CN116803992A - A kind of synthesis method and application of 2-oxazolidinone derivatives - Google Patents

Abstract

The invention discloses a synthesis method and application of a 2-oxazolidone derivative, and belongs to the technical field of organic synthesis. The 2-oxazolidinone compound with various structures shown in the formula II can be obtained by taking the para-quinolamine shown in the formula I as a starting material and matching with a specific acid catalyst. Meanwhile, the compound shown in the formula II has a certain anti-tumor effect, and has development prospect in the field of anti-tumor drug preparation.

Description

A kind of synthesis method and application of 2-oxazolidinone derivatives

Technical field

The invention belongs to the technical field of organic synthesis, and specifically relates to a synthesis method and application of 2-oxazolidinone derivatives.

Background technique

2-oxazolidinones, which belong to amino acid lactones, are a very important nitrogen-containing five-membered heterocycle. They have attracted strong curiosity and attention from biological and chemical workers since 1951. 2-oxazolidinone compounds are widely used in medicine, pesticides, chiral auxiliaries and other fields. Among them, in the field of medicine, 2-oxazolidinone compounds are widely used: for example (1) linezolidone (also known as: molinoxone), an antibiotic containing a 2-oxazolidinone core structure, It can inhibit the synthesis of bacterial proteins and show good antibacterial effects; (2) the nitrosourea drug carmustine, the synthetic substrate is 2-oxazolidinone, this type of drug has broad-spectrum anti-tumor activity; (3) Amoxalone, a new type of 2-oxazolidinone antidepressant, can selectively and reversibly inhibit monoamine oxidase, and has obvious effects on patients with severe depression. It has greatly improved since it was first launched in France in 1985. application market. It can be seen that the 2-oxazolidinone skeleton is commonly found in the drug structure and plays a key role in the drug's effect. However, the current 2-oxazolidinone compounds are relatively single and lack diversity, especially those containing 2-oxazolidinone. It is a polycyclic compound with an oxazolidinone skeleton. Therefore, the design and development of efficient, simple and structurally diverse synthetic methods for 2-oxazolidinone compounds plays an important role in the development of related drugs.

The important value of 2-oxazolidinones in the synthesis of natural products and drugs has attracted many scientific researchers to carry out extensive preparation research on it. The traditional method of preparing this framework mainly includes: 1) cyclization of phosgene and aminoalcohol; 2) transesterification of aminoalcohol and cyclic or linear carbonate; 3) _CO2 insertion into aziridine; 4) aminoalcohol and Addition of _CO2 ; 5) Isocyanate addition to epoxy compounds. However, these synthesis methods mainly have the following shortcomings: the resulting compound structure is relatively simple, expensive transition metal catalysts or highly toxic reagents are used, and there are safety issues during the preparation process that are not conducive to large-scale production.

Contents of the invention

The technical problem to be solved by the present invention is to provide a method for synthesizing 2-oxazolidinone compounds with diverse structures in view of the existing synthetic pathways that require the use of expensive reagents, have safety issues, and lack structural diversity of compounds. The synthesis method is simple, green and environmentally friendly, has a wide substrate application range, convenient purification and high yield, and can obtain 2-oxazolidinone compounds with diverse and complex structures.

Another object of the present invention is to provide applications of a class of 2-oxazolidinone compounds in the field of anti-tumor drug preparation.

In order to achieve the above objects, the present invention adopts the following technical solutions:

The invention provides a method for synthesizing 2-oxazolidinone derivatives, which uses p-quinone amine represented by formula I as raw material, and reacts with Brønsted acid or Lewis acid as a catalyst to obtain formula II. 2-oxazolidinone compounds;

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R ¹ is selected from: C1-C8 linear or branched alkyl group containing 0-2 unsaturated double bonds, C1-C8 cycloalkyl group, C2-C8 alkynyl group;

R ² is taken from: unsubstituted or substituent-substituted C3-C6 cycloalkyl, 3-6-membered heterocyclyl, aryl group; the substituent substitution includes any one of mono-substitution to tri-substitution, and the substituent is selected from From halogen (F, Cl, Br, I), nitro, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, phenyl or

In one embodiment of the invention, the aryl group is selected from: phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuranyl.

