Preparation method of gamma-amino acid derivative or dipeptide
Through cobalt-catalyzed carbonylation reaction, γ-amino acids and dipeptides are synthesized using cheap raw materials under CO and ethylene atmospheres, solving the problems of difficult, high cost and limited applicability in the prior art, and achieving an efficient, low-cost and widely applicable synthesis method.
Patent Information
- Application Number
- CN202311220078.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-09-21
- Publication Date
- 2025-03-21
AI Technical Summary
The prior art is difficult to efficiently synthesize γ-amino acids and dipeptides, and it is cost-effective and has limited applicability.
The carbonylation reaction is catalyzed by cobalt, and inexpensive and easy-to-get raw materials such as phenols or alcohols, amines, amides and peroxides are used to react under CO and ethylene atmospheres, and various γ-amino acid derivatives and dipeptides are synthesized through different amino-containing compounds.
The high yield, low cost and wide substrate applicability of γ-amino acids and dipeptides are achieved, and a variety of γ-amino acid derivatives and dipeptides are provided.
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Abstract
Description
Technical Field
[0001] The present invention relates to a method for synthesizing gamma-amino acid and dipeptide. Background Art
[0002] γ-amino acid derivatives are four-carbon non-protein amino acids and are an indispensable component of free amino acids in most organisms. Compared with the ubiquitous α-amino acids, γ-amino acid derivatives are an emerging drug carrier (biocompatibility, degradability and versatility). γ-amino acids can also be used to modify peptide drugs, such as resistance to hydrolysis, half-life, pharmacokinetics and physiological properties. It can also be used as a drug carrier. These properties can help it improve the safety and efficacy of drugs while improving the bioavailability of drugs. In addition, due to the presence of three carbon atoms between nitrogen and carbonyl groups, γ-amino acids can better expand amino acid residues and encode amino acid peptides, with more possibilities. γ-amino acids, as an inhibitory neurotransmitter system in the central nervous system of mammals, are gradually being widely used in medicine and chemical industries due to their various physiological functions.
[0003] Dipeptides are compounds formed by the condensation of two amino acid molecules. They are closely related to nutrition, hormones, enzyme inhibition, immune regulation, antibacterial, antiviral, and antioxidant. They are also one of the main forms of protein absorption in the body. They are of various types, diverse structures, and widely distributed in the body. Dipeptides play an important nutritional function in the body. In addition to participating in the regulation of various physiological functions of the body, they can also serve as potential biomarkers for various diseases.
[0004] Compared with the previous synthesis methods of γ-amino acids and dipeptides, we have developed a cobalt-catalyzed carbonylation reaction to synthesize γ-amino acids and dipeptides. Using phenols, alcohols or amines that are easy to obtain, amides that are widely present in various useful natural products and cheap peroxides, as well as industrial raw materials ethylene, we can synthesize γ-amino acid derivatives and dipeptide compounds with high yield, good selectivity and a wide range of substrates in a CO atmosphere. In this method, we can synthesize a variety of different γ-amino acid derivatives and dipeptide compounds by using different amino-containing compounds.
[0005] In summary, this paper describes a cobalt-catalyzed four-component carbonylation method for the preparation of γ-amino acids and dipeptides. Summary of the invention
[0006] The object of the present invention is to provide a method for synthesizing γ-amino acid derivatives.
[0007]
[0008] Reaction equation 1: Synthesis of γ-amino acid derivatives and dipeptides
[0009] The specific operation steps are as follows (reaction equation 1):
[0010] The reaction is carried out in a 300 ml high-pressure reactor, the catalyst and catalyst promoter, the hydroxyl or amine-containing compound 3 are weighed, the peroxide and amide 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 100-160° C., preferably 110-130° C. The reaction time is 12-36 hours, preferably 20-30 hours; after the reaction is completed, the γ-amino acid derivative or the second compound 4 is separated.
[0011] The catalyst is cobalt di(acetylacetonate), cobalt acetate, cobalt bromide, preferably cobalt di(acetylacetonate). The catalyst promoter is one or more of 1,10-phenanthroline, 6,6'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, preferably 1,10-phenanthroline.
