Preparation method of oxazolidine-2, 4-diketone compound

Abstract

The invention discloses a preparation method of an oxazolidine-2, 4-diketone compound, which comprises the following steps: by taking an N-substituted acrylamide substrate as an initial raw material and iodine pentoxide (I2O5) as an oxidant and an iodine source, carrying out heating reaction in an acetone solvent under the promotion of alkali, and preparing a series of oxazolidine-2, 4-diketone compounds at excellent yield. The method has the advantages of mild and simple reaction conditions, economy, cheapness, small environmental pollution, wide substrate universality, high target product yield and the like.

Description

Technical Field

[0001] The present application belongs to the technical field of fine chemical intermediate synthesis, and specifically relates to a method for preparing an oxazolidine-2,4-dione compound. Background Art

[0002] Oxazolidine-2,4-dione is an important skeleton, widely present in the structure of materials, pesticides, and biopharmaceutical natural products, and has a wide range of uses. For example, N-phenyl-2-thio-2,4-oxazolidine-2,4-dione is an important photosensitive material (Journal of Liaoning University, Natural Science Edition, Ge Gang et al., No. 1, 1984, pp. 77-80); Patents EP1123082B1, EP0916652B1, etc. have shown that N-phenyloxazolidine-2,4-dione compounds can be used to treat androgenic alopecia or hirsutism, seborrheic dermatitis and acne, and can also be used in cosmetics; and patent JPS5756445B2 reports the bactericidal activity of N-phenyloxazolidine-2,4-dione compounds. In view of the wide range of uses of this type of compound, it is obviously particularly important to develop a new and convenient way to synthesize N-phenyloxazolidine-2,4-dione compounds.

[0003] Gong-Qing Liu et al. reported a general synthesis method for N-phenyloxazolidine-2,4-dione compounds (Eur.J.Org.Chem. Vol. 2018, No. 47, pp. 6671-6681): The method is promoted by iodine monochloride and alkali, and the reaction is completed at room temperature in acetonitrile for 1-2h. However, the iodine monochloride used in the method is liquid at room temperature, has a pungent smell similar to chlorine, and is easily hydrolyzed and decomposed, and there is a risk of causing combustion and explosion, so the method is not suitable for industrial production. Further, Gong-Qing Liu et al. also reported that the N-phenylacrylamide substrate shown in formula 5e, using iodine pentoxide (I2O5) as an oxidant and LiI as an iodine source, can be prepared by room temperature reaction in an acetone / water (v / v=1:1) system. N-phenyloxazolidine-2,4-diketone shown in formula 6e (ACS Sustainable Chem. Eng., 2019, Vol. 7, pp. 16777-16785): According to literature research, this method cannot be carried out without adding an iodine source (LiI), which significantly increases the industrial production cost.

[0004] After long-term, in-depth and extensive experimental research, the inventors found that acrylamide substrates can be used as an oxidant in the presence of iodine pentoxide (I2O5) and acetone as a solvent. Under the conditions of appropriate heating and prolonged reaction time, oxazolidine-2,4-dione compounds can be prepared in good yield without the need to add an iodine source. Moreover, the reaction can significantly improve the yield of the target product in the presence of a base, thereby completing the present invention. Summary of the invention

[0005] The purpose of the present invention is to provide a new method for synthesizing oxazolidine-2,4-dione. The method uses N-substituted acrylamide substrates as starting materials, uses iodine pentoxide (I2O5) as an oxidant and an iodine source, and performs a heating reaction in an acetone solvent under the promotion of a base to prepare a series of oxazolidine-2,4-dione compounds with excellent yields. The method has the advantages of mild and simple reaction conditions, low cost, low environmental pollution, wide substrate universality, high yield of target products, and the like.

[0006] A method for preparing an oxazolidine-2,4-dione compound provided by the present invention comprises the following steps:

[0007] Add the N-substituted acrylamide substrate shown in formula I, I2O5, base and organic solvent acetone into the reactor, heat and stir the reaction mixture until the reaction is complete, and purify to obtain the oxazolidine-2,4-dione compound shown in formula II.

[0008] The reaction formula is as follows:

[0009]

[0010] In the above reaction formula, R1 is selected from C 1-20 Alkyl, substituted or unsubstituted C 6-20 Aryl, C 6-20 Aryl-C 1-6 Alkyl; R2 is selected from C 1-4 Branched alkyl, C 1-4 haloalkyl; wherein the substituted or unsubstituted C 6-20 The substituents in the aryl group are selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl, -NO2, -CN, C 1-6 Acyloxy, C 1-6 Acyl, C 1-6 Alkoxycarbonyl, C 6-20 Aryl.