In one embodiment of the present invention, the 3-6-membered heterocyclic group contains 1-3 heteroatoms, and the heteroatoms are selected from N, O, and S. Further specific options include: tetrahydropyran ring, morpholine ring, piperidine ring, and piperazine ring.

In one embodiment of the invention, C2-C8 alkynyl is R ³ is H, C1-C6 alkyl.

In one embodiment of the invention, R ¹ can specifically select C1-6 linear or branched alkyl, C _n H _2n+1 -C=CC _n H _2n -,

Most preferably, the 2-oxazolidinone compounds have any of the following structures:

In one embodiment of the present invention, the reaction is carried out in an organic solvent; the organic solvent is any one or more of dichloromethane, chloroform, toluene, acetonitrile, and tetrahydrofuran; dichloromethane is preferred.

In one embodiment of the invention, the catalyst includes p-toluenesulfonic acid, trifluoroacetic acid, camphorsulfonic acid, ferric chloride, aluminum trichloride, indium trifluoromethanesulfonate, boron trifluoride ether Any one of them; preferably boron trifluoride ether.

In one embodiment of the present invention, the ratio of the amount of the catalyst represented by Formula I to the quinone amine is (0.05-1):1, preferably 0.1:1.

In one embodiment of the present invention, the reaction temperature is -70 degrees Celsius to 30 degrees Celsius, preferably 30 degrees Celsius, and the reaction time is 12 to 24 hours.

The invention also provides a 2-oxazolidinone derivative, the structure of which is as follows:

The present invention also provides the use of the above-mentioned 2-oxazolidinone derivatives in preparing anti-cancer drugs.

In one embodiment of the invention, the cancer includes: lung cancer, bladder cancer, breast cancer, and cervical cancer.

Compared with the existing technology, the present invention has the following beneficial effects:

The reported methods for synthesizing 2-oxazolidinone compounds have obvious disadvantages. They require the use of relatively expensive metal catalysts, and some require the use of toxic or dangerous reagents, which seriously restricts the industrialization of 2-oxazolidinone compounds. Production, in view of the above situation, the present invention has developed a method with simple synthesis operation, wide substrate trial range, cheap and easy to obtain catalyst and small dosage, only 0.1 equivalent is needed, and at the same time, it greatly enriches the content of 2-oxazolidinones. The type of framework compound promotes the drug development of this type of framework compound.

The compound of the present invention has a certain proliferation inhibitory effect on various tumor cells and has potential application space in the development of anti-tumor drugs.

Detailed ways

The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

The present invention relates to the following chemical abbreviations: Bn is benzyl, Et is ethyl, ⁿ Bu is n-butyl, t-Bu is tert-butyl, ⁿ hexyl is n-hexyl.

The p-quinone amine represented by formula I involved in the present invention can be prepared by itself according to existing literature, such as the literature Org. Lett. 2021, 23, 7873-7877.

Example 1

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S1 (0.2mmol, 62mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and the reaction ends after 2 hours. . The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P1 (48.9 mg, 95% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.43-7.28 (m, 5H), 6.24 (dd, J = 10.5, 1.9Hz, 1H), 5.96 (d, J = 10.5Hz, 1H), 4.63 -4.58(m,1H),4.54(d,J＝15.8Hz,1H),4.48(d,J＝15.7Hz,1H),2.99(dd,J＝17.8,2.5Hz,1H),2.68(dd, J＝17.8,4.0Hz,1H),1.43(s,3H). ¹³ CNMR(125MHz,CDCl ₃ )δ192.5,156.9,143.6,137.8,129.1,128.2,128.1,128.0,79.0,58.9,44.7,37.0,21.5 .HRMS(ESI)calculated for C ₁₅ H ₁₅ NNaO ₃ [M+Na] ⁺ :280.0944,found280.0939.