[0012] The molar ratio of phenol or alcohol or amine to di(acetylacetonate)cobalt and 1,10-phenanthroline is 100:1:1-100:20:20, preferably 100:3:3-100:10:10.
[0013] The gas pressure of carbon monoxide is 1 to 40 atmospheres, preferably 5 to 20 atmospheres.
[0014] The gas pressure of ethylene is 1 to 20 atmospheres, preferably 1 to 5 atmospheres.
[0015] The present invention has the following advantages:
[0016] First, the use of abundant transition metal cobalt to catalyze carbonylation to synthesize γ-amino acid derivatives and dipeptides provides an effective way to synthesize a variety of γ-amino acid derivatives and dipeptides. Second, the system can apply a variety of phenols, alcohols, and amines to the reaction, broadening the applicability of the reaction. Third, the use of gaseous CO as a carbonyl source is cheap and easy to obtain, greatly reducing costs. Fourth, the use of ethylene gas as a C2 source provides more possibilities for large-scale production and conversion of ethylene gas. Fifth, under this general method, γ-amino acid derivatives or dipeptide compounds can be selectively obtained using different amino-containing compounds.
[0017] The present invention uses gaseous CO as a C1 source and ethylene gas as a C2 source, and under the action of a catalytic amount of a high-yield metal cobalt catalyst, obtains γ-amino acid and dipeptide products with high yield, low cost and wide substrate applicability. DETAILED DESCRIPTION
[0018] 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.
[0019] Table 1 Reaction results of different substituted amides, phenols or alcohols, and amines
[0020]
[0021]
[0022]
[0023] As follows (γ-amino acid derivatives)
[0024]
[0025] As follows (dipeptide compound)
[0026]
[0027] Example 1
[0028] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4a was separated by column chromatography with a yield of 79%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0029] The test data are as follows:
[0030] 1 H NMR(400MHz, CDCl3)δ7.42–7.31(m,2H),7.25–7.17(m,1H),7.12–7.00(m,2H),3.46 / 3.39 * (t, J = 7.2 Hz, 2H), 2.99 / 2.93 * (s,3H),2.62–2.50(m,2H),2.11 / 2.06 * (s, 3H), 2.04–1.88 (m, 2H).
[0031] 13 C NMR (101MHz, CDCl3) δ171.7 / 170.7 * ,171.2 / 170.5 * ,150.6 / 150.4 * ,129.4 * / 129.3,125.9 / 125.7 * ,121.5 / 121.3 * ,49.7 * / 46.5,36.0 / 33.1 * ,31.4 / 30.8 * ,23.2 * / 22.3,21.8 / 21.1 * .
[0032] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 13 H 18 NO3 236.1281; Found:236.1287.
[0033] Example 2
[0034] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110° C. for a reaction time of 30.0 hours. After the reaction was completed, the γ-amino acid compound 4b was separated by column chromatography with a yield of 80%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0035] The test data are as follows:
[0036] 1 H NMR(400MHz, CDCl3)δ7.85–7.59(m,2H),7.47–7.05(m,2H),3.49 / 3.42 * (t, J = 7.0 Hz, 2H), 3.02 / 2.95* (s,3H),2.72–2.49(m,2H),2.13 * / 2.09(s,3H),2.07–1.85(m,2H).
[0037] 13 C NMR (101MHz, CDCl3) δ170.9 / 170.9 * ,170.5 / 170.5 * ,154.0 / 153.7 * ,133.8 * / 133.7,122.8 / 122.7 * ,118.3 / 118.1 * ,109.9 * / 109.6,49.7 * / 46.3,36.1 / 33.2 * ,31.4 / 30.9 * ,23.1 * / 22.2,21.9 / 21.2 * .
[0038] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 14 H 17 N2O3I 261.1234; Found:261.1238.
