2-oxazoline compounds and processes for their preparation

Abstract

The application discloses a preparation method of 2-oxazoline compounds. The application realizes efficient and green preparation of 2-oxazoline compounds (a structural formula is as shown in the figure) by taking N-alkynyl oxazolidine-2-ketone alkynyl amide (a structural formula is as shown in the figure) as raw material for the first time. The reaction operation is simple, the yield is high, the substrate is suitable for a wide range, the 2-oxazoline compound can be synthesized in a gram scale, and the product does not need to be separated by column chromatography, reaction solvents can be recycled in a large amount, and production cost is reduced.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, and particularly relates to a 2-oxazoline compound and its preparation method. Background Technology

[0002] 2-Oxazoline compounds are highly valuable intermediates in organic synthesis, and their derivatives are widely used in the preparation of industrial-grade drugs such as chloramphenicol, thiamphenicol, and fluoromycin. Furthermore, chiral and bisoxazoline compounds also function extensively as ligands in asymmetric catalysis. Due to the important applications of 2-oxazoline compounds in medicine, biology, and industry, their synthetic methods are increasingly diverse. Therefore, research on 2-oxazoline heterocyclic compounds, their preparation methods, and applications is of great interest.

[0003] In 2011, Chen Huiying's research group used PPh3-DDQ as a dehydration and activation reagent to synthesize 2-oxazoline compounds and 2-benzoxazole compounds, respectively, using acylamino alcohols and acylphenols as raw materials, under neutral conditions, with yields of 44-99% (Xu, Q.; Li, Z.; Chen, H. Chin. J. Chem. 2011, 29, 925-932).

[0004] In 2012, Pathak's group synthesized N-(β-hydroxyethyl)thioamide rings by transamidation of thioamide with 2-aminoethanol, followed by dehydrogenation sulfidation under alkaline conditions, achieving a mild and efficient synthesis of 2-oxazoline compounds with yields of 35-87% (Goud, D.; Pathak, U. Synthesis 2012, 44, 3678-3682).

[0005] In 2016, Orelli's research group used a polyphosphate (PPA) ester / chloroform system to generate 5-7 membered ring 2-oxazoline compounds by microwave-assisted ω-amide alcohol cyclization at 90 °C. The reaction was highly efficient and the yield was moderate to good (Mollo, M.; Orelli, L.Org.Lett. 2016, 18, 6116-6119).

[0006] In summary, although numerous synthetic methods exist for the synthesis of 2-oxazoline compounds, no reports have been found in the literature regarding the use of N-ynyloxazolidine-2-one acetylides as starting materials for the synthesis of 2-oxazoline heterocyclic compounds. Therefore, from both environmental and economic perspectives, developing efficient methods for the synthesis of 2-oxazoline heterocyclic compounds using readily available and inexpensive N-ynyloxazolidine-2-one acetylides as starting materials is highly attractive. Summary of the Invention

[0007] First, the purpose of this invention is to provide a method for preparing 2-oxazoline compounds, aiming to solve the problem that existing literature does not address the use of N-alkynyloxazolidine-2-one alkynylamides as raw materials to synthesize 2-oxazoline compounds; second, the purpose of this invention is to provide 2-oxazoline compounds obtained by the above preparation method; finally, the purpose of this invention is to provide applications of the above-mentioned 2-oxazoline compounds.

[0008] This invention is achieved by providing a method for preparing a 2-oxazoline compound, the method comprising the following steps:

[0009] (1) The base and acetylene amide are added to the reaction solvent in sequence, and the reaction is stirred at 0-100℃ for 2-10h to obtain the reaction solution; wherein the molar volume ratio of the acetylene amide, the base and the reaction solvent are (0.2-0.4) mmol: (0.2-0.8) mmol: (2-6) mL, respectively.

[0010] (2) Remove the reaction solvent from the reaction solution to obtain 2-oxazoline compounds.

[0011] Preferably, in step (1), the alkali is any one of potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and diethylamine.

[0012] Preferably, in step (1), the acetylamid is an N-acetylinyloxazolidine-2-one compound with the structural formula:

[0013] Preferably, the acetylide is selected from any one of those in Table 1.