Example 2

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S2 (0.2mmol, 71.8mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P2 (53.2 mg, 98% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.24 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.7 Hz, 2H), 6.23 (d, J = 10.5 Hz, 1H), 5.95(d,J＝10.5Hz,1H),4.58(s,1H),4.52(d,J＝15.6Hz,1H),4.42(d,J＝15.7Hz,1H),2.98(d,J＝17.8 Hz, 1H), 2.67 (dd, J = 17.8, 3.8Hz, 1H), 2.35 (s, 3H), 1.43 (s, 3H). ¹³ C NMR (75MHz, DMSO-d ₆ ) δ 193.7, 156.3, 144.5, 136.3,135.3,128.9,127.3,126.9,78.4,58.7,43.0,36.8,20.5,20.0.HRMS(ESI)calculated for C ₁₆ H ₁₇ NNaO ₃ [M+Na] ⁺ :294.1101, found294.1095.

Example 3

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S3 (0.2mmol, 85.4mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 25 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P3 (52.6 mg, 96% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.41-7.29 (m, 2H), 7.12-6.99 (m, 2H), 6.26 (dd, J = 10.5, 2.0Hz, 1H), 5.99 (d, J＝10.4Hz,1H),4.65-4.56(m,1H),4.48(s,2H),2.99(dd,J＝17.7,2.5Hz,1H),2.68(dd,J＝17.8,4.0Hz,1H ), 1.44 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.4, 162.6 (d, J = 245.6Hz), 156.8, 143.4, 133.61 (d, J = 3.2Hz), 129.78 (d, J = 8.1Hz),128.3,116.0(d,J=21.4Hz),79.1,58.9,44.0,37.0,21.6.HRMS(ESI)calculated forC ₁₅ H ₁₄ FNNaO ₃ [M+Na] ⁺ :298.0850, found 298.0845.

Example 4

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S4 (0.2mmol, 69.4mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P4 (54.9 mg, 94% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.39-7.26 (m, 4H), 6.28 (dd, J = 10.5, 2.0Hz, 1H), 6.00 (d, J = 10.4Hz, 1H), 4.65 -4.56(m,1H),4.47(s,2H),3.00(dd,J＝17.8,2.4Hz,1H),2.69(dd,J＝17.8,3.9Hz,1H),1.43(s,3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ192.3,156.8,143.2,136.3,134.1,129.4,129.3,128.4,79.1,58.9,44.1,37.0,21.6.HRMS(ESI)calculated for C ₁₅ H ₁₄ ClNNaO ₃ [M+ Na] ⁺ :314.0554,found 314.0551.

Example 5

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S5 (0.2mmol, 78.2mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P5 (61.4 mg, 92% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.49 (d, J = 8.2Hz, 2H), 7.24 (d, J = 9.2Hz, 2H), 6.29 (dd, J = 10.4, 1.4Hz, 1H ),6.01(d,J＝10.5Hz,1H),4.66-4.57(m,1H),4.52-4.37(m,2H),3.00(dd,J＝17.8,2.5Hz,1H),2.69(dd, J=17.8, 3.8Hz, 1H), 1.43 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.3, 156.8, 143.2, 136.8, 132.2, 129.7, 128.4, 122.2, 79.1, 58.9, 44.1, 37.0, 21.6.HRMS(ESI)calculated for C ₁₅ H ₁₄ BrNNaO ₃ [M+Na] ⁺ :358.0049,found358.0046.

Example 6

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S6 (0.2mmol, 68.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P6 (55.6 mg, 97% ), the substance is a white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ7.33-7.26 (m, 2H), 6.88 (d, J = 8.5Hz, 2H), 6.21 (dd, J = 10.4, 1.6Hz, 1H), 5.94 (d, J＝10.5Hz,1H),4.60-4.48(m,2H),4.39(d,J＝15.6Hz,1H),3.81(s,3H),2.98(dd,J＝17.8,2.3Hz,1H), 2.67 (dd, J=17.8, 3.9Hz, 1H), 1.44 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.5, 159.6, 156.8, 143.8, 129.8, 129.5, 128.0, 114.5, 79.0, 58.9, 55.4,44.2,37.0,21.5.HRMS(ESI)calculated for C ₁₆ H ₁₇ NNaO ₄ [M+Na] ⁺ :310.1050,found310.1067.

