Preparation method of gamma-amide ester

Abstract

The invention relates to a method for preparing gamma-amide ester. Specifically, under the catalytic condition of cheap metal cobalt, formamide, phenol or alcohol and ethylene gas are subjected to carbonylation to prepare gamma-amide ester. Formamide compounds and phenol or alcohol widely existing in the nature are used as raw materials, wherein the raw materials comprise formamide, phenol and alcohol. According to the method, a formamide gamma-position carbonylation product is obtained with high atom utilization rate and high yield under the action of one or two of a catalytic amount of cheap metal agents by taking gas CO as a C1 source and ethylene gas as a C2 source.

Description

Technical Field

[0001] The invention relates to a method for synthesizing gamma-amide ester. Background Art

[0002] Amide is a biologically active chemical structure fragment, because it is widely present in biological and medical drugs. At the same time, amide can not only be used as an important intermediate in the industrial synthesis of vitamins and hormones, but also a common and easily available reaction solvent. The functionalization of amide compounds is of great significance for the synthesis of biologically active compounds and drug discovery. γ-Amide ester is one of the important fragments, and its presence can be seen in many drug molecules. Ethylene gas is an important C2 source and a basic chemical raw material for synthetic fibers, synthetic rubber, synthetic plastics, and synthetic ethanol. It is also used to make vinyl chloride, styrene, ethylene oxide, acetic acid, acetaldehyde, and explosives. Ethylene is one of the world's largest chemical products. The ethylene industry is the core of the petrochemical industry. Ethylene products account for more than 75% of petrochemical products and occupy an important position in the national economy. The world has used ethylene production as one of the important indicators to measure the level of development of a country's petrochemical industry. Introducing simple small molecules of ethylene into molecules is of great significance for scientific development. In recent years, transition metal-catalyzed carbonylation esterification / amination reactions to prepare amides and esters with various functional groups have become a promising method. However, these reported reactions also have some disadvantages, such as the need to use expensive palladium-phosphine catalysts; the use of activated substrates; the narrow applicability range of substrates, etc.

[0003] Compared with the previous synthesis methods of γ-amide esters, we have developed a cheap metal cobalt-catalyzed carbonylation reaction to synthesize γ-amide esters. Using simple and easy-to-prepare phenols or alcohols with amide compounds and cheap peroxides, as well as industrial raw materials ethylene, in a CO atmosphere, we can synthesize γ-amide esters with high yield, good selectivity and a wide range of substrates.

[0004] In summary, this paper describes a method for preparing γ-amide esters via a cobalt-catalyzed carbonylation esterification reaction. Summary of the invention

[0005] The object of the present invention is to provide a method for synthesizing γ-amide ester.

[0006]

[0007] Reaction equation 1: γ-amide ester

[0008] The specific operation steps are as follows (reaction equation 1):

[0009] The reaction is carried out in a 300 ml autoclave, the catalyst and the hydroxyl-containing compound 1 are weighed, peroxide and formamide are injected under a nitrogen atmosphere, the reaction is placed in a carbon monoxide gas and ethylene gas atmosphere, and the reaction is carried out at 70-160° C., preferably 120-140° C. The reaction time is 10-36 hours, preferably 18-24 hours; after the reaction is completed, the γ-amide ester derivative 4 is separated.

[0010] The catalyst is one or more of di(acetylacetonate)cobalt, cobalt acetate, cobalt chloride, cobalt iodide, and cobalt bromide, preferably cobalt chloride;

[0011] The molar ratio of phenol or alcohol to cobalt chloride is 100:1-100:30, preferably 100:15-100:20.

[0012] The gas pressure of carbon monoxide is 1 to 30 atmospheres, preferably 5 to 15 atmospheres.

[0013] The gas pressure of carbon monoxide is 1 to 30 atmospheres, preferably 1 to 10 atmospheres.

[0014] The present invention has the following advantages:

[0015] First, it does not require expensive transition metal catalytic systems to carbonylate and synthesize γ-amide esters, which greatly reduces costs. Second, the system can be used for a variety of phenols and alcohols in the reaction, broadening the applicability of the reaction. Third, using gaseous CO as a carbonyl source is cheap and easy to obtain, greatly reducing costs. Fourth, using ethylene gas as a C2 source provides more possibilities for large-scale production and conversion of ethylene gas.

[0016] The invention uses gaseous CO as a carbonyl source and ethylene gas as a C2 source, and under the action of a catalytic amount of a cheap metal cobalt catalyst, obtains a γ-amide ester product with high atomic utilization, high yield and wide substrate applicability. DETAILED DESCRIPTION

[0017] In order to better understand the present invention, the following examples are provided for illustration. The reaction materials and results of Examples 1-10 are shown in Table 1.

