A process for the preparation of alpha-amino acid derivatives

Abstract

The present application relates to a kind of method for preparing alpha-amino acid derivatives. Specifically under the catalytic conditions of cobalt and nitrogen ligand, N, N-dimethylamide is prepared into alpha-amino acid derivatives by carbonylation with nucleophilic reagent. The present application uses the methylamide widely existing in industry as raw material, and the nucleophilic reagent includes alcohol, phenol, amine. Alpha-amino acid derivatives are obtained with high atom utilization and high yield under the action of catalytic amount of cobalt catalyst with carbon monoxide as carbon source.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing α-amino acid derivatives. BACKGROUND

[0002] Non-natural amino acids and their derivatives are indispensable building blocks for biochemical applications, industries, materials and fine chemicals, polypeptide preparation, etc. Especially, α-amino acid derivatives, which constitute the basis of peptide and protein structure, are one of the most important hundreds of amino acids, and 22 α-amino acids appear in the genetic code. In addition, α-amino acids, as the simplest amino acids, are also widely used in the synthesis of various polypeptides and proteins in living cells due to their various physiological functions, and are gradually widely used in medical and chemical industries.

[0003] Compared with the previous synthesis method of α-amino acid, we developed a cobalt-catalyzed carbonylation reaction to synthesize α-amino acid. With simple and easy-to-prepare phenol or alcohol or amine, amide widely existing in various useful natural products and cheap peroxide, we can synthesize α-amino acid derivatives with high yield, good selectivity and wide substrate.

[0004] In summary, a method for preparing α-amino acid by cobalt-catalyzed carbonylation reaction is described herein SUMMARY

[0005] The purpose of the present application is to provide a method for synthesizing α-amino acid derivatives.

[0006]

[0007] The specific operation steps are as follows (reaction equation 1):

[0008] The reaction is carried out in a 300 ml high-pressure reaction kettle, and the catalyst and catalyst aid, the compound 2 containing hydroxyl or amine are weighed, the peroxide and amide are injected under nitrogen atmosphere, and the reaction is placed in carbon monoxide gas, and the reaction is carried out at 70-150 ℃, preferably 110-130 ℃. The reaction time is 10-36 hours, preferably 18-24 hours; after the reaction is completed, the α-amino acid derivative 3 is separated.

[0009] The catalyst is cobalt bis(acetylacetone), cobalt tris(acetylacetone), cobalt chloride, preferably cobalt bis(acetylacetone). The catalyst aid is one or two or more of 4,4'-di-tert-butyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, preferably 4,4'-di-tert-butyl-2,2'-bipyridine.

[0010] The molar ratio of phenol or alcohol or amine to cobalt di(acetylacetone) to 1,10-phenanthroline is 100:2:2 to 100:15:15, preferably 100:5:5 to 100:8:8.

[0011] The carbon monoxide gas pressure is 10 to 70 atmospheres, preferably 20 to 50 atmospheres.

[0012] The present application has the following advantages:

[0013] First, the expensive transition metal catalytic system is not required for carbonylation synthesis of α-amino acid derivatives, greatly reducing the cost. Second, the system can be used for reactions of various phenols, alcohols and amines, widening the applicability of the reaction. Third, the gas carbon monoxide is used as the carbon source, which is inexpensive and easy to obtain, greatly reducing the cost.

[0014] The present application uses gas carbon monoxide as the carbon source, under the action of a catalytic amount of inexpensive cobalt catalyst, to obtain α-amino acid products with high atomic utilization and high yield, and wide substrate applicability. DETAILED DESCRIPTION

[0015] In order to better understand the present application, the following examples are provided. The reaction materials and results of Examples 1-10 are shown in Table 1.

[0016] Table 1 Reaction results of different substituted amides, phenols or alcohols, and amines

[0017]

[0018]

[0019]

[0020] Example 1

[0021] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of hydroxyl or amino compound 2 (structure shown in Table 1 and the above reaction formula, the same below), 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial for mixing. Under a nitrogen atmosphere, 3 mmol of amide 1 (structure shown in Table 1 and the above reaction formula, the same below) and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide to obtain the final mixture. The small glass bottle was sealed tightly with a rubber cap. A syringe needle was inserted into the bottle through the cap, allowing the bottle to communicate with the outside environment. The bottle was then placed in a high-pressure reactor, and the reactor was purged with carbon monoxide at 50 atmospheres. The carbon monoxide in the reactor was then connected to the inside of the bottle through the needle. The reaction was then carried out at 120°C for 20 hours. After the reaction, the α-amino acid compound 3a was obtained by column chromatography with a yield of 82%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0022] The test data is as follows:

[0023] 1 H NMR (400MHz, CDCl3) δ7.50–7.31(m,2H),7.32–7.18(m,1H),7.11(d,J=7.9Hz,2H),4.36 / 4.28 * (s,2H),3.15 / 3.06 * (s,3H),2.16 / 2.14 * (s,3H). 13 C NMR (101MHz, CDCl3) δ171.4 / 170.9 * 167.9 / 167.5 * ,150.3,129.5 / 129.4 * 126.3 / 125.9 * 121.3 / 121.0 * 52.5 / 49.3 * 37.2 / 34.7 * 21.3 / 21.2 * .

[0024] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 11 H 14 NO3 208.0968; Found:208.0969.

[0025] Example 2

[0026] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3b was obtained by column chromatography with a yield of 71%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0027] The test data is as follows:

[0028] 1 H NMR(400MHz, CDCl3)δ7.33(d,J=8.8Hz,2H),7.07(d,J=8.9Hz,2H),4.34 / 4.29 * (s,2H),3.16 / 3.05 * (s,3H),2.17 / 2.13 * (s,3H).

[0029] 13 C NMR (101MHz, CDCl3) δ171.5,167.8,148.8,131.4,129.6 * / 129.4,122.7 / 122.4 * 52.4 * / 49.4,37.3 / 34.7 * ,21.27.

[0030] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 11 H 13 ClNO3 242.0578; Found:242.0578.

[0031] Example 3

[0032] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3c was obtained by column chromatography with a yield of 75%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0033] The test data is as follows:

[0034] 1 H NMR(400MHz, CDCl3)δ4.25–3.96(m,4H),3.06 / 2.95 * (s,3H),2.13 / 2.04 * (s,3H),1.74–1.52(m,2H),1.46–1.21(m,6H),0.87(t,J=6.9Hz,3H).

[0035] 13 C NMR (101MHz, CDCl3) δ171.2 / 170.9 * 169.4 / 169.0 * 65.7 * / 65.3,52.5 * / 49.1,37.2 / 34.7 * 31.3 / 31.3 * 28.44, 25.5 / 25.4 * 22.4 / 22.4 * 21.3 / 21.2 * 13.9 / 13.9 * .

[0036] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 11 H 22NO3 216.1594; Found: 216.1596. Example 4

[0037] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound was obtained by column chromatography with a 3-day yield of 56%. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0038] The test data is as follows:

[0039] 1 H NMR(400MHz, CDCl3)δ4.39–4.13(m,2H),4.11 / 4.01 * (s,2H),3.08 / 2.97 * (s,3H),2.14 / 2.05 * (s, 3H), 1.27 (t, J = 7.2 Hz, 3H).

[0040] 13 C NMR (176MHz, CDCl3) δ171.3 / 171.0 * 169.3 / 168.9 * 61.6 * / 61.1,52.5 * / 49.2,37.2 / 34.7 * 21.4 / 21.2 * 14.2 * / 14.1.

[0041] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C7H 14 NO3 160.0968; Found: 160.0964. Example 5

[0042] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3e was obtained by column chromatography with a yield of 53%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0043] The test data is as follows:

[0044] 1 H NMR (400MHz, CDCl3) δ8.71 (s, 1H), 7.50 (d, J = 7.9Hz, 2H), 7.28 (t, J = 7.1Hz, 2H), 7.08 (t, J = 7.3Hz, 1H), 4.12 / 4.08 * (s,2H),3.17 / 3.04 * (s,3H),2.17 / 2.13 * (s,3H).

[0045] 13 C NMR (101MHz, CDCl3) δ172.2,167.2,137.8,129.0 * / 128.9,124.18,120.3 * / 119.7,53.7,37.9,21.5.

[0046] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 11 H 15 N2O2 207.1128; Found: 207.1129. Example 6

[0047] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3f was obtained by column chromatography with a yield of 56%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0048] The test data is as follows:

[0049] 1 H NMR (400MHz, DMSO-d6) δ 10.22 * / 10.06(s,1H),7.89–7.57(m,6H),7.44(t,J=6.7Hz,2H),7.33(t,J=6.7Hz,1H),4.20 * / 4.13(s,2H),3.07 / 2.84 * (s,3H),2.06 / 1.98 * (s,3H).