Example 7

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S7 (0.2mmol, 65.4mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P7 (49.8 mg, 92% ), the substance is a white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ7.32-7.15(m,4H),6.25(dd,J＝10.5,1.9Hz,1H),6.00(d,J＝10.5Hz,1H),4.66-4.59( m,1H),4.56(s,2H),2.99(dd,J＝17.8,2.4Hz,1H),2.69(dd,J＝17.8,4.0Hz,1H),2.36(s,3H),1.38(s ,3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ192.5,156.6,143.5,136.4,134.8,131.0,128.6,128.31,128.27,126.4,78.9,58.9,43.2,37.1,21.6,19.4.HRMS(ESI) calculated for C ₁₆ H ₁₇ NNaO ₃ [M+Na] ⁺ :294.1101, found 294.1101.

Example 8

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S8 (0.2mmol, 71.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P8 (50.5 mg, 83% ), the substance is a white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ8.26-8.15(m,2H),7.76(d,J＝7.7Hz,1H),7.63-7.52(m,1H),6.40(dd,J＝10.5,2.0 Hz,1H),6.07(d,J＝10.4Hz,1H),4.73-4.63(m,2H),4.48(d,J＝16.1Hz,1H),3.03(dd,J＝17.8,2.4Hz,1H ), 2.72 (dd, J=17.9, 3.9Hz, 1H), 1.47 (s, 3H). ¹³ CNMR (125MHz, CDCl ₃ ) δ192.1,156.9,148.6,142.6,139.8,134.1,130.2,128.8,123.2,122.5 ,79.2,59.0,44.0,37.0,21.8.HRMS(ESI)calculated for C ₁₅ H ₁₄ N ₂ NaO ₅ [M+Na] ⁺ :325.0795,found 325.0796.

Example 9

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S9 (0.2mmol, 63.8mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P9 (41.5 mg, 79% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ6.53 (dd, J＝10.5, 2.0Hz, 1H), 6.10 (d, J＝10.5Hz, 1H), 4.62-4.52 (m, 1H), 3.22 (dd,J＝14.0,6.8Hz,1H),2.98(dd,J＝17.8,2.3Hz,1H),2.83(dd,J＝14.0,7.9Hz,1H),2.69(dd,J＝17.8,3.9 Hz,1H),1.81-1.62(m,6H),1.50(s,3H),1.30-1.12(m,3H),1.02-0.86(m,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ192. 6,157.2,143.3,128.6,78.5,58.9,47.5,37.6,37.1,31.10,31.05,26.5,25.88,25.87,21.7.HRMS(ESI)calculated for C ₁₅ H ₂₁ NNaO ₃ [M+Na] ⁺ :286.1414, found 286.1412.

Example 10

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S10 (0.2mmol, 64.2mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 1.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P10 (44.6 mg, 84% ), the substance is a yellow solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ6.52 (d, J = 10.4Hz, 1H), 6.12 (d, J = 10.4Hz, 1H), 4.60 (s, 1H), 4.07-3.93 (m ,2H),3.44-3.25(m,3H),2.99(dd,J＝17.8,2.3Hz,1H),2.83(dd,J＝13.9,8.4Hz,1H),2.70(dd,J＝17.8,3.7 Hz, 1H), 2.11-1.94 (m, 1H), 1.67 (t, J = 10.6Hz, 2H), 1.51 (s, 3H), 1.42-1.28 (m, 2H). ¹³ C NMR (125MHz, CDCl ₃ )δ192.4,157.2,142.9,128.8,78.6,67.6,67.5,59.0,47.1,37.0,34.7,31.0,30.9,21.7.HRMS(ESI)calculatedfor C ₁₄ H ₁₉ NNaO ₄ [M+Na] ⁺ :288.1206, found 288.1206.

Example 11

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S11 (0.2mmol, 72.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P11 (57.1 mg, 93% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.92-7.72 (m, 4H), 7.59-7.44 (m, 3H), 6.24 (dd, J = 10.4, 1.8Hz, 1H), 5.93 (d, J＝10.5Hz,1H),4.77-4.60(m,3H),3.00(dd,J＝17.7,2.2Hz,1H),2.68(dd,J＝17.8,3.9Hz,1H),1.45(s,3H ). ¹³ C NMR (125MHz, CDCl ₃ ) δ192.5,157.0,143.6,135.3,133.4,133.2,129.1,128.1,127.93,127.89,126.8,126.7,126.5,125.9,79.1,59.0,45.0,3 7.0,21.6.HRMS (ESI)calculated for C ₁₉ H ₁₇ NNaO ₃ [M+Na] ⁺ :330.1101,found 330.1099.