[0018] Table 1 Reaction results of different substituted phenols, alcohols or formamides

[0019]

[0020]

[0021] The product structure is as follows:

[0022]

[0023] Example 1

[0024] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl-containing compound 1 (0.2 mmol) and cobalt chloride (0.04 mmol) were added into a 4 ml glass vial for mixing. Under a nitrogen atmosphere, 1 ml of formamide 2 was added as a solvent, reactant and solvent to the mixture, and di-tert-butyl peroxide (0.4 mmol) was injected to obtain a mixed material. The mouth of the small glass vial was tightly covered with a rubber bottle cap. One end of the needle tip of a syringe needle was inserted into the vial through the bottle cap, so that the vial was connected to the outside through the needle. The reaction vial was then placed in a high-pressure reactor, carbon monoxide was replaced in the high-pressure reactor, and 10 atmospheres of carbon monoxide and 5 atmospheres of ethylene gas were filled into the autoclave. At this time, the carbon monoxide in the autoclave was connected to the inside of the vial through the needle. Then, the reaction was placed at 130° C. for a reaction time of 20.0 hours. After the reaction was completed, the yield of the γ-amide ester compound 4a was 66% after separation by column chromatography. The compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0025] The test data are as follows:

[0026] 4a: 1 H NMR (400MHz, CDCl3) δ4.05 (t, J = 6.8Hz, 2H), 3.00 (s, 3H), 2.92 (s, 3H), 2.66 –2.56(m,4H),1.63–1.57(m,2H),1.36–1.21(m,6H),0.86(t,J=6.9Hz,3H).

[0027] 13 C NMR (101MHz, CDCl3) δ173.3 171.2, 64.7, 36.9, 35.4, 31.4, 29.3, 28.5, 28.0, 25.5, 22.5, 13.9.

[0028] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 12 H 24 NO3 230.1751; Found:230.1756.

[0029] Embodiment 2:

[0030] The operation process and conditions are the same as those of Example 1, except that the raw material containing hydroxyl compound 1 in Table 1 has a yield of 53% for 4b, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4b: 1H NMR (400MHz, CDCl3) δ7.39–7.33(m,2H),7.23-7.18(m,1H),7.12–7.09(m,2 H),3.04(s,3H),2.97(s,3H),2.91(t,J=6.6Hz,2H),2.72(t,J=6.6Hz,2H).

[0031] 13 C NMR (101MHz, CDCl3) δ171.9,170.9,150.8,129.3,125.7,121.6,37.0,35.5,29.6,28.1

[0032] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 12 H 16 NO3 222.1125; Found:222.1128.

[0033] Embodiment 3:

[0034] The operation process and conditions are the same as those of Example 1, except that the raw material containing hydroxyl compound 1 in Table 1, 4c has a yield of 51%, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4c: 1 H NMR (400MHz, CDCl3) δ7.10–7.00(m,4H),3.03(s,3H),2.96(s,3H),2.88(t,J=6.6Hz,2H),2.71(t,J=6.5Hz,2H)

[0035] 13 C NMR (101MHz, CDCl3) δ172.0,170.9,161.3,158.9,146.6,123.0,122.9,116.0,115.8,37.0,35.5,29.5,28.1.

[0036] 19 F NMR (376MHz,CDCl3)δ-117.35.

[0037] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C12H15FNO3 240.1030; Found:240.1032.

[0038] Embodiment 4:

[0039] The operation process and conditions are the same as those in Example 1, except that the raw material containing hydroxyl compound 1 in Table 1 has a yield of 51% for 4d, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4d: 1 H NMR (400MHz, CDCl3) δ4.81–4.70(m,1H),3.03(s,3H),2.94(s,3H),2.67–2.56(m ,4H),1.89–1.79(m,2H),1.74–1.65(m,1H),1.58–1.48(m,1H),1.47–1.18(m,6H)

[0040] 13 C NMR (101MHz, CDCl3) δ172.6,171.3,72.8,37.0,35.5,31.6,29.7,28.1,25.4,23.7.

[0041] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C12H22NO3 228.1594; Found:228.1599.

[0042] Embodiment 5:

[0043] The operation process and conditions are the same as those of Example 1, except that the yield of the raw material hydroxyl compound 1, 4e, which is shown in Table 1, is 61%. The compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4e: 1 H NMR (400MHz, CDCl3) δ7.47–7.28(m,5H),5.14(s,2H),3.01(s,3H),2.95(s,3H),2.78–2.66(m,2H),2.65–2.58(m,2H).

[0044] 13 C NMR (101MHz, CDCl3) δ173.1,171.1,136.0,128.5,128.2,128.1,66.4,36.4,35.5,29.4,28.0.

[0045] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C13H18NO3 236.1281; Found:236.1286.