[0050] 13 C NMR (101MHz, DMSO-d6) δ 171.2 * / 171.0,167.8 / 167.6 * 140.1 / 140.1 * 138.9 / 138.7 * 135.6 * / 135.3,129.3 * / 129.4,127.5 * / 127.5 127.5 * / 127.4,126.7 * / 126.7,120.0 * / 119.9,53.9 * / 51.1,37.8 / 34.6 * 21.8 / 21.7 *.

[0051] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 17 H 19 N2O2 283.1441; Found: 283.1450. Example 7

[0052] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. One end of a syringe needle was inserted through the cap into a vial, allowing the vial to communicate with the outside environment via the needle. The vial was then placed in a high-pressure reactor, and the reactor was purged with carbon monoxide at 40 atmospheres. At this point, the carbon monoxide inside the reactor was connected to the inside of the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction was completed, 3g of the α-amino acid compound was obtained by column chromatography with a yield of 66%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0053] The test data is as follows:

[0054] 1 H NMR(700MHz, CDCl3)δ7.31(t,J=7.5Hz,2H),7.28–7.22(m,3H),6.84(br,1H),4.47 * / 4.40(d,J=5.9Hz,2H),4.00 / 3.96 * (s,2H),3.10 / 2.92 * (s,3H),2.09 / 2.01 * (s,3H).

[0055] 13 C NMR (176MHz, CDCl3) δ171.7 / 171.4 * 168.8 / 167.8 * 138.0 / 137.8 * 128.7 * / 128.6,127.7 * / 127.5,127.6 * / 127.3,54.4* / 52.1,43.4 * / 43.2,37.6 / 34.8 * 21.4 / 21.3 * .

[0056] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 12 H 17 N2O2 221.1285; Found: 221.1288. Example 8

[0057] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound was obtained by column chromatography with a yield of 62% after 3 hours. The structure of the compound was identified by NMR (1H and 1C) and high-resolution mass spectrometry.

[0058] The test data is as follows:

[0059] 1 H NMR (700MHz, CDCl3) δ6.28 / 5.93 * (s, 1H), 4.28 * –4.22 * / 4.18–4.10(m, 1H), 3.92 / 3.91 * (s,2H),3.10 / 2.96 * (s,3H),2.13 / 2.07 * (s,3H),2.04 * -1.97 * / 2.00–1.89(m,2H),1.73–1.49(m,4H),1.46–1.24(m,2H).

[0060] 13C NMR (176MHz, CDCl3) δ171.6 / 171.5 * 168.4 / 167.2 * 54.6 * / 52.5,51.2 * / 51.1,37.6 / 34.8 * 33.0 * / 33.0,23.7,21.5 / 21.4 * .

[0061] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 10 H 19 N2O2 199.1441; Found: 199.1449. Example 9

[0062] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3i was obtained by column chromatography with a yield of 81%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0063] The test data is as follows:

[0064] 1 H NMR(700MHz,CDCl3)δ4.19–3.99(m,4H),3.04 / 2.95 * (s,3H),2.38 / 2.23 * (q,J=7.4Hz,2H),1.71–1.54(m,2H),1.40–1.21(m,6H),1.20–1.01(m,3H),0.93–0.76(m,3H).

[0065] 13C NMR (176MHz, CDCl3) δ174.4 / 174.0 * 169.5 / 169.1 * 65.6 * / 65.2,51.5 * / 49.4,36.3 / 34.8 * 31.3 / 31.2 * 28.4, 26.3 / 26.1 * 25.4 / 25.4 * 22.4 / 22.4 * 13.9 / 13.9 * 9.2 * / 9.0.

[0066] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 12 H 24 NO3 230.1751; Found: 230.1754. Example 10

[0067] The reaction was carried out in a 300 mL high-pressure reactor. First, 0.3 mmol of a hydroxyl or amino compound 2, 0.015 mmol of cobalt bis(acetylacetone), and 0.015 mmol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a 4 mL glass vial and mixed. Under a nitrogen atmosphere, 3 mmol of amide 1 and 1.5 mL of trifluorotoluene were added to the mixture, followed by the injection of 0.75 mmol of di-tert-butyl peroxide. The vial was then tightly capped with a rubber cap. A syringe needle was inserted into a vial through the cap, allowing the vial to communicate with the outside environment. The vial was then placed in a high-pressure reactor, which was purged with carbon monoxide at 40 atmospheres. The carbon monoxide inside the reactor was then connected to the vial via the needle. The reactor was then placed at 120°C for 20 hours. After the reaction, the α-amino acid compound 3j was obtained by column chromatography with a yield of 74%. The structure of the compound was identified by NMR (1H and 1C spectra) and high-resolution mass spectrometry.