Example 12

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S12 (0.2mmol, 72.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P12 (57.0 mg, 93% ), the substance is a white solid.

¹ H NMR (300MHz, CDCl ₃ ) δ8.16 (d, J = 8.0 Hz, 1H), 7.96-7.80 (m, 2H), 7.65-7.38 (m, 4H), 6.14 (dd, J = 10.5, 1.9 Hz,1H),5.86(d,J＝10.5Hz,1H),5.10-4.97(m,2H),4.64-4.55(m,1H),2.96(dd,J＝17.7,2.3Hz,1H),2.65 (dd, J=17.7, 4.1Hz, 1H), 1.33 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.5, 156.6, 143.4, 134.0, 132.5, 131.4, 129.4, 129.0, 128.2, 127.2, 127.1 ,126.4,125.2,123.6,78.9,59.0,43.6,37.0,21.5.HRMS(ESI)calculated forC ₁₉ H ₁₇ NNaO ₃ [M+Na] ⁺ :330.1101,found 330.1099.

Example 13

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S13 (0.2mmol, 70.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P13 (40.4 mg, 68% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.55 (d, J = 7.3Hz, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.36-7.21 (m, 2H), 6.76 (s ,1H),6.40(dd,J＝10.5,2.0Hz,1H),6.01(d,J＝10.4Hz,1H),4.72-4.55(m,3H),3.01(dd,J＝17.8,2.3Hz, 1H), 2.71 (dd, J=17.8, 4.0Hz, 1H), 1.59 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.4, 156.3, 154.9, 152.6, 143.1, 128.6, 128.2, 124.9, 123.3 ,121.4,111.4,106.1,79.2,58.7,38.0,37.0,21.3.HRMS(ESI)calculated forC ₁₇ H ₁₅ NNaO ₄ [M+Na] ⁺ :320.0893,found 320.0893.

Example 14

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S14 (0.2mmol, 73.8mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P14 (55.2 mg, 88% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.84-7.77(m,1H),7.76-7.69(m,1H),7.41-7.31(m,2H),7.30(s,1H),6.40( dd,J＝10.5,2.0Hz,1H),5.99(d,J＝10.5Hz,1H),4.76(s,2H),4.66-4.60(m,1H),3.01(dd,J＝17.8,2.6Hz ,1H),2.70(dd,J=17.8,4.0Hz,1H),1.56(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ192.3,156.4,143.2,141.2,140.2,139.5,128.5,124.9, 124.8,123.8,123.4,122.6,79.2,59.0,40.3,37.0,21.4.HRMS(ESI)calculated forC ₁₇ H ₁₅ NNaO ₃ S[M+Na] ⁺ :366.0665,found366.0662.

Example 15

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S15 (0.2mmol, 77.8mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 30 minutes. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P15 (51.2 mg, 77% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.59 (d, J＝7.9Hz, 4H), 7.50-7.40 (m, 4H), 7.40-7.32 (m, 1H), 6.32 (dd, J＝ 10.5,1.9Hz,1H),5.99(d,J＝10.5Hz,1H),4.66-4.59(m,1H),4.55(s,2H),3.01(dd,J＝17.8,2.4Hz,1H), 2.70 (dd, J=17.8, 3.9Hz, 1H), 1.47 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.5, 156.9, 143.6, 141.2, 140.5, 136.7, 129.0, 128.5, 128.2, 127.73, 127.70,127.2,79.1,59.0,44.5,37.0,21.7.HRMS(ESI)calculated forC ₂₁ H ₁₉ NNaO ₃ [M+Na] ⁺ :356.1257,found356.1257.