[0039] Example 3
[0040] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then placed at 110°C for reaction for 30.0 hours. After the reaction was completed, the γ-amino acid compound 4c was separated by column chromatography with a yield of 83%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0041] The test data are as follows:
[0042] 1 H NMR(400MHz, CDCl3)δ5.03–4.56(m,1H),3.42–3.30 / 3.30 * –3.21 * (m,2H),2.94 / 2.86 * (s,3H),2.31–2.13(m,2H),2.04 * / 2.01(s,3H),1.86–1.73(m,4H),1.73–1.59(m,2H),1.56–1.43(m,1H),1.38–1.20(m,5H).
[0043] 13 C NMR (101MHz, CDCl3) δ172.5 / 172.0 * ,170.5 / 170.4 * ,72.9 * / 72.5,49.7 * / 46.6,36.0 / 33.0 * ,31.7 * / 31.5,31.5 / 31.0 * ,25.2 / 25.2 * ,23.6 * / 23.6,23.3 * / 22.5,21.7 / 21.0 * .
[0044] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 13 H 24 NO3 242.1751; Found: 242.1751. Example 4
[0045] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vessel was inserted into the vial through the bottle cap, so that the vial was connected to the outside through the needle, and then the reaction vial was placed in a high-pressure reactor, carbon monoxide was replaced in the high-pressure reactor, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110° C. for a reaction time of 30.0 hours. After the reaction was completed, the γ-amino acid compound 4d was separated by column chromatography with a yield of 77%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0046] The test data are as follows:
[0047] 1 H NMR (400MHz, CDCl3) δ9.32 / 8.41 * (s,1H),7.64 / 7.53 * (d, J = 7.6 Hz, 2H), 7.29 * (t,J=7.3Hz,2H),7.10–7.04(m,1H),3.50 / 3.37 * (t,J=7.2Hz,2H),3.00 / 2.91 * (s,3H),2.38 * / 2.31(t,J=7.0Hz,2H),2.11 / 2.09 * (s,3H),1.99–1.89(m,2H).
[0048] 13 C NMR (101 MHz, CDCl3) δ 172.0 * / 171.2,170.8 / 170.2 * ,138.6 / 138.1 * ,128.9 * / 128.7,124.1 * / 123.7,119.8 * / 119.6,49.8 * / 46.4,36.0 / 33.1 * ,34.5 / 33.0 * ,23.6 / 23.4* ,21.9 / 21.2 * .
[0049] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 13 H 19 N2O2 235.1441; Found:235.1442.
[0050] Example 5
[0051] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4e was separated by column chromatography with a yield of 82%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0052] The test data are as follows:
[0053] 1 H NMR (400MHz, CDCl3) δ6.65 / 5.72 * (s,1H),3.84–3.57(m,1H),3.37 / 3.30 * (t,J=6.5Hz,2H),2.95 / 2.86 * (s,3H),2.39–1.98(m,5H),1.95–1.73(m,4H),1.73–1.62(m,2H),1.62–1.50(m,1H),1.45–1.23(m,2H),1.23–0.97(m,3H).
[0054] 13 C NMR (101MHz, CDCl3) δ171.5 / 170.6 * ,171.3 / 170.6 * ,49.9 * / 48.1,48.2* / 46.4,36.0 / 33.1 * ,33.4 / 33.0 * ,32.9 / 32.5 * ,25.4 / 25.4 * ,24.8 / 24.8 * ,23.7 * / 23.4,21.8 / 21.1 * .
[0055] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 13 H 25 N2O2 241.1911; Found:241.1919.
[0056] Example 6
[0057] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4f was separated by column chromatography with a yield of 66%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0058] The test data are as follows:
[0059] 1 H NMR(400MHz, CDCl3)δ7.43–6.70(m,6H),4.42 / 4.40 * (s,2H),3.38 / 3.31 * (t,J=6.7Hz,2H),,2.96 / 2.86 * (s,3H),2.42–2.11(m,2H),2.03 * / 2.02(s,3H),1.95–1.81(m,2H).
[0060] 13 C NMR (101MHz, CDCl3) δ172.5 / 171.6 * ,171.3 / 170.6 * ,138.5 / 138.2 * ,128.5 * / 128.4,127.7 * / 127.6,127.3 * / 127.1,49.8 * / 46.5,43.4 * / 43.3,35.9 / 32.9 * ,33.2 / 32.2 * ,23.6 * / 23.2,21.7 / 21.0 * .
