, ester groups, and thioethers are all compatible with this reaction system. Specific Embodiments

[0018] To better understand the present invention, it is illustrated by the following examples. The reaction raw materials and results of Examples 1 - 10 are shown in Table 1.

[0019] Table 1 Reaction Results of Different Substituted Amines

[0020]

[0021]

[0022]

[0023] Example 1

[0024] The reaction was carried out in a reaction kettle. First, 0.01 mmol of palladium acetate (the dosage was 5 mol% of the amount of amine 1a), 0.01 mmol of ligand 1,1'-binaphthalene-2,2'-bis(di(3,5-dimethylphenyl)phosphine) (the dosage was 5 mol% of the amount of amine 1a), p-toluenesulfonic acid (the dosage was 10 mol% of the amount of amine 1a), 0.2 mmol of amine 1a and 1.0 mL of toluene as the solvent were added. Then, the process of flushing and discharging carbon monoxide gas was carried out three times, and then 5 bar of carbon monoxide gas was charged, and then 10 bar of ethylene gas was charged. The reaction was carried out at 100 °C for 15 hours. After the reaction was completed, the allylsilicon compound 4a was obtained by column chromatography separation with a yield of 99%. The compound was characterized by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum).

[0025] The detection data are as follows:

[0026] N-phenyl-N-propionylpropionamide(4a):Colorless oil,81mg,99%yield,R f =0.3(PE / EtOAc 10 / 1). 1 H NMR(400MHz,CDCl3)δ7.48–7.37(m,3H),7.13(d,J=7.8Hz,2H),2.58(q,J=7.3Hz,4H),1.10(t,J=7.3Hz,6H). 13 C NMR(100MHz,CDCl3)δ176.7,139.1,129.7,128.9,128.7,32.2,9.0.

[0027] Example 2:

[0028] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, in addition to the differences described in Table 1, the catalyst was palladium tetrakis(triphenylphosphine), and the addition amount was 10% (the dosage was 10 mol% of the amount of amine 1b), the ligand was 1,1'-binaphthalene-2,2'-bis(di(3,5-dimethylphenyl)phosphine) 0.02 mmol (the dosage was 10 mol% of the amount of amine 1b), and the yield of 4b was 82%. The compound was characterized by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry for its structure determination.

[0029] N-propionyl-N-(p-tolyl)propionamide(4b):Colorless oil,82mg,94%yield,R f =0.3(PE / EtOAc 10 / 1). 11H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 2.58 (d, J = 7.3 Hz, 4H), 2.39 (s, 3H), 1.10 (t, J = 7.3 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 176.8, 138.6, 136.4, 130.4, 128.6, 32.1, 21.2, 9.0. HRMS calculated for C 13 H 17 NO2 [M+Na] + : 242.1151, found 242.1153.

[0030] Example 3:

[0031] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that the solvent was 1,2-dichloroethane (2.0 mL), the yield of 4c was 97%, and the structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0032] N-(4-methoxyphenyl)-N-propionylpropionamide (4c): Colorless oil, 91 mg, 97% yield, Rf = 0.2 (PE / EtOAc 5 / 1). 1 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 2.58 (q, J = 7.3 Hz, 4H), 1.10 (t, J = 7.3 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 177.0, 159.5, 131.6, 129.8, 114.9, 55.5, 32.1, 9.0. HRMS calculated for C 13 H 17 NO3 [M+H] + : 236.1281, found 236.1285.

[0033] Example 4:

[0034] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that in addition to the differences described in Table 1, the reaction temperature was 50 °C, the yield of the product 4d was 89%, and the structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0035] N-(4-(methylthio)phenyl)-N-propionylpropionamide (4d): Colorless oil, 89 mg, 89% yield, R f = 0.3 (PE / EtOAc 5 / 1). 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.6 Hz, 2H), 2.58 (q, J = 7.3 Hz, 4H), 2.50 (s, 3H), 1.10 (t, J = 7.3 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 176.7, 139.7, 135.8, 129.2, 127.2, 32.1, 15.5, 9.0. HRMS calculated for C 13 H 17 NO2S [M + H] + : 274.0872, found 274.0860.

[0036] Example 5:

[0037] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences stated in Table 1, the acid is benzoic acid, the addition amount is 40% (40 mol% of the amount of Amine 1), the yield of product 4e is 96%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. N-(4-fluorophenyl)-N-propionylpropionamide (4e): Colorless oil, 86 mg, 96% yield, R f = 0.2 (PE / EtOAc 10 / 1). 1 H NMR (400 MHz, CDCl3) δ 7.21–7.07 (m, 4H), 2.58 (q, J = 7.2 Hz, 4H), 1.11 (t, J = 7.2 Hz, 6H). 13 C NMR (100 MHz, CDCl3) δ 176.6, 162.4 (d, J = 248.7 Hz), 135.0 (d, J = 3.5 Hz), 130.7 (d, J = 8.7 Hz), 116.7 (d, J = 22.9 Hz), 32.2, 8.9. 19 F NMR (56 MHz, CDCl3) δ -117.60. HRMS calculated for C 12 H 14 FNO2 [M + H] +: 2224.1081, found 224.1075.