Example 16

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S16 (0.2mmol, 72.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P16 (44.3 mg, 72% ), the substance is a light yellow solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ8.02 (dd, J = 7.7, 0.9Hz, 1H), 7.67-7.56 (m, 1H), 7.54-7.41 (m, 2H), 7.37-7.25 ( m,5H),4.80(t,J＝4.2Hz,1H),4.74(d,J＝16.1Hz,1H),4.37(d,J＝16.1Hz,1H),3.18(dd,J＝16.5,4.4 Hz, 1H), 2.94 (dd, J = 16.5, 3.9Hz, 1H), 1.61 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.7, 156.9, 139.4, 137.6, 134.4, 131.2, 129.1, 128.8 ,127.8,127.6,127.4,127.3,79.7,61.0,45.4,39.1,24.5.HRMS(ESI)calculated forC ₁₉ H ₁₇ NNaO ₃ [M+Na] ⁺ :330.1100,found 330.1095.

Example 17

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S17 (0.2mmol, 109.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography and eluted with dichloromethane and methanol (dichloromethane:methanol=20:1) to obtain product P17 (82.3 mg, 94%). The substance is a white solid.

Characterization data: ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.37 (s, 4H), 6.77 (d, J = 10.2Hz, 2H), 6.01 (d, J = 10.4Hz, 2H), 4.80 (s ,2H),4.53(d,J＝16.1Hz,2H),4.42(d,J＝16.1Hz,2H),3.33(s,2H),3.10(dd,J＝17.6,3.5Hz,2H),2.71 (dd, J=17.4, 1.7Hz, 2H), 2.50 (s, 3H), 1.41 (s, 6H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ 193.6, 156.3, 144.3, 137.3, 127.5, 127.0, 78.4,58.7,42.9,36.8,20.0.

HRMS(ESI)calculated for C ₂₄ H ₂₄ N ₂ NaO ₆ [M+Na] ⁺ :459.1527,found 459.1525.

Example 18

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S18 (0.2mmol, 109.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P18 (34.2 mg, 63% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.41-7.27(m,5H),6.17(dd,J＝10.5,1.5Hz,1H),6.02(d,J＝10.5Hz,1H),4.74 -4.66(m,1H),4.58(d,J＝15.7Hz,1H),4.40(d,J＝15.7Hz,1H),2.99(dd,J＝17.9,2.6Hz,1H),2.65(dd, J＝17.9, 4.4Hz, 1H), 1.90-1.73 (m, 2H), 0.90 (t, J＝7.6Hz, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ 192.9, 157.0, 143.5, 137.8, 129.5, 129.0,128.2,128.1,76.5,62.0,44.8,38.6,28.2,8.0.HRMS(ESI)calculated forC ₁₆ H ₁₇ NNaO ₃ [M+Na] ⁺ :294.1101,found294.1097.

Example 19

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S19 (0.2mmol, 67.9mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P19 (30.6 mg, 54% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.46-7.26 (m, 5H), 6.02 (d, J = 10.6Hz, 1H), 5.98-5.89 (m, 1H), 4.75-4.68 (m, 1H),4.61(s,2H),2.99(dd,J＝18.0,2.2Hz,1H),2.68(dd,J＝18.0,3.9Hz,1H),1.01-0.88(m,1H),0.68-0.55 (m,2H),0.53-0.40(m,1H),0.19-0.07(m,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ192.8,156.9,138.7,138.3,131.0,128.9,128.14,128.09,79.3 ,62.3,45.0,37.5,15.0,0.8,0.1.HRMS(ESI)calculated for C ₁₇ H ₁₇ NNaO ₃ [M+Na] ⁺ :306.1101,found 294.1097.

Example 20

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S20 (0.2mmol, 71.1mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 2:1) to obtain product P20 (38.9 mg, 65% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.42-7.27(m,5H),6.18(dd,J＝10.5,1.6Hz,1H),6.00(d,J＝10.5Hz,1H),4.74 -4.65(m,1H),4.57(d,J＝15.7Hz,1H),4.41(d,J＝15.7Hz,1H),2.98(dd,J＝17.9,2.5Hz,1H),2.66(dd, J＝17.9, 4.3Hz, 1H), 1.78-1.68 (m, 2H), 1.30-1.13 (m, 4H), 0.84 (t, J＝7.0Hz, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ192 .9,157.0,143.7,137.8,129.2,129.0,128.2,128.1,76.8,61.7,44.8,38.4,35.0,25.6,23.0,13.8.HRMS(ESI)calculated for C ₁₈ H ₂₁ NNaO ₃ [M+Na] ⁺ : 322.1414, found 322.1412.