[0014] Table 1

[0015] 1 4-Fluorophenyl hydrogen 3-((4-fluorophenyl)ethynyl)oxazolidin-2-one 2 4-Chlorophenyl hydrogen 3-((4-chlorophenyl)ethynyl)oxazolidin-2-one 3 4-Bromophenyl hydrogen 3-((4-bromophenyl)ethynyl)oxazolidin-2-one 4 2-Methylphenyl hydrogen 3-((2-methylphenyl)ethynyl)oxazolidin-2-one 5 3-Methylphenyl hydrogen 3-((3-methylphenyl)ethynyl)oxazolidin-2-one 6 4-Methylphenyl hydrogen 3-((4-methylphenyl)ethynyl)oxazolidin-2-one 7 4-Trifluoromethylphenyl hydrogen 3-((4-trifluoromethylphenyl)ethynyl)oxazolidin-2-one 8 4-Nitrophenyl hydrogen 3-((4-nitrophenyl)ethynyl)oxazolidin-2-one 9 2-Naphthyl hydrogen 3-((1-naphthyl)ethynyl)oxazolidin-2-one 10 3-Pyridyl hydrogen 3-((3-pyridyl)ethynyl)oxazolidin-2-one 11 1-Cyclohexenyl hydrogen 3-((1-cyclohexylenyl)ethynyl)oxazolidin-2-one 12 Triisopropylsilyl hydrogen 3-((triisopropylsilyl)ethynyl)oxazolidin-2-one 13 Estradiol hydrogen Estradiol ethynyloxazolidin-2-one

[0016] Preferably, in step (1), the reaction solvent is selected from any one of methanol, ethanol, and dimethyl sulfoxide. Preferably, the reaction solvent is methanol.

[0017] Preferably, in step (1), the reaction temperature is any temperature between 0 and 100°C. Preferably, the reaction temperature is 25°C.

[0018] The present invention further provides 2-oxazoline compounds obtained by the preparation method described above.

[0019] The present invention further discloses that the above steps can be used to prepare 2-oxazoline compounds with methylene-substituted estrone and bioactive fragments.

[0020] The method of the present invention has the following advantages:

[0021] (1) This method uses readily available acetylides as raw materials. These raw materials can be obtained commercially or by coupling acetylide bromine with the corresponding amide via carbon-nitrogen bond. The cost of obtaining these raw materials is low. Furthermore, the reaction is applicable to a wide range of substrates, such as various aryl and alkyl-substituted acetylides.

[0022] (2) This method uses inexpensive, stable and easy-to-store solvents as reaction solvents, and can be recovered in large quantities;

[0023] (3) This method uses common bases, which is inexpensive; the reaction conditions are mild and do not require high temperature and high pressure.

[0024] The present invention uses ethynyl-substituted oxazolidin-2-one as a raw material to prepare ethynyl-substituted 2-oxazoline compounds 1, which can be used as potential bioactive molecules. Attached Figure Description

[0025] Figure 1 It is the 1H NMR spectrum of 2-(2-methylbenzyl)-4,5-dihydrooxazole;

[0026] Figure 2 It is the carbon NMR spectrum of 2-(2-methylbenzyl)-4,5-dihydrooxazole;

[0027] Figure 3 This is the carbon NMR spectrum of compound 1, a 2-oxazoline compound with methylene substitution of estrone. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0029] Example 1

[0030] (1) In a 10 mL Shrek tube, add 0.4 mmol of 3-((2-methylphenyl)ethynyl)oxazolidin-2-one, 0.8 mmol of cesium carbonate, and 6 mL of dimethyl sulfoxide. Stir the reaction at room temperature. The reaction equation is:

[0031]

[0032] (2) After the reaction was completed by TLC monitoring, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent, oily liquid, 2-(2-methylbenzyl)-4,5-dihydrooxazole, with a yield of 87%. 1H NMR (400MHz, CDCl3) δ 6.97-7.39 (m, 4H), 4.21 (t, J=9.5Hz, 2H), 3.82 (t, J=9.5Hz, 2H), 3.60 (s, 2H), 2.35 (s, 3H). 13 C NMR (100MHz, CDCl3) δ166.6, 136.6, 133.6, 120.2, 129.7, 127.2, 126.0, 67.4, 54.3, 32.3, 19.5.

[0033] Example 2

[0034] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((4-fluorophenyl)ethynyl)oxazolidine-2-one. In a 10 mL Shrek tube, 0.2 mmol of 3-((4-fluorophenyl)ethynyl)oxazolidine-2-one and 0.6 mmol of sodium bicarbonate were added, along with 3 mL of ethanol. The mixture was stirred at room temperature, and the reaction equation is as follows:

[0035]

[0036] (2) After the reaction was complete as monitored by TLC, the solvent was removed by vacuum rotary evaporator. The product was a colorless, transparent, oily liquid, 2-(4-fluorobenzyl)-4,5-dihydrooxazole, with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=8.0Hz, 2H), 7.43 (d, J=8.0Hz, 2H), 4.25 (t, J=9.5Hz, 2H), 3.82 (t, J=9.5Hz, 2H), 3.67 (s, 2H)· 13 CNMR (100MHz, CDCl3) δ166.8, 162.5 (d, J=243.6Hz), 130.8 (d, J=3.4Hz), 130.5 (d, J=8.0Hz), 130.3 (d, J=21.4Hz), 67.6, 54.4, 33.8. 19 F NMR (376MHz, CDCl3) δ-62.5.

