Synthesis method of polysubstituted pyrrolidone

Abstract

The invention relates to a synthesis method of polysubstituted pyrrolidone. The method is characterized in that # imgabs0 # R1 is alkyl-substituted phenyl, trifluoromethyl-substituted phenyl, cyano-substituted phenyl, methylthio-substituted phenyl, dimethylamino-substituted phenyl, alkenyl-substituted phenyl, alkynyl-substituted phenyl, naphthyl, benzothienyl, cyclohexyl, benzyl and indolyl, R2 is long-chain alkyl and phenyl, R3 and R4 are cyano and ester groups, and R3 and R4 can be the same or different. According to the method, azide and vinyl cyclopropane which are different in substitution are taken as raw materials, palladium and phosphine are taken as a catalytic system, the polysubstituted pyrrolidone compound is synthesized by taking carbon dioxide as a raw material, and the yield of a target product is as high as 90%. The palladium and the phosphine which are cheap and easy to obtain are used, and the catalyst cost is low. The nitrine substrate used in the method is easy to prepare, does not have explosiveness, is wide in application range, effectively realizes high-value utilization of carbon dioxide, and meets the requirements of green chemistry.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis and relates to a method for synthesizing polysubstituted pyrrolidone. Background Art

[0002] Pyrrolidone compounds are widely found in drug molecules, natural products, bioactive molecules and functional materials. Many synthetic drugs such as Piracetam, Oxiracetam, and Roxiracetam are all pyrrolidone structures, and they have shown different degrees of biological activity in promoting intelligence, anti-Alzheimer's disease, anti-inflammatory, anti-tumor and antiviral aspects. Pyrrolidone compounds are also found in monoamine oxidase inhibitors and 11-β-hydroxysteroid dehydrogenase inhibitors. It can be seen that pyrrolidone is an important class of active structural units with potential biological activity and application value. It is of certain significance to study the synthesis of this class of compounds.

[0003] The traditional method of preparing pyrrolidone from primary amine usually requires two steps of reaction, with low yield. The condensation with acyl chloride needs to consider that acyl chloride compounds are unstable and have certain toxicity, while the condensation with halogenated carboxylic acid ester requires long-term reflux and many by-products. In addition, the substrate universality of the traditional condensation reaction is poor, and it is not compatible with some substrates with weak nucleophilicity. Sometimes toxic tin and carbon monoxide are required; cross-coupling reactions usually require the participation of precious metals, and some require higher temperatures and longer reaction times; the CN coupling reaction of iodobenzene and aliphatic amides can obtain the target compound with a yield of 85%, but the substrate universality of this reaction is poor, limited to substituted iodobenzene, and not suitable for aryl bromide and aryl chloride. Among many synthetic routes, the synthesis and application of pyrrolidone are limited due to the single product, poor substrate universality, low yield, expensive catalysts, and cumbersome steps. The key step in the synthesis of pyrrolidone is the construction of a five-membered lactam ring, and obtaining multiple feasible chemically active sites or active groups on the ring is a prerequisite for constructing abundant pyrrolidone derivatives. Based on this, the present invention provides an efficient method for synthesizing polysubstituted pyrrolidone. Summary of the invention

[0004] The present invention aims to provide a method for synthesizing polysubstituted pyrrolidone, which has the characteristics of high yield, simplicity, and low difficulty in separation and purification, and comprises the following steps:

[0005]

[0006] Under a nitrogen atmosphere, azide, catalyst, solvent and cyclopropane were added into a reaction bottle, the nitrogen was evacuated with a vacuum pump, and then carbon dioxide was introduced. The reaction was heated and stirred. After the reaction was completed, the room temperature was restored. After extraction, the solvent was removed under reduced pressure, and the target product was separated by silica gel column chromatography. The yield was calculated.