[0068] The test data is as follows:

[0069] 1 H NMR(700MHz,CDCl3)δ4.33–3.87(m,4H),3.04 / 2.94 * (s,3H),2.33 / 2.18 *(t,J=7.5Hz,2H),1.76–1.53(m,4H),1.39–1.14(m,6H),1.02–0.88(m,3H),0.86(t,J=6.8Hz,3H).

[0070] 13 C NMR (176MHz, CDCl3) δ173.7 / 173.3 * 169.5 / 169.1 * 65.6 * / 65.2,51.6 * / 49.3,36.5 / 34.8 * 35.0 / 34.8 * 31.3 / 31.3 * 28.4, 25.4 / 25.4 * 22.4 / 22.4 * 18.4 * / 18.3,13.9 / 13.9 * 13.8 * / 13.8.

[0071] HRMS(ESI-TOF)m / z:[M+H] + Calcd for C 13 H 26 NO3 244.1907; Found:244.1915.

[0072] Example 11

[0073] 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 130 degrees Celsius, and the yield of the target product α-amino acid compound is reduced to 71%.

[0074] Example 12

[0075] 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 changed to 4 equivalents (relative to 2 hydroxyl or amino compounds, i.e. 1.2 mmol), and the yield of the target product α-amino acid compound is reduced to 77%.

[0076] Example 13

[0077] 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 carbon monoxide in the reaction is reduced to 35 bar, and the yield of the target product α-amino acid compound is reduced to 65%.

[0078] Example 14

[0079] 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 catalyst used in the reaction is changed to 3.5 mol% (relative to hydroxyl or amino compound 2), and the yield of the target product α-amino acid compound is reduced to 59%.

[0080] Application Examples

[0081]

[0082] 3k is an N-acylsarcosine, a highly valuable surfactant that can be used in formulations of corrosion inhibitors, lubricants, fuel additives, foaming agents, fiber cleaning agents, antistatic agents, mineral flotation, shampoos, toothpaste, leather chemicals, cosmetics, and personal hygiene products. It is also used in other industrial sectors such as food, petroleum products, electroplating mineral flotation, and oil extraction.

[0083] 3l is a metabolite of an enzyme-degraded substrate that can be detected by magnetic resonance spectroscopy. It is mainly located in mature neurons and neurites, serving as a marker of neurons.

[0084] Our strategy for synthesizing α-amino acid derivatives enables the synthesis of the skeletal structures for both application examples.

[0085] Comparative Example 1

[0086] 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 40 degrees Celsius, the yield of the target product α-amino acid compound is reduced to 0%, and the raw materials are largely left over.

[0087] Comparative Example 2

[0088] 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 peroxide in the reaction is changed to potassium peroxymonosulfonate, the yield of the target product α-amino acid compound is reduced to 0%, and the raw material portion remains.

[0089] Comparative Example 3

[0090] 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 co-catalyst for the reaction is changed to triphenylphosphine, the yield of the amide / ester compound of the target product α-ether is reduced to 10%, and a large amount of raw materials remain.

[0091] Comparative Example 4

[0092] 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 for the reaction is removed, the yield of the target product α-amino acid compound is reduced to 0%, and a large amount of raw materials remain.

[0093] Comparative Example 5

[0094] 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 for the reaction is removed, the yield of the target product α-amino acid compound decreases by 3%, and a large amount of raw materials remain.

[0095] Comparative Example 6

[0096] 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 peroxide in the reaction is removed, the yield of the target product α-amino acid compound decreases to 0%, and a large amount of raw materials remain.

[0097] Comparative Example 7

[0098] 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 for the reaction is changed to copper chloride, the yield of the target product α-amino acid compound decreases to 0%, and a large amount of raw materials remain.

[0099] Comparative Example 8

[0100] 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 time is reduced to 5 hours, the yield of the target product α-amino acid compound is reduced by 12%, and a large amount of raw materials remain.

[0101] Comparative Example 9

[0102] 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 substrate amide is changed to N,N-diethylamide, the yield of the corresponding target product α-amino acid compound decreases by 0%, and a large amount of raw materials remain.

[0103] Comparative Example 10

[0104] 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 substrate amide is changed to N-methylamide, the yield of the corresponding target product α-amino acid compound decreases by 0%, and a large amount of raw materials remain.