[0061] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 14 H 21 N2O2 249.1598; Found:249.1589.
[0062] Example 7
[0063] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction bottle was inserted into the vial through the bottle cap, so that the vial was connected to the outside through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then placed at 110° C. for reaction for 30.0 hours. After the reaction was completed, 4 g of γ-amino acid compound was obtained by column chromatography separation with a yield of 83%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0064] The test data are as follows:
[0065] 1 H NMR(700MHz, CDCl3)δ4.12–3.94(m,2H),3.39 / 3.31 *(t, J = 7.3 Hz, 2H), 2.97 / 2.91 * (s,3H),2.38–2.24(m,4H),1.97–1.80(m,2H),1.60(q,J=7.8Hz,2H),1.38–1.23(m,6H),1.19–1.07(m,3H),0.95–0.84(m,3H).
[0066] 13 C NMR (176MHz, CDCl3) δ173.7 / 173.7 * ,173.3 / 172.8 * ,64.9 * / 64.6,48.8 * / 46.9,35.2 * / 33.3,31.5 / 31.4 * ,31.4 / 30.9 * ,28.5 / 28.1 * ,26.7 * / 25.5,25.5 / 23.4 * ,22.6 * / 22.5,14.0,9.6 * / 9.2.
[0067] HRMS(ESI-TOF)m / z:[M+H]+Calcd forC 14 H 28 NO3 258.2064; Found:258.2065.
[0068] Example 8
[0069] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound was separated by column chromatography with a 4h yield of 79%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0070] The test data are as follows:
[0071] 1 H NMR (700MHz, CDCl3) δ4.07 / 4.04 * (t, J = 6.8 Hz, 2H), 3.39 / 3.31 * (t,J=7.2Hz,2H),2.97 / 2.91 * (s,3H),2.51–2.15(m,4H),1.97–1.79(m,2H),1.70–1.52(m,4H),1.37–1.16(m,6H),0.95(t,J=7.4Hz,3H),0.91–0.78(m,3H). 13 C NMR (176MHz, CDCl3) δ173.3 / 173.0 * ,172.9 / 172.8 * ,64.9 * / 64.6,48.9 / 48.9 * ,46.8 * / 46.8,35.5 * / 35.5,35.3 * / 35.3,34.8 * / 34.8,31.5 * / 31.4,30.9 * / 28.5,28.1 / 25.5 * ,23.6 * / 23.5,22.6 * / 22.5,18.8* / 18.4,14.0 * / 14.0.
[0072] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 15 H 30 NO3 272.2220; Found:272.2225.
[0073] Example 9
[0074] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4i was separated by column chromatography with a yield of 56%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0075] The test data are as follows:
[0076] 1 H NMR (400MHz, CDCl3) δ4.12–3.98(m,2H),3.70–3.01(m,3H),2.53–2.15(m,2H),2.10 / 2.08 * (s,3H),1.96–1.72(m,2H),1.61(td,J=6.9,3.4Hz,2H),1.36–1.26(m,6H),1.25–1.12(m,6H),0.89(t,J=6.2Hz,3H).
[0077] 13 C NMR(101MHz,CDCl3)δ173.4 / 173.0 * ,170.7 / 170.1 * ,64.8 * / 64.6,53.0 / 49.2 * ,38.7 * / 35.4,32.7 * / 31.5,31.9 / 31.5 * ,31.5 / 30.8 * ,29.9 * / 29.5,28.5 * / 28.0,25.5 / 22.5 * ,22.2 / 22.0 * ,19.7 * / 19.0,16.2,14.6 * / 13.9.
[0078] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 15 H 30 NO3 272.2220; Found:272.2220.
[0079] Example 10
[0080] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4j was separated by column chromatography with a yield of 56%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0081] The test data are as follows:
[0082] 1 H NMR(400MHz, CDCl3)δ8.00(d,J=8.7Hz,2H),7.21(d,J=8.7Hz,2H),3.55–3.41(m,1H),3.40–3.19(m,2H),2.68–2.53(m,5H),2.14 / 2.13 *(s,3H),2.03–1.91(m,2H),1.90–1.73(m,4H),1.72–1.60(m,2H),1.59–1.27(m,4H).