[0007] In substrate 1, R1 is phenyl substituted by C1~C8 alkyl, phenyl substituted by trifluoromethyl, phenyl substituted by cyano, phenyl substituted by methylthio, phenyl substituted by dimethylamino, phenyl substituted by alkenyl, phenyl substituted by alkynyl, phenyl substituted by ester, disubstituted phenyl, trisubstituted phenyl, naphthyl, furanyl, thienyl, alkoxy, benzothienyl, cyclohexyl, benzyl, indolyl, C1~C8 alkyl, C3~C6 cycloalkyl, R2 is a long-chain alkyl, phenyl, C1~C8 alkyl, C3~C6 cycloalkyl, R3 and R4 are cyano, ester, phenyl, C3~C6 cycloalkyl, and R3 and R4 may be the same or different.

[0008] According to the preferred embodiment of the present invention, the solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dioxane, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, ether, dichloromethane, ethyl acetate, 1,2-dichloroethane or ethylene glycol dimethyl ether. The ratio of the volume of the solvent to the molar number of the azide substrate is 1 mL: 0.1 mmol. The solvent is anhydrous.

[0009] According to the preferred embodiment of the present invention, the palladium catalyst is tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)dipalladium, bis(tri-tert-butylphosphine)palladium, bis[1,2-bis(diphenylphosphine)ethane]palladium, bis(dibenzylideneacetone)palladium, bis(tricyclohexylphosphine)palladium. The molar ratio of the palladium metal catalyst to the azide substrate is 0.02:0.1.

[0010] According to the preferred embodiment of the present invention, the phosphine is triphenylphosphine, tricyclohexylphosphine, dimethoxyphenylphosphine, diphenylethoxyphosphine, dicyclohexylphenylphosphine, diphenylmethylphosphine, trimethoxyphosphine, diphenylpropylphosphine. The molar ratio of the phosphine catalyst to the azide substrate is 1:1.

[0011] Preferably, the method according to the present invention is characterized in that the gas atmosphere is changed, and the material is initially added under the protection of nitrogen, and then the gas in the bottle needs to be evacuated to a vacuum, and then CO2 gas is introduced, and the gas pressure is 0.1-10atm.

[0012] According to the preferred embodiment of the present invention, the molar ratio of the azide substrate 1 to the cyclopropane substrate 2 is 1:2, the reaction temperature is 40-60°C, and the reaction time is 12-24h. The yield of the target product prepared is as high as 90%.

[0013] According to the preferred embodiment of the present invention, the product separation and characterization can be carried out according to conventional separation and purification methods. The post-reaction treatment steps are as follows: extracting with deionized water and ethyl acetate and then removing the solvent under reduced pressure, separating the obtained crude product by silica gel column chromatography to obtain pyrrolidone compounds, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the mixed solvent of petroleum ether and ethyl acetate in the mixed solvent is 3 to 1:1.

[0014] Compared with the prior art, the present invention has the advantages of high reaction efficiency, convenient operation, wide application range of substrates, cheap and easy to obtain reaction raw materials, low purification difficulty, etc., and meets the requirements of green chemistry. DETAILED DESCRIPTION

[0015] The present invention is further described below by way of specific implementations in the form of examples, but this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention.

[0016] Meanwhile, the experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents, materials and equipment described are all commercially available unless otherwise specified.

[0017] Example 1

[0018]

[0019] Under N2 atmosphere, 0.1mmol 1a, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and then CO2 was introduced. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3a in a yield of 90%.

[0020] 1 H NMR (400MHz, CDCl3) δ7.45-7.29(m,5H),5.76-5.68(m,1H),5.42-5.34(m,2H),4 .84(q,J=6.8Hz,1H),3.15(dd,J=13.6,7.2Hz,1H),2.70(dd,J=13.6,6.4Hz,1H);

[0021] 13 C NMR (101MHz, CDCl3) δ158.8,135.4,133.5,129.4,127.7,123.9,122.1,112.0,111.7,60.3,38.3,37.6;

[0022] HRMS(ESI):calcd.forC 14 H 11 N3O[M+H] + :237.0902.Found:237.0901.