[0046] Embodiment 6:

[0047] The operation process and conditions are the same as those of Example 1, except that the raw material containing hydroxyl compound 1 in Table 1, 4f has a yield of 49%, and the compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4f: 1 H NMR (400MHz, CDCl3) δ7.42-7.40(m,1H),6.40(d,J=3.2Hz,1H),6.37-6.33(m,1H ),5.08(s,2H),3.01(s,3H),2.94(s,3H),2.71–2.66(m,2H),2.65-2.59(m,2H).

[0048] 13 C NMR (101MHz, CDCl3) δ172.9,171.1,149.5,143.2,110.5,110.5,58.2,37.0,35.5,29.2,28.0.

[0049] HRMS (ESI-TOF) m / z: [M+Na] + Calcd for C11H15NO4Na 248.0893; Found:248.0892.

[0050] Embodiment 7:

[0051] The operation process and conditions are the same as those in Example 1, except that the raw material containing hydroxyl compound 1 in Table 1 has a yield of 4g and is 53%. The compound is identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry. 4g: 1 H NMR (400MHz, CDCl3) δ7.31–7.24(m,2H),7.19–7.15(m,3H),4.14-4.08(m,2H),3.01(s,3H),2.93(s,3H),2.68–2.58(m,6H),1.71–1.65(m,4H).

[0052] 13 C NMR (101MHz, CDCl3) δ173.2,171.1,142.0,128.3,128.2,125.7,64.3,36.9,35.4,35.3,29.3,28.1,28.0,27.6.

[0053] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C16H24NO3 278.1751; Found:278.1756.

[0054] Embodiment 8:

[0055] The operation process and conditions are the same as those in Example 1, except that the raw material contains formamide compound 2 as shown in Table 1, and the yield is 59% in 4 hours. The structure of the compound is identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0056] 4h: 1 H NMR(400MHz, CDCl3)δ4.06(t,J=6.8Hz,2H),3.40-3.29(m,4H),2.68–2.57(m,4H),1.65–1.56( m,2H),1.33–1.25(m,6H),1.18(t,J=7.1Hz,3H),1.09(t,J=7.1Hz,3H),0.87(t,J=6.9Hz,3H).

[0057] 13 C NMR (101MHz, CDCl3) δ173.4,170.3,64.7,41.8,40.3,31.4,29.5,28.5,25.5,22.5,22.5,14.1,14.0,13.0.

[0058] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C14H28NO3 258.2064; Found:258.2069.

[0059] Embodiment 9:

[0060] The operation process and conditions are the same as those in Example 1, except that the raw materials contain formamide compounds 2 and 4i in Table 1 with a yield of 54%. The compound was identified by NMR (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0061] 4i: 1 H NMR(400MHz, CDCl3)δ4.07(t,J=6.8Hz,2H),3.60–3.50(m,2H),3.44–3.37(m,2H) ,2.70–2.57(m,4H),1.67–1.52(m,8H),1.37–1.27(m,6H),0.88(t,J=6.9Hz,3H).

[0062] 13 C NMR (101MHz, CDCl3) δ173.4,169.4,64.8,46.4,42.9,31.4,29.4,28.5,27.9,26.3,25.5,25.5,24.5,22.5,14.0.

[0063] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C15H28NO3 270.2064; Found:270.2069.

[0064] Embodiment 10:

[0065] The operation process and conditions are the same as those in Example 1, except that the raw materials contained formamide compounds 2 and 4j in Table 1, and the yield was 50%. The structure of the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.

[0066] 4j: 1 H NMR(400MHz, CDCl3)δ4.07(t,J=6.8Hz,2H),3.72–3.63(m,2H),3.62–3.57(m,1H),3.52–3.47(m,1H) ,2.69–2.64(m,2H),2.63–2.57(m,2H),1.66–1.57(m,2H),1.38–1.26(m,6H),0.88(t,J=6.8Hz,3H).

[0067] 13 C NMR (101MHz, CDCl3) δ173.1,167.0,66.8,66.5,64.8,45.7,42.1,31.4,29.2,28.5,27.7,25.5,22.5,14.0.

[0068] HRMS (ESI-TOF) m / z: [M+H] + Calcd for C14H26NO4 272.1856; Found:272.1859.

[0069] Embodiment 11

[0070] The other reaction conditions described in Example 1 remain unchanged (ie, the operation process and conditions are the same as in Example 1), except that the reaction temperature is reduced to 120 degrees Celsius, and the yield of the target product γ-amide ester compound is reduced to 38%.

[0071] Example 12

[0072] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the amount of di-tert-butyl peroxide used in the reaction is reduced to 1.5 equivalents, and the yield of the target product γ-amide ester compound is reduced to 30%.

[0073] Example 13

[0074] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the pressures of carbon monoxide and ethylene in the reaction are respectively increased to 15 bar, and the yield of the target product γ-amide ester compound is reduced to 42%.