[0083] 13 C NMR (101MHz, CDCl3) δ196.8,171.4 / 170.7 * ,170.4,154.4 / 154.1 * ,134.9 * / 134.6,130.0 * / 129.9,121.8 / 121.6 * ,58.2 / 53.5 * ,43.7 * / 40.7,32.0 * / 31.7,31.4 * / 31.0,28.0 * / 26.6,26.0 / 25.9 * ,25.8 * / 25.5,25.2 / 24.7 * ,22.1.
[0084] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 20 H 28 NO4 346.2013; Found:346.2009. Example 11
[0085] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 4k was separated by column chromatography with a yield of 72%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0086] The test data are as follows:
[0087] 1 H NMR (700MHz, CDCl3) δ7.32–7.25(m,2H),7.26–7.21(m,1H),7.16(d,J=6.8Hz,1H),7.13–7.04(m,1H),4.93–4.76(m,1H),3.73 * / (s,3H),3.47–3.29(m,2H),3.27–3.13(m,2H),3.05(dd,J=14.0,7.5Hz,1H),2.96 / 2.88 * (s,3H),2.24–2.15(m,2H),2.08 / 2.06 * (s, 3H), 1.97–1.74 (m, 2H).
[0088] 13 C NMR (176MHz, CDCl3) δ175.1 / 174.7 * ,172.4 / 172.2 * ,171.3 * / 171.3,136.2 / 135.8 * ,129.1 / 129.0 * ,128.5 * / 128.4,127.1 * / 126.8,53.4 / 53.0 * ,52.3 * / 52.1,46.7 * / 46.4,37.7 / 36.0 * ,33.1 * / 32.9,32.2 / 31.2 * ,23.5 * / 23.1,21.7 / 21.0 * .
[0089] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 17 H 25 N2O4 321.1809; Found:321.1816 Example 12
[0090] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end was inserted into the vial through the bottle cap, so that the vial was connected to the outside world through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110°C for reaction, and the reaction time was 30.0 hours. After the reaction was completed, the γ-amino acid compound 41 was separated by column chromatography with a yield of 78%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0091] The test data are as follows:
[0092] 1 H NMR (700 MHz, CDCl3) δ 8.67 * / 8.56(s,1H),7.52(dd,J=21.3,8.0Hz,1H),7.34(dd,J=11.3,8.1Hz,1H),7.20–7.14(m,1H),7.14–7.06(m,1H),7.02 / 6.97 * (s,1H)6.78 / 6.10 * (d,J=7.8Hz,1H),4.99–4.73(m,1H),3.71 * / 3.67(s,3H),3.50–3.15(m,4H),2.92 / 2.84 * (s,3H),2.30–2.08(m,2H),2.05 / 2.01 * (s, 3H), 1.93–1.63 (m, 2H).
[0093] 13 C NMR (176MHz, CDCl3) δ172.6 / 172.4 * ,172.4 / 171.4 * ,171.1 / 170.7 * ,136.2 * / 136.1,127.6 * / 127.5,123.0 / 122.8 * ,122.2 * / 122.0,119.6 * / 119.4,118.5 / 118.3 * ,111.4 * / 111.3,110.0 / 109.7 * ,53.0,52.4 * / 52.3,49.8 * / 46.5,36.0 / 33.1 * ,33.2 / 32.4 * ,27.5 / 27.4 * ,23.5 * / 23.1,21.8 / 21.1 * .