[0023] Example 2

[0024]

[0025] Under N2 atmosphere, 0.1mmol 1c, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3c in a yield of 78%.

[0026] 1 H NMR (400MHz, CDCl3) δ7.27 (s, 4H), 5.71 (m, 1H), 5.41-5.35 (m, 2H), 4.80 (q, J = 6. 8Hz, 1H), 3.14 (dd, J=13.6, 6.8Hz, 1H), 2.68 (dd, J=14, 6.4Hz, 1H), 2.49 (s, 3H);

[0027] 13 C NMR(101MHz, CDCl3)δ158.9,138.7,133.4,132.3,126.9,124.3,122.2,112.0,111.6,60.4,38.2,37.6,15.6; HRMS(ESI):calcd.forC 15 H 13 N3OS[M+H] + :284.0852.Found:284.0856.

[0028] Example 3

[0029]

[0030] Under N2 atmosphere, 0.1mmol 1d, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mLDF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then added. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3d in a yield of 70%.

[0031] 1 H NMR (400MHz, CDCl3) δ7.43(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),6.68(dd,J=17.2,10.8Hz,2H),5.77-5.6 6(m,2H),5.41-5.29(m,2H),4.84(q,J=6.8Hz,1H),3.14(dd,J=13.6,7.2Hz,1H),2.68(dd,J=13.2,6Hz,1H);

[0032] 13 C NMR (101MHz, CDCl3) δ158.7,137.0,135.6,134.7,133.4,127.0,123.8,122.0,115.3,112.1,111.8,60.3,38.3,37.4;

[0033] HRMS(ESI):calcd.for C 16 H 13 N3O[M+H] + :264.1132.Found:264.1138.

[0034] Example 4

[0035]

[0036] Under N2 atmosphere, 0.1mmol 1e, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3e in a yield of 83%.

[0037] 1HNMR (400MHz, CDCl3) δ7.88-7.80(m,4H),7.54-7.50(m,2H),7.45(dd,J=8.8,2Hz,1H),5.79-5.71(m,1H ),5.44-5.32(m,2H),4.96(q,J=7.2Hz,1H),3.20(dd,J=13.6,7.2Hz,1H),2.74(dd,J=13.6,6.4Hz,1H);

[0038] 13 C NMR (101MHz, CDCl3) δ159.1,133.6,133.2,132.9,132.3,129.5,128.1,127.9,127.2,127.0,123.0,122.3,121.8,112.2,111.9;

[0039] HRMS(ESI):calcd.forC 18 H 13 N3O[M+H] + :288.1131.Found:288.1139.

[0040] Example 5

[0041]

[0042] Under N2 atmosphere, 0.1mmol 1f, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3f in a yield of 56%.

[0043] 1 H NMR (400MHz, CDCl3) δ7.34-7.24(m,3H),7.17(d,J=6.8Hz,2H),5.54-5.45(m,1H),5.39(d,J=9.6Hz,1H),5.23(d,J=16.4Hz,1 H),3.85(m,1H),3.74(q,J=7.2Hz,1H),3.30-3.23(m,1H),2.99-2.92(m,1H),2.87-2.79(m,2H),2.38(dd,J=13.6,6.8Hz,1H);

[0044] 13C NMR (101MHz, CDCl3) δ159.7,137.6,133.4,129.0,128.9,127.2,123.1,112.3,111.9,59.7,44.1,37.8,37.5,33.2;

[0045] HRMS(ESI):calcd.for C 16 H 15 N3O[M+H] + :266.1288.Found:266.1294.

[0046] Example 6

[0047]

[0048] Under N2 atmosphere, 0.1mmol 1g, 0.2mmol 2a, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mLDF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The mixture was stirred at 40°C for 24h, returned to room temperature, and extracted with deionized water and ethyl acetate to obtain a crude product. The crude product was then separated by silica gel column chromatography to obtain 3g of the target product in a yield of 92%.