[0011] Preferably, R1 is selected from substituted or unsubstituted phenyl, naphthyl, benzyl; R2 is selected from tert-butyl, isopropyl, chloromethyl, dichloromethyl, trichloromethyl. The substituents in the substituted or unsubstituted phenyl are selected from methyl, ethyl, methoxy, fluorine, chlorine, bromine, iodine, -CF3, -NO2, -CN, acetyl, acetoxy, ethoxycarbonyl, phenyl.

[0012] Most preferably, R1 is selected from phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-trifluoromethylphenyl, p-nitrophenyl, m-methoxyphenyl, p-methoxyphenyl, 2,6-dimethoxyphenyl, benzyl, naphthyl; R2 is selected from tert-butyl.

[0013] According to the aforementioned preparation method of the present invention, the base is selected from sodium bicarbonate or sodium carbonate, preferably sodium bicarbonate. In the present invention, adding a certain amount of sodium bicarbonate in the reaction can significantly increase the yield of the target product.

[0014] According to the aforementioned preparation method of the present invention, the feeding molar ratio of the N-substituted acrylamide substrate shown in formula I, iodine pentoxide (I2O5) and the base is 1:1~2:0.8~1.5; preferably, the feeding molar ratio of the N-substituted acrylamide substrate shown in formula I, iodine pentoxide (I2O5) and the base is 1:1.5:1.0.

[0015] According to the aforementioned preparation method of the present invention, the reaction temperature of the heated stirring reaction is 40-80°C, and the reaction time is 12-48h; preferably, the reaction temperature is 60-70°C, and the reaction time is 24-40h, and most preferably 30-36h.

[0016] According to the aforementioned preparation method of the present invention, the amount of the organic solvent acetone is not particularly limited, as long as the reaction materials are uniformly dispersed and stirred. However, different solvents, such as water, will cause the raw material to be hydrolyzed into N-phenyl-methacrylamide (structural formula: ) and the target product cannot be prepared. When other organic solvents, such as acetonitrile, DMF, etc. are used as solvents, no target product is generated by GC detection, that is, the reaction cannot occur. When THF, ethyl acetate, toluene, etc. are used as solvents, only trace amounts of product generation can be detected by GC. Therefore, acetone is a preferred solvent of the present invention.

[0017] According to the aforementioned preparation method of the present invention, the purification treatment operation is as follows: water is added to the reaction mixture for quenching, extracted with ethyl acetate, the organic phases are combined and dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the oxazolidine-2,4-dione compound shown in formula II.

[0018] Compared with the prior art, the method of the present invention has the following advantages:

[0019] 1) The method of the present invention avoids the use of ICl, which is beneficial to reducing operational risks and achieving safe production; the method of the present invention does not require the additional addition of iodine source compounds, which is beneficial to reducing production costs.

[0020] 2) Under the specific conditions, the method of the present invention achieves a significantly higher yield of the target product than the prior art, has the advantages of mild and simple reaction conditions, low cost, low environmental pollution, wide substrate universality, high yield of the target product, etc., and is more suitable for industrial production. DETAILED DESCRIPTION

[0021] The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the N-substituted acrylamide substrate shown in formula I used is prepared by a synthetic method known in the art; the remaining reagents are purchased through conventional commercial channels and are not further purified.

[0022] Example 1-17 Reaction Condition Optimization Test

[0023] Using N-phenyl-N-tert-butyloxycarbonyl-methacrylamide as a template substrate, the effects of different reaction conditions on the yield of the target product were investigated. The results are shown in Table 1. The reaction formula is as follows:

[0024]

[0025] Table 1

[0026]

[0027] Taking Example 12 as an example, the typical test operation is as follows:

[0028] To a 25 mL sealed tube reactor were added 52.3 mg (0.2 mmol) of N-phenyl-N-tert-butyloxycarbonyl-(methyl)acrylamide shown in formula 1a, 102 mg (0.3 mmol) of diiodine pentoxide, 17 mg (0.2 mmol) of sodium bicarbonate and 1.5 mL of acetone in sequence, and finally a magnetic bar was added. The reaction mixture was stirred and refluxed at 60°C for 30 h. The reaction was complete when monitored by TLC. 10 mL of water was added to the reaction system to terminate the reaction. The reaction solution was extracted three times with ethyl acetate (40 mL each time), and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a residue. The residue was separated by silica gel column chromatography (eluting solvent was petroleum ether / ethyl acetate = 12:1) to obtain the target product 2a as a white solid. The yield was 60 mg, 91%. 1H NMR (400MHz, CDCl3) δ7.53-7.43(m,5H),3.69(d,J=11.3Hz,1H),3.53(d,J=11.3Hz,1H),1.86(s,3H); 13 C NMR (100MHz, CDCl3) δ172.4,152.7,130.7,129.4,129.2,125.7,83.1,21.8,6.1.