[0037] Example 3

[0038] (1) This example is basically the same as Example 1 above, except that the acetylacetamide is 3-((4-trifluoromethylphenyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.4 mmol of 3-((4-trifluoromethylphenyl)ethynyl)oxazolidin-2-one and 0.4 mmol of sodium carbonate are added, along with 4 mL of methanol, and the mixture is heated to 80 °C. ℃ The reaction is carried out under stirring, and the reaction equation is as follows:

[0039]

[0040] (2) After the reaction was complete as monitored by TLC, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent, oily liquid, 2-(4-trifluoromethylbenzyl)-4,5-dihydrooxazole, with a yield of 84%. 1 H NMR (400MHz, CDCl3, ppm): δ7.19-7.36 (m, 2H), 6.87-7.13 (m, 2H), 4.24 (t, J=9.5Hz, 1H), 3.84 (t, J=9.5Hz, 1H), 3.58 (s, 2H). 13 CNMR (100MHz, CDCl3) δ166.1, 139.1, 129.30 (q, J=32.3Hz), 129.37, 125.5 (q, J=3.8Hz), 124.1 (q, J=270.4Hz), 67.7, 54.4, 34.4. 19 F NMR (376MHz, CDCl3) δ-62.5.

[0041] Example 4

[0042] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((1-naphthyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.4 mmol of 3-((1-naphthyl)ethynyl)oxazolidin-2-one and 0.6 mmol of potassium bicarbonate were added, along with 4 mL of dimethyl sulfoxide. The reaction was stirred at 80 °C. The reaction equation is as follows:

[0043]

[0044] (2) After the reaction was complete as monitored by TLC, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent oily liquid, 2-((1-naphthyl)methyl)-4,5-dihydrooxazole, with a yield of 99%. 1 H NMR (400MHz, CDCl3, ppm): δ8.12 (d, J=8.4Hz, 1H), 7.85 (d, J=7.9Hz, 1H), 7.75-7.82 ( m, 1H), 7.40-7.57 (m, 4H), 4.20 (t, J=9.5Hz, 1H), 4.06 (s, 2H), 3.83 (t, J=9.5Hz, 1H); 13 C NMR (100MHz, CDCl3) δ166.7, 133.7, 131.9, 131.3, 128.5, 127.8, 127.5, 126.1, 125.6, 125.4, 123.8, 67.5, 54.3, 32.3.

[0045] Example 5

[0046] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((1-cyclohexenyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.2 mmol of 3-((1-cyclohexenyl)ethynyl)oxazolidin-2-one and 0.6 mmol of potassium hydroxide were added, along with 3 mL of methanol. The reaction was stirred at 80 °C. The reaction equation is as follows:

[0047]

[0048] (2) After the reaction was completed by TLC monitoring, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent oily liquid, 2-((1-cyclohexenyl)methyl)-4,5-dihydrooxazole, with a yield of 87%. 1 H NMR (400MHz, CDCl3) δ5.47-5.69 (m, 1H), 4.24 (t, J=9.5Hz, 2H), 3.84 (t, J=9.4Hz, 2H), 2.94 (s, 2H), 1.94-1.98 (m, 4H), 1.51-1.69 (m, 4H); 13 C NMR (100MHz, CDCl3) δ166.8, 131.9, 124.7, 67.2, 54.3, 36.8, 28.0, 25.1, 22.6, 21.9.

[0049] Example 6

[0050] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((3-pyridyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.3 mmol of 3-((3-pyridyl)ethynyl)oxazolidin-2-one and 0.6 mmol of potassium phosphate were added, along with 3 mL of ethanol. The mixture was stirred at 80 °C. The reaction equation is as follows:

[0051]

[0052] (2) After the reaction was completed by TLC monitoring, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent oily liquid, 2-((1-cyclohexyl)methyl)-4,5-dihydrooxazole, with a yield of 94%. 1H NMR (400MHz, CDCl3) δ8.55 (d, J=2.3Hz, 1H), 8.48-8.53 (dd, J1=4.8Hz, J2=1.7Hz, 1H), 7.58-7.74 (dt, J1=7.8Hz, J2=2. 0Hz, 1H), 7.20-7.29 (ddd, J1=7.8Hz, J2=4.9Hz, J3=0.9Hz, 1H), 4.21-4.31 (m, 2H), 3.85 (t, J=9.5Hz, 2H), 3.62 (s, 2H). 13 C NMR (100MHz, CDCl3) δ166.0, 150.1, 148.3, 136.5, 130.8, 123.4, 67.7, 54.4, 31.9.