[0049] 1 H NMR (400MHz, CDCl3) δ7.97-7.93(m,2H),7.61(d,J=8.4Hz,1H),7.53-7.49(m,1H),7.45-7.37(m,3H),5.76-5.67(m,1H),5 .30(d,J=16.8Hz,1H),5.22(q,J=8Hz,1H),5.15(d,J=10Hz,1H),3.30(dd,J=13.6,6.8Hz,1H)2.80(dd,J=13.6,7.2Hz,1H);

[0050] 13 C NMR (101MHz, CDCl3) δ159.2,156.1,149.8,133.0,128.1,125.1,123.6,123.4,122.6,121.1,121.0,120.0,111.7,60.6,38.1,38.0;

[0051] HRMS(ESI):calcd.forC 20 H 13 N3O2[M+H] + :328.1081.Found:328.1082.

[0052] Example 7

[0053]

[0054] Under N2 atmosphere, 0.1mmol 1a, 0.2mmol 2h, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4 and 1mLDF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The reaction was stirred at 40°C for 24h, and the mixture was returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the target product 3h was separated by silica gel column chromatography. The yield was 62%.

[0055] 1 H NMR (400MHz, CDCl3) δ7.38-7.34(m,2H),7.27-7.29(m,2H),7.23(t,J=8.0Hz,1H),5.81-5.72(m,1H),5.34-5.19(m ,2H),4.96(q,J=8.0Hz,1H),3.40(s,3H),3.32(s,3H),3.01(dd,J=13.3,7.9Hz,1H),2.82(dd,J=13.4,7.6Hz,1H);

[0056] 13 C NMR (101MHz, CDCl3) δ166.4,166.3,164.8,151.2,137.0,136.2,128.9,127.0,124.6,120.2,62.9,61.9,32.1,29.6,29.3;

[0057] HRMS(ESI):calcd.for C 17 H 17 N3O4[M+H] + :328.1292.Found:328.1298.

[0058] Example 8

[0059]

[0060] Under N2 atmosphere, 0.1mmol 1a, 0.2mmol 2i, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4, and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump, and CO2 was then introduced. The reaction was stirred at 40°C for 24h, and then returned to room temperature. The crude product was extracted with deionized water and ethyl acetate, and then the crude product was separated by silica gel column chromatography to obtain the target product 3i in a yield of 72%.

[0061] 1 H NMR (400MHz, CDCl3) δ7.39-7.35(m,5H),6.94-6.83(m,3H),5.73-5.64(m,1H),5.30-5.22(m,4H),4.78 (q,J=7.2Hz,1H),3.88(s,3H),3.83(s,3H),3.09(dd,J=13.6,7.2Hz,1H),2.46(dd,J=13.6,7.2Hz,1H); 13 C NMR (101MHz, CDCl3) δ164.6,162.5,149.4,149.2,135.9,135.5,129.1,127.2, 126.8,124.4,121.1,120.8,111.4,111.0,69.6,60.7,56.0,55.9,51.7,36.0;

[0062] HRMS(ESI):calcd.forC 23 H 22 N2O5[M+H] + :407.1062.Found:407.1061.

[0063] Example 9

[0064]

[0065] Under N2 atmosphere, 0.1mmol 1a, 0.2mmol 2j, 0.1mmol PPh(MeO)2, 0.002mmol Pd(PPh3)4 and 1mL DMF were added to the reaction flask. The N2 in the reaction flask was evacuated with a vacuum pump and then filled with CO2. The reaction was stirred at 40°C for 24h and returned to room temperature. The crude product was extracted with deionized water and ethyl acetate and then separated by silica gel column chromatography to obtain the target product 3j in a yield of 56%.