Example 21

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S21 (0.2mmol, 59.7mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1) to obtain product P21 (37.7 mg, 58% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.42-7.27 (m, 5H), 6.18 (dd, J = 10.5, 1.4Hz, 1H), 6.00 (d, J = 10.5Hz, 1H), 4.73 -4.66(m,1H),4.57(d,J＝15.7Hz,1H),4.40(d,J＝15.7Hz,1H),2.97(dd,J＝17.9,2.6Hz,1H),2.65(dd, J＝17.9, 4.3Hz, 1H), 1.81-1.65 (m, 2H), 1.31-1.11 (m, 8H), 0.86 (t, J＝6.6Hz, 3H). ¹³ C NMR (125MHz, CDCl ₃ ) δ192 .9,157.1,143.7,137.8,129.2,129.0,128.2,128.1,76.7,61.7,44.8,38.4,35.3,31.5,29.5,23.6,22.5,14.1.HRMS(ESI)calculated for C ₂₀ H ₂₅ NNaO ₃ [M+ Na] ⁺ :350.1727, found 350.1725.

Example 22

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S22 (0.2mmol, 70.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1) to obtain product P22 (40.4 mg, 68% ), the substance is a white solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.42-7.27 (m, 5H), 6.21 (dd, J = 10.5, 1.7Hz, 1H), 6.02 (d, J = 10.5Hz, 1H), 5.74 -5.58(m,1H),4.98(t,J＝13.6Hz,2H),4.78-4.69(m,1H),4.57(d,J＝15.7Hz,1H),4.43(d,J＝15.7Hz, 1H),2.99(dd,J＝17.9,2.7Hz,1H),2.67(dd,J＝17.9,4.3Hz,1H),2.03-1.92(m,2H),1.89-1.77(m,2H). ¹³ C NMR (125MHz, CDCL ₃ ) Δ192.7,157.0,143.3,137.7,135.9,129.4,128.3,128.1,116.4,76.5,44.9,34.27.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6.6 Lated for C ₁₈ h ₁₉ NNaO ₃ [M+Na] ⁺ :320.1257,found320.1255.

Example 23

The reaction formula for preparing 2-oxazolidinone compounds in this example is as follows:

The preparation method is: dissolve S23 (0.2mmol, 70.6mg) in CH ₂ Cl ₂ (1.0 mL) under air conditions, add BF ₃ ·Et ₂ O (2.5 μL, 10 mol%) at room temperature, and react for 2.5 hours. Finish. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 5:1) to obtain product P23 (49.0 mg, 92% ), the substance is a light yellow solid.

Characterization data: ¹ H NMR (300MHz, CDCl ₃ ) δ7.45-7.30 (m, 5H), 6.02 (dd, J = 10.3, 1.9Hz, 1H), 5.93 (d, J = 10.3Hz, 1H), 4.98 -4.93(m,1H),4.83(d,J＝15.3Hz,1H),4.45(d,J＝15.3Hz,1H),3.01(dd,J＝17.6,2.3Hz,1H),2.89-2.80( m,2H). ¹³ C NMR (125MHz, CDCl ₃ ) δ191.6,155.5,139.4,137.1,129.0,128.7,128.4,128.0,79.1,78.1,76.4,60.0,45.9,37.1.HRMS(ESI)calculated for C ₁₆ H ₁₃ NNaO ₃ [M+Na] ⁺ :290.0788, found 290.0788.

Example 24: Amplification reaction

Referring to Example 1, S1 (3mmol, 939mg) was dissolved in CH ₂ Cl ₂ (1.0 mL) under air conditions, BF ₃ ·Et ₂ O (37.5 μL, 10 mol%) was added at room temperature, and the reaction was completed after 2 hours. . The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography, eluting with petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:1) to obtain product P1 (732 mg, 95%). , the substance is a white solid.