[0029] Except for the variables in Table 1 that are different from those in Example 12, the remaining operations of Examples 1-11 and 13-17 are the same as those of Example 12.

[0030] As can be seen from Table 1, under the preferred conditions of the present invention (Example 12), a target product yield of up to 91% can be obtained. When water is used as the solvent, the reaction cannot occur, and the raw material is hydrolyzed into N-phenyl-methacrylamide (structural formula: )(Example 1-3). When acetonitrile and DMF are used as solvents, the reaction cannot proceed (Example 4-5), while when THF, toluene and ethyl acetate are used as reaction solvents, only trace amounts of the target product (about 5%) can be detected by TLC and GC (Example 6-8). Examples 9-14 show that when the reaction temperature, reaction time and iodine pentoxide feed amount vary within a certain range (60-70°C, 24-30h, 1.2~2.0eq), the yield of the target product also varies within a small range, among which 60°C / 30h / 1.5eq is appropriate. Studies have shown that when sodium bicarbonate is used as a base, the yield of the target product can be significantly increased from 63% to 89% (Example 9-10). Furthermore, when the reaction of the present invention is carried out at room temperature, only a yield of about 12% can be obtained (Example 15). Other oxidative iodination systems, such as K2S2O8 / KI, (NH4)2S2O8 / NH4I, etc., cannot produce the target product or can only produce trace amounts of the target product.

[0031] After obtaining the optimized reaction conditions of the present invention (Example 12), the universality of the substituents under the optimized reaction conditions was further explored based on the optimal reaction conditions.

[0032] (I) Effect of R2 substituent: Using N-substituted acrylamide substrates shown in formula 1a-1g as starting materials, the universality of the R2 substituent was explored.

[0033]

[0034] The above results show that when R2 is a branched alkyl group such as tert-butyl, isopropyl and chloromethyl, moderate to excellent yields of the target product can be obtained.

[0035] (II) Influence of R1 substituents. R2 was fixed as tert-butyl, and the universality of different R1 substituents was further investigated. The results are as follows:

[0036]

[0037]

[0038] From the above substrate extension test, it can be seen that the optimal reaction conditions of the present invention have excellent functional group universality, and the yield is as high as 98%. Among them, the structural characterization data of the product are as follows:

[0039] Compound 2b:

[0040] 1 H NMR (500MHz, CDCl3) δ7.33-7.28(m,4H),3.67(d,J=11.3Hz,1H),3.51(d,J=11.3Hz,1H),2.39(s,3H),1.83(s,3H); 13 C NMR (125MHz, CDCl3) δ172.5,152.8,139.3,129.9,128.0,125.5,83.0,21.7,21.2,6.3.

[0041] Compound 2c:

[0042] 1 H NMR (500MHz, CDCl3) δ7.49-7.47(m,2H),7.45-7.42(m,2H),3.68(d,J=11.3Hz,1H),3.53(d,J=11.3Hz,1H),1.85(s,3H); 13 CNMR (125MHz, CDCl3) δ172.2, 152.3, 135.0, 129.6, 129.2, 126.8, 83.3, 21.7, 6.0.

[0043] Compound 2d:

[0044] 1 H NMR (500MHz, CDCl3) δ7.65-7.62(m,2H),7.39-7.36(m,2H),3.68(d,J=11.2Hz,1H),3.53(d,J=11.3Hz,1H),1.85(s,3H); 13CNMR (125MHz, CDCl3) δ172.1,152.2,132.6,129.7,127.0,123.0,83.3,21.7,6.1.

[0045] Compound 2e:

[0046] 1 H NMR (500MHz, CDCl3) δ7.83(d,J=8.8Hz,2H),7.23(d,J=8.7Hz,2H),3.67(d,J=11.3Hz,1H),3.52(d,J=11.3Hz,1H),1.84(s,3H); 13 C NMR (125MHz, CDCl3) δ172.1, 152.2, 138.5, 130.4, 127.1, 94.5, 83.2, 21.7, 6.1.

[0047] Compound 2f:

[0048] 1 H NMR (500MHz, CDCl3) δ7.77(d,J=8.4Hz,2H),7.66(d,J=8.3Hz,2H),3.69(d,J=11.4Hz,1H),3.54(d,J=11.3Hz,1H),1.86(s,3H); 13 C NMR (125MHz, CDCl3) δ172.0, 152.0, 133.8, 131.0 (q, J = 33.0Hz), 126.5, (q, J = 3.8Hz), 125.7, 123.5 (q, J = 270.0Hz), 83.4, 21.7, 6.0.