[0066] 1 HNMR(400MHz, CDCl3)δ7.32-7.26(m,4H),7.19-7.14(m,1H),5.05(s,1H),4.98(s,1H),4. 81(t,J=7.0Hz,1H),2.96(dd,J=13.6,7.2Hz,1H),2.58(dd,J=14,7.2Hz,1H),1.55(s,3H);

[0067] 13C NMR (101MHz, CDCl3) δ159.0,138.8,135.7,129.2,127.4,122.9,118.6,112.1,111.9,62.6,38.4,35.5,16.7;

[0068] HRMS(ESI):calcd.forC 15 H 13 N3O[M+H] + :252.1131.Found:252.1131.

[0069] The above are only some embodiments of the present invention, and do not limit the present invention in any form. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention are within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing polysubstituted pyrrolidone, comprising the following steps: Under a nitrogen atmosphere, azide, catalyst, solvent and cyclopropane were added into a reaction bottle, the nitrogen was evacuated with a vacuum pump, and then CO2 gas was introduced. The reaction was heated and stirred. After the reaction was completed, the room temperature was restored. The solvent was removed under reduced pressure after extraction, and the target product 3 was obtained by silica gel column chromatography. The yield was calculated. In substrate 1, R1 is phenyl substituted by C1~C8 alkyl, phenyl substituted by trifluoromethyl, phenyl substituted by cyano, phenyl substituted by methylthio, phenyl substituted by dimethylamino, phenyl substituted by alkenyl, phenyl substituted by alkynyl, phenyl substituted by ester, disubstituted phenyl, trisubstituted phenyl, naphthyl, furanyl, thienyl, alkoxy, benzothienyl, cyclohexyl, benzyl, indolyl, C1~C8 alkyl, C3~C6 cycloalkyl, R2 is a long-chain alkyl, phenyl, C1~C8 alkyl, C3~C6 cycloalkyl, R3 and R4 are cyano, ester, phenyl, C3~C6 cycloalkyl, and R3 and R4 may be the same or different.

2. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that: The solvent is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, toluene, dioxane, dimethyl sulfoxide, 2-methyltetrahydrofuran, tetrahydrofuran, ether, dichloromethane, ethyl acetate, 1,2-dichloroethane or ethylene glycol dimethyl ether. The ratio of the volume of the solvent to the molar number of the azide substrate 1 is 1 mL: 0.1 mmol. The solvent is anhydrous.

3. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that: The palladium catalyst is tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, bis(tri-tert-butylphosphine)palladium, bis[1,2-bis(diphenylphosphine)ethane]palladium, bis(dibenzylideneacetone)palladium, bis(tricyclohexylphosphine)palladium. The molar ratio of the palladium metal catalyst to the azide compound is 0.02:0.

1.

4. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that: The phosphine is triphenylphosphine, tricyclohexylphosphine, dimethoxyphenylphosphine, diphenylethoxyphosphine, dicyclohexylphenylphosphine, diphenylmethylphosphine, trimethoxyphosphine, diphenylpropylphosphine. The molar ratio of the phosphine catalyst to the azide compound is 1:

1.

5. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that The change of gas atmosphere begins with adding materials under nitrogen protection, then the gas in the bottle needs to be evacuated to vacuum, and then CO2 gas is introduced with a gas pressure of 0.1-10atm.

6. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that: The molar ratio of the azide substrate 1 to the vinylcyclopropane substrate 2 is 1:2, the reaction temperature is 40-60°C, and the reaction time is 12-24h. The yield of the prepared target product is as high as 90%.

7. The method for synthesizing polysubstituted pyrrolidone according to claim 1, characterized in that: The product can be separated and characterized by conventional separation and purification methods. The post-reaction treatment steps are as follows: extract with deionized water and ethyl acetate and then remove the solvent under reduced pressure, and separate the crude product by silica gel column chromatography to obtain pyrrolidone compounds, the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the mixed solvent of petroleum ether and ethyl acetate in the mixed solvent is 3 to 1:1.

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