[0038] Example 6:

[0039] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the amount of palladium acetylacetonate catalyst is 5% (5 mol% of the amount of Amine 1), and the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, with an amount of 5% (5 mol% of the amount of Amine 1). The yield of product 4f is 65%. The structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0040] N-(4-formylphenyl)-N-propionylpropionamide (4f): Yellow solid, 61 mg, 65% yield, R f = 0.2 (PE / EtOAc 5 / 1). 1 1H NMR (400 MHz, CDCl3) δ 10.07 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 2.59 (q, J = 7.2 Hz, 4H), 1.12 (t, J = 7.2 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 191.0, 176.1, 144.5, 136.3, 130.9, 130.0, 32.2, 8.9. HRMS calculated for C 13 H 15 F3NO3 [M+H] + : 234.1125, found 234.1122.

[0041] Example 7:

[0042] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, in addition to the differences described in Table 1, the ligand is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, with an amount of 5% (5 mol% of the amount of Amine 1). The yield of product 4g is 98%. The structure of the compound was identified by nuclear magnetic resonance (1H NMR and 13C NMR) and high-resolution mass spectrometry.

[0043] N-(4-(ethylperoxy)phenyl)-N-propionylpropionamide (4g): White solid, 104 mg, 98% yield, R f = 0.3 (PE / EtOAc 10 / 1). 11H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 2.58 (q, J = 7.3 Hz, 4H), 1.40 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.3 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 176.2, 165.6, 143.2, 131.0, 130.9, 129.1, 61.3, 32.2, 14.3, 8.9. HRMS calculated for C 15 H 19 NO4 [M + H] + : 278.1387, found 278.1394.

[0044] Example 8:

[0045] The operation process and conditions are the same as those in Example 1. The difference from Example 1 is that, except for the differences described in Table 1, the addition amount of phenylboronic acid is 1.0 eq. (the amount used is the amount of amine 1), the yield of product 4h is 84%, and the structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0046] N-(4-acetylphenyl)-N-propionylpropionamide (4h): White solid, 83 mg, 84% yield, R f = 0.2 (PE / EtOAc 5 / 1). 1 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 2.63 (s, 3H), 2.58 (q, J = 7.3 Hz, 4H), 1.11 (t, J = 7.3 Hz, 6H). 13 13C NMR (100 MHz, CDCl3) δ 196.9, 176.2, 143.4, 137.1, 129.7, 129.4, 32.2, 26.7, 8.7. HRMS calculated for C 14 H 17 NO3 [M + H] + :

[0047] Example 9:

[0048] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the differences described in Table 1, the reaction time was 24 h, the yield of product 4i was 57%, and the compound was analyzed by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0049] N-butyl-N-propionylpropionamide (4i): Colorless oil, 42 mg, 57% yield, R f = 0.3 (PE / EtOAc 20 / 1). 1 H NMR (400 MHz, CDCl3) δ 3.65 (t, J = 7.6 Hz, 2H), 2.72 (q, J = 7.2 Hz, 4H), 1.53 (p, J = 8.0, 7.6 Hz, 2H), 1.35 (p, J = 8.0, 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 6H), 0.95 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 176.9, 44.0, 31.4, 31.3, 20.2, 13.7, 9.2. HRMS calculated for C 10 H 19 NO2 [M+H] + : 186.1489, found 186.1484.

[0050] Example 10:

[0051] The operation process and conditions were the same as those in Example 1. The difference from Example 1 was that, except for the differences described in Table 1, the reaction temperature was 120 °C, the yield of product 4j was 46%, and the structure of the compound was identified by nuclear magnetic resonance (proton NMR and carbon NMR) and high-resolution mass spectrometry.

[0052] N-phenethyl-N-propionylpropionamide (4j): Colorless oil, 43 mg, 46% yield, R f = 0.2 (PE / EtOAc 20 / 1). 1 H NMR (400 MHz, CDCl3) δ 7.35–7.28 (m, 2H), 7.27–7.17 (m, 3H), 3.87 (t, J = 7.8 Hz, 2H), 2.85 (t, J = 7.8 Hz, 2H), 2.66 (q, J = 7.2 Hz, 4H), 1.13 (t, J = 7.2 Hz, 6H). 1313C NMR (100 MHz, CDCl3) δ 176.9, 138.3, 128.9, 128.7, 126.7, 46.0, 35.5, 31.4, 9.2.