[0049] Compound 2g:

[0050] 1 H NMR (400MHz, CDCl3) δ8.38(d,J=12.0Hz,2H),7.79(d,J=12.0Hz,2H),3.71(d,J=12.0Hz,1H),3.55(d,J=12.0Hz,1H),1.89(s,3H); 13 C NMR (100MHz, CDCl3) δ171.8,152.6,147.2,136.1,125.8,124.7,83.5,21.7,5.9.

[0051] Compound 2h:

[0052] 1 H NMR (500MHz, CDCl3) δ7.40 (t, J = 8.2 Hz, 1H), 7.05-7.03 (m, 1H), 6.98 (dd, J = 8.7, 1. 9Hz,2H),3.83(s,3H),3.68(d,J=11.2Hz,1H),3.52(d,J=11.3Hz,1H),1.84(s,3H); 13 C NMR (125MHz, CDCl3) δ172.34,160.17,152.58,131.58,130.08,117.84,114.97,111.54,83.03,77.26,77.00,76.75,55.49,21.74,6.18.

[0053] Compound 2i:

[0054] 1 H NMR (500MHz, CDCl3) δ7.44-7.41(m,2H),7.35-7.29(m,3H),4.69(d,J=0.9Hz,2H),3.53(d,J=11.3Hz,1H),3.41(d,J=11.3Hz,1H),1.70(s,3H); 13 CNMR (125MHz, CDCl3) δ173.1,153.7,134.3,129.0,128.8,128.5,83.3,44.1,21.9,5.4.

[0055] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an oxazolidine-2,4-dione compound, comprising the following steps: Adding an N-substituted acrylamide substrate represented by formula I, I2O5, a base and an organic solvent acetone into a reactor, heating and stirring the reaction mixture until the reaction is complete, and purifying to obtain an oxazolidine-2,4-dione compound represented by formula II; The reaction formula is as follows: In the above reaction formula, R1 is selected from C 1-20 Alkyl, substituted or unsubstituted C 6-20 Aryl, C 6-20 Aryl-C 1-6 Alkyl; R2 is selected from C 1-4 Branched alkyl, C 1-4 haloalkyl; wherein the substituted or unsubstituted C 6-20 The substituents in the aryl group are selected from C 1-6 Alkyl, C 1-6 Alkoxy, halogen, C 1-6 Halogenated alkyl, -NO2, -CN, C 1-6 Acyloxy, C 1-6 Acyl, C 1-6 Alkoxycarbonyl, C 6-20 Aryl; in, The alkali is selected from sodium bicarbonate or sodium carbonate.

2. The preparation method according to claim 1, characterized in that: R1 is selected from substituted or unsubstituted phenyl, naphthyl, benzyl; R2 is selected from tert-butyl, isopropyl, chloromethyl, dichloromethyl, trichloromethyl. The substituents in the substituted or unsubstituted phenyl are selected from methyl, ethyl, methoxy, fluorine, chlorine, bromine, iodine, -CF3, -NO2, -CN, acetyl, acetoxy, ethoxycarbonyl, phenyl.

3. The preparation method according to claim 2, characterized in that: R1 is selected from phenyl, p-tolyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-iodophenyl, p-trifluoromethylphenyl, p-nitrophenyl, m-methoxyphenyl, p-methoxyphenyl, 2,6-dimethoxyphenyl, benzyl, and naphthyl; R2 is selected from tert-butyl.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The alkali is sodium bicarbonate.

5. The preparation method according to any one of claims 1 to 3, characterized in that: The N-substituted acrylamide substrate shown in formula I, the feeding molar ratio of iodine pentoxide (I2O5) and alkali is 1:1-2:0.8-1.

5.

6. The preparation method according to claim 5, characterized in that: The molar ratio of the N-substituted acrylamide substrate shown in formula I, iodine pentoxide (I2O5) and the base is 1:1.5:1.

0.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The reaction temperature of the heated and stirred reaction is 40-80°C, and the reaction time is 12-48h.

8. The preparation method according to claim 7, characterized in that: The reaction temperature of the heated and stirred reaction is 60-70°C, and the reaction time is 24-40h.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The purification treatment operation is as follows: water is added to the reaction mixture to quench, extracted with ethyl acetate, the organic phases are combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the oxazolidine-2,4-dione compound shown in formula II.

Images