[0094] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 19 H 26 N3O4 360.1918; Found: 360.1820 Example 13
[0095] The reaction was carried out in a 300 ml autoclave. First, a hydroxyl or amino compound 3 (0.5 mmol), di(acetylacetonato)cobalt (0.025 mmol), and 1,10-phenanthroline (0.025 mmol) were added to a 4 ml glass vial for mixing. In a nitrogen atmosphere, amide (5 mmol) and 2.0 ml of chlorobenzene were added to the mixture, and di-tert-butyl peroxide (1.5 mmol) was injected to obtain a mixture. The mouth of the glass vial was tightly covered with a rubber cap, and the tip of a syringe needle was inserted into the vial. The end of the reaction vial was inserted into the vial through the bottle cap, so that the vial was connected to the outside through the needle, and then the reaction vial was placed in a high-pressure reactor, the carbon monoxide in the high-pressure reactor was replaced, and 10 atmospheres of carbon monoxide and 1 atmosphere 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, and then it was placed at 110° C. for a reaction time of 30.0 hours. After the reaction was completed, the γ-amino acid compound 4m was separated by column chromatography with a yield of 63%, and the compound was identified by nuclear magnetic resonance (hydrogen spectrum and carbon spectrum) and high-resolution mass spectrometry.
[0096] The test data are as follows:
[0097] 1 H NMR (400MHz, DMSO-d6) δ8.05(s,1H),7.81(s,1H),4.16(d,J=8.5Hz,1H),3.62(s,3H) ,3.23–2.84(m,2H),2.46–2.03(m,2H),1.79(s,3H),1.73–1.33(m,2H),0.93(s,9H).
[0098] 13 C NMR (101MHz, DMSO-d6) δ172.7,172.1,169.5,60.8,51.8,38.6,33.9,32.9,27.0,26.2,23.1.
[0099] HRMS(ESI-TOF)m / z:[M+H]+Calcd for C 13 H 25 N2O4 273.1089; Found:273.1081
[0100] Embodiment 14
[0101] 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 auxiliary agent of the reaction is changed to terpyridine, and the yield of the target product compound is reduced to 75%, at which time the raw material is fully converted.
[0102] Embodiment 15
[0103] The other reaction conditions described in Example 1 were kept unchanged (ie, the operation process and conditions were the same as in Example 1), except that the reaction temperature was reduced to 130 degrees Celsius, and the yield of the target product compound was reduced to 59%.
[0104] Example 16
[0105] 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 di-tert-butyl peroxide used in the reaction is reduced to 2 molar equivalents, and the yield of the target product compound is reduced to 74%.
[0106] Embodiment 17
[0107] The other reaction conditions described in Example 1 were kept unchanged (ie, the operation process and conditions were the same as in Example 1), except that the carbon monoxide in the reaction was reduced to 1 bar, and the yield of the target product compound was reduced to 46%.
[0108] Embodiment 18
[0109] 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 solvent is changed to benzene, and the yield of the target product compound is reduced to 56%.
[0110] Embodiment 19
[0111] Keeping the other reaction conditions described in Example 1 unchanged (i.e., the operation process and conditions are the same as Example 1), the difference is that the amount of catalyst used in the reaction is changed to 3 mol% of the hydroxyl- or amino-containing compound 3, and the yield of the target product compound is reduced to 63%.
[0112] Comparative Example 1
[0113] 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 60 degrees Celsius, the yield of the target product compound is reduced to 0%, and a large amount of raw materials remain.
[0114] Comparative Example 2
[0115] 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 cobalt iodide, the yield of the target product compound is reduced to 5%, and the raw material is not fully converted.
[0116] Comparative Example 3
[0117] The other reaction conditions described in Example 1 remain unchanged (i.e., the operation process and conditions are the same as in Example 1), except that urea peroxide is selected as the peroxide for the reaction, the yield of the target product compound is reduced to 0%, and the raw material portion remains.
[0118] Comparative Example 4
[0119] 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 catalyst of the reaction is removed, the yield of the target product compound is reduced to 0%, and a large amount of raw materials remain.
[0120] Comparative Example 5
[0121] 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 catalyst aid in the reaction is removed, the yield of the target product compound is reduced by 10%, and the raw material is fully converted.
[0122] Comparative Example 6
[0123] 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 peroxide in the reaction is removed, the yield of the target product compound is reduced to 0%, and a large amount of raw materials remain.
[0124] Comparative Example 7
[0125] 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 changed to palladium chloride, the yield of the target product compound is reduced to 0%, and a large amount of raw materials remain.