[0053] Application Example 1:

[0054]

[0055] Reaction Equation 2: The drug-active derivative synthesis product 4k can be completed in one step through a dicarbonylation reaction and can be simply and quickly converted into a derivative of the drug-active Dermagan.

[0056] The specific operation is as follows (Equation 2):

[0057] The reaction is carried out in a reaction kettle. First, 0.01 mmol of palladium acetate as a catalyst (the dosage is 5 mol% of the amount of amine 1k), 0.01 mmol of 1,1'-binaphthalene-2,2'-bis(di(3,5-dimethylphenyl)phosphine) as a ligand (the dosage is 5 mol% of the amount of amine 1k), p-toluenesulfonic acid as an acid (the dosage is 10 mol% of the amount of amine 1k), amine 1k (0.2 mmol), and toluene as a solvent (1.0 mL) are added. Then, carbon monoxide gas is flushed and released three times, and then 5 bar of carbon monoxide gas is flushed in. Subsequently, 10 bar of ethylene gas is flushed in. The reaction is carried out at 100 °C for 15 hours. After the reaction is completed, the imide compound 4k is obtained through column chromatography separation. The yield of product 4k is 47%. The structure of the compound is identified by nuclear magnetic resonance (proton spectrum and carbon spectrum) and high-resolution mass spectrometry.

Claims

1. A method for preparing an imide compound, characterized in that: Using amine 1, carbon monoxide 2, and ethylene 3 shown by the following formula as raw materials to produce an imide derivative 4, and the reaction formula is as follows: ； R is one or more of a C1-C20 alkyl chain, cyclohexyl, and aryl, where the aryl is one or more of phenyl or aryl with substituents on the benzene ring, and the substituents on the benzene ring are methyl, fluorine, chlorine, bromine, iodine, formyl, and the ketone is R 1 -CO-, R 1 is a C1-C15 alkyl chain, and the ester is R 2 -COO-, R 2 is one of a C1-C15 alkyl chain, cyclohexyl, and phenyl, and the ether is R 3 -O-, R 3 is a C1-C15 alkyl chain, and the thioether is R 4 -S-, R 4 is one of a C1-C15 alkyl chain, cyclohexyl, and phenyl, and the amide group is R 5 -CONH-, R 5 is one or two of a C1-C15 alkyl chain, cyclohexyl, phenyl, and 2-methyl-4-o-methylazobenzene; the number of substituents on the benzene ring is 1-2; The catalyst is one or more of palladium chloride, palladium acetylacetonate, palladium acetate, and tetrakis(triphenylphosphine)palladium; the dosage of the catalyst is 1 mol % - 10 mol% of the dosage of amine 1; The ligand is one or more of triphenylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,1'-bis(diphenylphosphino)ferrocene, 1,1'-binaphthalene-2,2'-bis(di(3,5-dimethylphenyl)phosphine), and 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthrene; the dosage of the ligand is 1 mol % - 10 mol% of the dosage of amine 1.

2. The method for preparing an imide compound according to claim 1, characterized in that: The specific operation steps are as follows: Carry out the reaction in a reaction kettle. First, add the catalyst, ligand, acid, amine 1, and solvent, then replace the atmosphere in the reaction kettle with carbon monoxide 2 gas. After replacement, charge 5 - 20 bar of carbon monoxide gas, and then charge 10 - 30 bar of ethylene 3 gas; react at 50 - 120 °C; the reaction time is 5 - 24 hours; after the reaction is completed, separate to obtain the imide derivative 4.

3. The method for preparing an imide compound according to claim 2, characterized in that: React at 100 - 120 °C, and the reaction time is 15 - 18 hours.

4. The method according to claim 1, characterized in that: The dosage of the catalyst is 5 - 10 mol% of the dosage of amine 1.

5. The method according to claim 1, characterized in that: The dosage of the ligand is 5 - 10 mol% of the dosage of amine 1.

6. The method according to claim 2, characterized in that: The acid is one or more of phenylboronic acid, benzoic acid, acetic acid, p-toluenesulfonic acid, and camphorsulfonic acid; the dosage of the acid is 1 mol % - 50 mol% of the dosage of amine 1.

7. The method according to claim 6, characterized in that: The dosage of the acid is 10 - 20 mol% of the dosage of amine 1.

8. The method according to claim 2, characterized in that: The solvent is one or more of n-hexane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, and 1,2-dichloroethane; the dosage of the solvent is 0.1 - 5.0 milliliters of solvent per millimole of amine 1.

9. The method according to claim 8, characterized in that: The dosage of the solvent is 2.0 - 4.0 milliliters of solvent per millimole of amine 1.

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