[0105] Comparative Example 11

[0106] 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 when the substrate amide is changed to an asymmetric amide, such as N-methylN-cyclohexylacetamide, the yield of the corresponding target product α-amino acid compound decreases by 0%, and a large amount of raw materials remain.

[0107] Comparative Example 12

[0108] 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 for the reaction is changed to 1,10-phenanthroline, and the yield of the corresponding target product α-amino acid compound decreases by 0%, and a large amount of raw materials remain.

Claims

1. A kind α A method for preparing amino acid derivatives, characterized in that: Prepared from dimethylamide 1, carbon monoxide and hydroxyl or amino compound 2 α -Amino acid derivative 3, the reaction formula is as follows: ， In the reaction formula, R in dimethylamide 1 1 Methyl, ethyl, propyl; In addition, compound 2 containing a hydroxyl or amino group is one of a phenol, alcohol, or amine; in the general formula R 2 It is phenyl, 4-chlorophenyl, n-hexyl, ethyl; R 3 It can be phenyl, 4-phenylphenyl, benzyl, or cyclopentyl. The specific steps are as follows: The reaction is carried out in a high-pressure reactor. A mixture is prepared by weighing and mixing one of the following: catalyst, catalyst promoter, and hydroxyl or amino compound 2. Under an inert atmosphere, peroxide, reaction solvent, and dimethylamide 1 are injected into the mixture to obtain a final mixture. This final mixture is then placed in the reactor or directly mixed or prepared within the reactor. The gas atmosphere in the reactor is replaced with carbon monoxide gas. The reaction is carried out at 70-150 °C for 10-36 hours. After the reaction is complete, the final product is separated. α -Amino acid derivative 3; The catalyst is one of cobalt di(acetylacetone), cobalt tri(acetylacetone), and cobalt chloride. The catalyst promoter is one of 4,4'-di-tert-butyl-2,2'-bipyridine, 6,6'-dimethyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, and 2,2'-bipyridine. The reaction solvent is trifluorotoluene.

2. The preparation according to claim 1 α The method for using amino acid derivatives is characterized by: The peroxide is one of hydrogen peroxide, cumene hydroperoxide, tert-butyl peroxide, and di-tert-butyl peroxide. The catalyst is cobalt di(acetylacetone); The catalyst promoter is 4,4'-di-tert-butyl-2,2'-bipyridine.

3. Preparation according to claim 1 or 2 α The method for using amino acid derivatives is characterized by: The mixture is placed in a reaction vessel or directly mixed or prepared in the reaction vessel. The gas atmosphere in the reaction vessel is replaced with carbon monoxide gas. The reaction is carried out at 110-130 °C for 18-24 hours. The peroxide is di-tert-butyl peroxide.

4. Preparation according to claim 1 α The method for using amino acid derivatives is characterized by: The molar ratio of hydroxyl or amino compound 2 to catalyst and catalyst promoter is 100:2:2-100:15:

15.

5. Preparation according to claim 1 or 2 α The method for using amino acid derivatives is characterized by: The molar ratio of hydroxyl or amino compound 2 to peroxide is 1:1 to 1:

5.

6. Preparation according to claim 1 α The method for using amino acid derivatives is characterized by: The pressure of carbon monoxide is 10-70 atmospheres.

7. Preparation according to claim 1 or 2 α The method for using amino acid derivatives is characterized by: The total volume of the reaction solvent, dimethylamide 1, hydroxyl or amino compound 2, catalyst, co-catalyst, and peroxide shall not exceed 50% of the volume of the high-pressure reactor.

8. The preparation according to claim 1 α The method for using amino acid derivatives is characterized by: The amount of dimethylamide 1 used is 1.0-3.0 mmol per 0.3 mmol of hydroxyl or amino compound 2, and the amount of solvent used is 1.5-4.0 mmol per 0.3 mmol of hydroxyl or amino compound 2.

9. Preparation according to claim 1 or 2 α The method for using amino acid derivatives is characterized by: The molar ratio of hydroxyl or amino compound 2 to catalyst and catalyst promoter is 100:5:5-100:8:

8. The molar ratio of hydroxyl or amino compound 2 to peroxide is 1:3-1:4; The pressure of carbon monoxide is 20-50 atmospheres; The dosage of dimethylamide 1 is 1.5-3.0 mmol per 0.3 mmol of hydroxyl or amino compound 2. The amount of solvent used is 1.5–2.0 mL per 0.3 mmol of hydroxyl or amino compound.

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