Example 25: Research and comparison of catalysts

Referring to Example 1, only the catalyst was replaced with an equimolar amount of other catalysts (shown in Table 1) to prepare the corresponding product. The results are shown in Table 1.

Table 1 Preparation results of different catalysts

catalyst P1 yield BF ₃ ·Et ₂ O (Example 1) 95% p-Toluenesulfonic acid 47% Anhydrous ferric chloride 34% Anhydrous aluminum trichloride 89%

Example 26: Anti-tumor activity test of the compounds of the present invention

Cell lines in the logarithmic phase were taken, washed lightly with PBS, digested with 0.25% trypsin, seeded into a 96-well plate at 3×103 cells/well, and incubated in a CO ₂ incubator (37°C, 5% CO ₂ ) Incubate for 24h. Then, samples with different concentration gradients were added to the culture wells, and blank controls were set, and then placed in a cell culture incubator to continue culturing for 48 hours. After 48 hours, add 20 μL of 5 mg/mL MTT culture medium to the culture medium and stain for 4 hours. Remove the MTT solution, add 150 μL DMSO reagent to each well, shake slightly for 10 minutes, use a microplate reader to detect the absorbance value of each well at a wavelength of 570 nm, and calculate the inhibition rate and IC ₅₀ value.

The effects of all compounds in the present invention on the inhibition of proliferation of several tumor cells were determined. The IC ₅₀ value is the concentration of the inhibitor at which the inhibition rate reaches 50%. The results are shown in Table 2:

Table 2 Anti-tumor activity results of the compounds of each example

It can be seen from the above results that the compound of the present invention has a certain inhibitory effect on the proliferation of various tumor cells. Compound P23 shows good inhibitory effect on A549 cells, T24 cells, MCF-7 and Hela cells. Therefore, the compound of the present invention has It has potential application space in the development of anti-tumor drugs.

Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not limiting. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified. Modifications or equivalent substitutions without departing from the spirit and scope of the technical solution of the present invention shall be included in the scope of the claims of the present invention.

Claims (10)

1. The synthesis method of the 2-oxazolidone derivative is characterized in that p-quinoid amine shown in a formula I is used as a raw material, and the 2-oxazolidone compound shown in a formula II is obtained through reaction under the action of Bronsted acid or Lewis acid serving as a catalyst;

wherein ,refers to->Or->

R ¹ Selected from: C1-C8 straight or branched alkyl, C1-C8 cycloalkyl, C2-C8 alkynyl containing 0-2 unsaturated double bonds;

R ² is taken from: C3-C6 cycloalkyl, 3-6 membered heterocyclyl, aryl which is unsubstituted or substituted by substituents; the substituent substitution includes any one of mono-substitution to tri-substitution, and the substituent is selected from halogen (F, cl, br, I), nitro, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl, phenyl or

2. The method of claim 1, wherein the aryl group is selected from the group consisting of: phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl.

3. The method of claim 1, wherein the 3-6 membered heterocyclic group contains 1-3 heteroatoms selected from N, O, S.

4. The method of claim 1, wherein C2-C8 alkynyl isR ³ H, C1 is C6 alkyl.

5. The process according to claim 1, wherein the reaction is carried out in an organic solvent; the organic solvent is one or more of dichloromethane, chloroform, toluene, acetonitrile and tetrahydrofuran.

6. The method according to claim 1, wherein the catalyst comprises any one of p-toluenesulfonic acid, trifluoroacetic acid, camphorsulfonic acid, ferric trichloride, aluminum trichloride, indium triflate, and boron trifluoride diethyl ether.

7. The method according to claim 1, wherein the ratio of the amount of the catalyst represented by formula i to the amount of the substance of the quinone amine is (0.05 to 1): 1, a step of; the reaction temperature is between 70 ℃ below zero and 30 ℃ and the reaction time is between 12 and 24 hours.

8. A 2-oxazolidinone derivative, characterized by the structure shown below:

9. use of a 2-oxazolidinone derivative according to claim 8 for the manufacture of an anticancer medicament.

10. The use of claim 9, wherein the cancer comprises: lung cancer, bladder cancer, breast cancer, cervical cancer.