[0053] Example 7

[0054] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((triisopropylsilyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.3 mmol of 3-((triisopropylsilyl)ethynyl)oxazolidin-2-one and 0.6 mmol of diethylamine were added, followed by 3 mL of methanol. The mixture was stirred at 50 °C, and the reaction equation was as follows:

[0055]

[0056] (2) After the reaction was complete as monitored by TLC, the solvent was removed by vacuum rotary evaporation. The product was a colorless, transparent oily liquid, 2-((1-triisopropylsilyl)methyl)-4,5-dihydrooxazole, with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ 4.16 (t, J=9.4Hz, 2H), 3.77 (t, J=9.5Hz, 2H), 1.82 (s, 2H), 1.02-1.89 (m, 21H). 13 C NMR (100MHz, CDCl3) δ168.1, 66.9, 54.4, 18.3, 11.1, 10.9.

[0057] Example 8

[0058] (1) This example is basically the same as Example 1 above, except that the acetylide is 3-((4-nitrophenyl)ethynyl)oxazolidin-2-one. In a 10 mL Shrek tube, 0.4 mmol of 3-((4-nitrophenyl)ethynyl)oxazolidin-2-one and 0.6 mmol of sodium hydroxide were added, along with 4 mL of ethanol. The mixture was stirred at 50 °C. The reaction equation is as follows:

[0059]

[0060] (2) After the reaction was complete as monitored by TLC, the solvent was removed by vacuum rotary evaporator. The product was a colorless, transparent oily liquid, 2-(4-nitrobenzyl)-4,5-dihydrooxazole, with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ 8.08-8.29 (m, 2H), 7.39-7.60 (m, 2H), 4.28 (t, J=9.5Hz, 2H), 3.87 (t, J=9.5Hz, 2H), 3.72 (s, 2H). 13 C NMR (100MHz, CDCl3) δ165.4, 147.0, 142.6, 129.9, 123.7, 67.7, 54.4, 34.3.

[0061] Example 9

[0062] (1) This example demonstrates the synthetic application of 2-oxazoline compounds, which can be used to modify the structures of active biomolecules. In a 10 mL Shrek tube, 0.2 mmol of estradiol ethynyl-substituted oxazolidin-2-one, 0.8 mmol of potassium carbonate, and 4 mL of dimethyl sulfoxide were added. The mixture was stirred at 50 °C. The reaction equation is as follows:

[0063]

[0064] (2) After the reaction was complete, the solvent was removed by vacuum concentration to obtain 2-oxazoline compound 1 with methylene substitution of estradiol, which was a pale yellow liquid with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ7.25 (d, J=8.5Hz, 1H), 7.09 (d, J=8.0Hz, 1H), 7.03 (s, 1H ), 4.23 (t, J=9.5Hz, 2H), 3.83 (t, J=9.5Hz, 2H), 3.58 (s, 2H), 2.86-2.99 (dd, J1 =8.9Hz, J2=4.2Hz, 2H), 2.45-2.53 (dd, J1=18.7Hz, J2=8.6Hz, 1H), 2.38-2.44 (m, 1H), 2.24-2.32 (m, 1H), 1.91-2.20 (m, 4H), 1.36-1.72 (m, 6H), 0.90 (s, 3H)· 13C NMR(100MHz,CDCl3)δ220.8,167.1,138.3,136.6,132.4,129.5,126.3,125.5,67.5,54.3,50.3,47.8,44.1,37.9,35.7,34.1,31.4,29.2,26.3,25.5,21.4,13.7。

Claims

1. A method for preparing compound 2-(4-fluorobenzyl)-4,5-dihydrooxazoline, characterized in that, The method includes the following steps: (1) The base and acetylene amide are added to the reaction solvent in sequence, and the reaction is stirred at 0-100℃ for 2-10h to obtain the reaction solution; wherein the molar volume ratio of the acetylene amide, the base and the reaction solvent are (0.2-0.4) mmol: (0.2-0.8) mmol: (2-6) mL, respectively. (2) Removing the reaction solvent from the reaction solution yields a 2-oxazoline compound with the following structural formula: The base is selected from potassium bicarbonate, sodium bicarbonate, potassium phosphate, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, and diethylamine; the acetylide is an N-acetylinyloxazolidine-2-one molecule with the structural formula [insert structural formula here].

2. The method for preparing 2-(4-fluorobenzyl)-4,5-dihydrooxazoline as described in claim 1, characterized in that, The alkali is potassium carbonate.

3. The method for preparing 2-(4-fluorobenzyl)-4,5-dihydrooxazoline as described in claim 1, characterized in that, The reaction solvent is methanol.

4. The method for preparing 2-(4-fluorobenzyl)-4,5-dihydrooxazoline as described in claim 1, characterized in that, In step (1), the reaction temperature is 25°C.

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