[0075] Embodiment 14

[0076] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to di(acetylacetonate)cobalt, and the yield of the target product γ-amide ester compound is reduced to 22%.

[0077] Embodiment 15

[0078] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), the difference is that the amount of catalyst used in the reaction is changed to 10 mol%, and the yield of the target product γ-amide ester is reduced to 47%.

[0079] Comparative Example 1

[0080] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the reaction temperature is reduced to 60 degrees Celsius, the yield of the target product γ-amide ester is reduced to 0%, and the raw material is largely surplus.

[0081] Comparative Example 2

[0082] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operating process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to nickel di(acetylacetonate), the yield of the target product γ-amide ester is reduced to 7%, and the raw materials are not fully converted.

[0083] Comparative Example 3

[0084] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is changed to palladium chloride, the yield of the target product γ-amide ester compound is reduced to 0%, and a large amount of raw materials remain.

[0085] Comparative Example 4

[0086] Keep the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as in Example 1), except that the peroxide for the reaction is selected as hydrogen peroxide, the yield of the target product γ-amide ester compound is reduced to 0%, and the raw material part remains.

[0087] Comparative Example 5

[0088] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), the difference is that the catalyst of the reaction is removed, the yield of the target product γ-amide ester compound is reduced to 0%, and a large amount of raw materials remain.

[0089] Comparative Example 6

[0090] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), the difference is that the peroxide in the reaction is removed, the yield of the target product γ-amide ester compound is reduced to 0%, and a large amount of raw materials remain.

[0091] Comparative Example 7

[0092] Keeping the other reaction conditions described in Example 1 unchanged (ie, the operation process and conditions are the same as in Example 1), the difference is that the reaction time is reduced to 8 hours, the yield of the target product γ-amide ester compound is reduced by 33%, and a large amount of raw materials remain.

Claims

1. A method for preparing a γ-amide ester, characterized in that: γ-amide ester derivatives are prepared from ethylene, carbon monoxide, a compound containing formamide 2, and phenol and / or alcohol. The hydroxyl-containing compound 1 (i.e., phenol and / or alcohol), the compound containing formamide 2, carbon monoxide and ethylene gas shown in the following formula are used as raw materials to generate γ-amide ester 4. The reaction formula is as follows: The hydroxyl-containing compound 1 in the reaction formula is one or more of phenol and alcohol; in the general formula, R 1 It is one or more of n-hexyl, phenyl, 4-halogenophenyl (halogen refers to one or more of F, Cl, Br, I), cyclohexyl, benzyl, furanyl, phenylbutyl; In addition, the formamide-containing compound 2 is one or more of N,N-dimethylformamide, N,N-diethylformamide, N-formylpiperidine, and N-formylmorpholine.

2. The preparation method according to claim 1, characterized in that: The reaction is carried out in a high-pressure reactor, the catalyst and the hydroxyl-containing compound 1 are weighed and mixed to obtain a mixture, and a peroxide and a formamide-containing compound 2 are injected into the mixture under an inert gas atmosphere (such as nitrogen) to obtain a mixed material, and the mixed material is placed in a reactor or the mixed material is directly mixed or prepared in the reactor, and the gas atmosphere in the reactor is replaced with carbon monoxide gas and ethylene gas, and the reaction is carried out at 70-160° C., preferably 120-140° C.; the reaction time is 10-36 hours, preferably 18-24 hours; after the reaction is completed, γ-amide ester 4 is separated; The peroxide is one or more of cumene hydroperoxide, tert-butyl perbenzoate, and di-tert-butyl peroxide, preferably di-tert-butyl peroxide; The catalyst is one or more of di(acetylacetonate)cobalt, cobalt acetate, cobalt chloride, cobalt iodide and cobalt bromide, preferably cobalt chloride.

3. The preparation method according to claim 2, characterized in that: The molar ratio of the hydroxyl-containing compound 1 to the catalyst is 100:1-100:30, preferably 100:10-100:

20.

4. The preparation method according to claim 2, characterized in that: The molar ratio of the hydroxyl-containing compound 1 to the peroxide is 1:1-1:3, preferably 1:1.5-1:2.

5.

5. The preparation method according to claim 2, characterized in that: The gas pressure of carbon monoxide is 1-30 atmospheres, preferably 5-15 atmospheres; The gas pressure of ethylene gas is 1 to 30 atmospheres, preferably 1 to 10 atmospheres.

6. The preparation method according to claim 2, characterized in that: The above formamide-containing compound 2 serves as both a solvent and a reaction substrate in the reaction; the amount of formamide-containing compound 2 used is 0.1-2.0 ml, preferably 0.5-1.5 ml, per 0.2 mmol of hydroxyl-containing compound 1.

7. The preparation method according to claim 2, characterized in that: The total volume of the reaction substrate, catalyst and peroxide does not exceed 50% of the volume of the high-pressure reactor.

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