[0126] Comparative Example 8
[0127] 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 time is reduced to 10 hours, the yield of the target product compound is reduced by 23%, and the raw materials are fully converted.
Claims
1. A method for preparing a γ-amino acid derivative or a dipeptide, characterized in that: One or more γ-amino acid derivatives are prepared from amide, ethylene, carbon monoxide and one or more phenols, alcohols or amines. The amide 1 shown in the following formula, one or more hydroxyl-containing or amino compounds 3 (i.e., one or more phenols, alcohols or amines), carbon monoxide and ethylene gas are used as raw materials to generate one or more γ-amino acid derivatives or dipeptide compounds 4. The reaction formula is as follows: In the reaction formula, R 1 is one or more of methyl, ethyl, and isopropyl, R 2 is one or more of methyl, ethyl, cyclohexyl, and hydrogen, R 3 It is one or more of methyl, ethyl, and hydrogen; The hydroxyl or amino compound 3 is one or more of phenol, alcohol, and amine; in the general formula, R 4 is one or more of phenyl, 4-cyanophenyl, cyclohexyl, n-hexyl, and 4-acetylphenyl; R 5 It is one or more of phenyl, cyclohexyl and benzyl; or In addition, in the synthesis reaction of the dipeptide compound, the amino compound 3 in the reaction formula is one or more of glycosyl benzyl ester, tryptophan methyl ester, and tert-leucine methyl ester; R 1 is one or more of methyl, ethyl, and isopropyl, R 2 is one or more of methyl, ethyl, cyclohexyl, and hydrogen, R 3 It is one or two or more of methyl, ethyl and hydrogen.
2. The method for preparing a γ-amino acid derivative or a dipeptide according to claim 1, characterized in that: The specific steps are as follows: The reaction is carried out in a high-pressure reactor, the catalyst and the catalyst promoter, and the hydroxyl- or amino-containing compound 3 are weighed and mixed to obtain a mixture, and the peroxide and the amide 1 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 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 100-160° C., preferably 110-130° C.; the reaction time is 12-36 hours, preferably 20-30 hours; after the reaction is completed, one or more of the γ-amino acid derivatives or dipeptides 4 are separated; The peroxide is one or more of m-chloroperbenzoic acid, urea peroxide, potassium peroxymonosulfate, and di-tert-butyl peroxide, preferably di-tert-butyl peroxide; The catalyst is one or more of di(acetylacetonate)cobalt, cobalt acetate, and cobalt bromide, preferably di(acetylacetonate)cobalt; The catalyst promoter is one or more of 1,10-phenanthroline, 6,6'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine and terpyridine, preferably 1,10-phenanthroline.
3. The method according to claim 2, characterized in that: The molar ratio of the hydroxyl or amino compound 3 to the catalyst and catalyst promoter is 100:1:1-100:20:20, preferably 100:3:3-100:10:
10.
4. The preparation method according to claim 2, characterized in that: The molar ratio of the hydroxyl- or amino-containing compound 3 to the peroxide is 1:2-1:5, preferably 1:2-1:
3.
5. The preparation method according to claim 2, characterized in that: The gas pressure of carbon monoxide is 1-40 atmospheres, preferably 5-20 atmospheres; The gas pressure of ethylene gas is 1 to 20 atmospheres, preferably 1 to 5 atmospheres.
6. The preparation method according to claim 2, characterized in that: The total volume of the reaction substrate, catalyst, co-catalyst and peroxide does not exceed 50% of the volume of the high-pressure reactor.
7. The preparation method according to claim 2, characterized in that: The amount of amide 1 used is 2.0-5.0 mmol, preferably 3.0-5.0 mmol, per 0.5 mmol of hydroxyl or amino compound 3. The reaction solvent is chlorobenzene or benzene. The amount of solvent used is 1.0-3.0 mmol, preferably 1.0-2.0 ml, per 0.5 mmol of hydroxyl or amino compound 3.
8. The preparation method according to claim 2, characterized in that: The substrate amide 1 of the present invention has a wide range of applications, including various N-alkyl substituted amides, namely R 3 It can be methyl or ethyl; R 2 It may be methyl or hydrogen.