A preparation method of 3-piperidone compounds

Abstract

The invention discloses a method for preparing a 3-piperidone compound, and belongs to the field of drug intermediate synthesis and organic chemical technology. The method of the invention uses a p-toluenesulfonyl protected piperidine compound as a reaction raw material, and can synthesize a 3-piperidone compound through two steps of oxidative nitration and atmospheric pressure hydrogenation reduction hydrolysis. The synthesis method of the invention does not require the use of toxic metal catalysts and metal oxidants, and the reaction conditions are relatively mild, and the selectivity is good, and has good application prospects.

Description

Technical Field

[0001] The invention relates to a method for preparing 3-piperidone compounds, belonging to the technical fields of drug intermediate synthesis and organic chemical engineering. Background Art

[0002] The skeleton of 3-piperidone compounds is widely present in various natural products and active pharmaceutical molecules, giving these molecules unique biological and pharmacological activities. In addition, 3-piperidone intermediates are widely used in the synthesis of active pharmaceutical molecules containing piperidine-3-ol, playing an important role in drug research and development. Therefore, developing a simple and efficient synthesis method to achieve the synthesis of 3-piperidone derivatives has important industrial application value.

[0003] There have been many reports on the synthesis of 3-piperidone compounds. For example, the synthesis of N-benzyl-3-piperidone can be achieved through high-pressure hydrogenation reduction of 3-hydroxypyridinium salts (Org. Lett., 2015, 17, 1640-1643); starting from complex triazole aldehydes and electron-rich aromatic hydrocarbons, the synthesis of multi-substituted 3-piperidone can be achieved through a two-component condensation reaction catalyzed by rhodium / scandium bimetallic (Org. Lett., 2017, 19, 3087- 3090); 3-piperidone can be prepared by electrochemical reduction, amino protection and acidification using γ-imidate as raw material (J.Org.Chem., 2004, 7710-7719); 3-piperidone can be efficiently synthesized by NaBH4 reduction, Jones oxidation and palladium carbon hydrogenation debenzylation of 3-hydroxy N-benzylpyridinium salt (Journal of Chemical Engineering of Colleges and Universities, 2011, 25(6), 1021-1025). In view of the important uses of 3-piperidone in the fields of medicine and chemical industry, it is urgent to find a synthetic route that is economical, efficient, environmentally friendly and has relatively mild reaction conditions.

[0004] In summary, although many methods for synthesizing 3-piperidone compounds have been developed, the use of a large amount of transition metals is not only costly but also may have problems such as metal residues; in addition, the use of toxic metal oxidants makes the reaction system more complicated and easily causes environmental pollution. Therefore, it is particularly important to find a cost-effective, environmentally friendly and relatively mild synthetic route to prepare 3-piperidone compounds. Summary of the invention

[0005] Technical issue: Avoid the use of toxic metal catalysts and toxic metal oxidants to achieve green and efficient preparation of 3-piperidinone compounds.

[0006] Technical solution:

[0007] In order to solve the above problems, the present invention provides a method for preparing a 3-piperidone compound, wherein the compound of formula 1, an oxidant, and a nitrating agent are added to an organic solvent to react to obtain a nitroalkene intermediate shown in formula 2; then the nitroalkene intermediate shown in formula 2 undergoes a reduction hydrolysis reaction of the nitroalkene under palladium-carbon catalysis to synthesize a 3-piperidone compound shown in formula 3;

[0008]

[0009] Wherein, R is mono- to tri-substituted and can be selected from H, C1-8 alkyl, phenyl, benzyl, -COOR'; R' is H, C1-8 alkyl.

[0010] In one embodiment of the present invention, in the first step reaction, the oxidant is selected from any one or more of tert-butyl peroxide (TBHP), tert-butyl peroxide (DTBP), and tert-butyl perbenzoate (TBPB).

[0011] In one embodiment of the present invention, in the first step reaction, the molar ratio of the oxidant to the compound of formula 1 is 2:1.

[0012] In one embodiment of the present invention, in the first step reaction, the nitrating agent is NOBF4.

[0013] In one embodiment of the present invention, in the first step reaction, the molar ratio of the nitrating agent to the compound of formula 1 is 4:1-3:1; preferably 4:1.

[0014] In one embodiment of the present invention, in the first step reaction, the solvent is acetonitrile.

[0015] In one embodiment of the present invention, in the first step reaction, the amount of the solvent relative to the compound of formula 1 is 8-15 mL / mmol; specifically, 10 mL / mmol may be selected.

[0016] In one embodiment of the present invention, the temperature of the first step reaction is 60-100°C and the reaction time is 4-10 hours, and the reaction temperature can be 80°C for 6 hours.

[0017] In one embodiment of the present invention, the first step reaction is carried out under an inert atmosphere, such as nitrogen.

[0018] In one embodiment of the present invention, the amount of the palladium carbon catalyst used in the second step reaction is 5-10 mol % of the compound of formula 1.

[0019] In one embodiment of the present invention, in the second step reaction, the compound shown in Formula 2 is used as a raw material, palladium carbon is used as a catalyst, ethanol is used as a solvent, and hydrochloric acid is added to carry out a reduction hydrolysis reaction.

[0020] In one embodiment of the present invention, in the second step reaction, the molar ratio of hydrochloric acid to the compound of formula 1 is (1.5-3):1. Specifically, 2:1 may be selected.

[0021] In one embodiment of the present invention, in the second step reaction, the amount of ethanol relative to the compound of formula 1 is 2-5 mL / mmol; specifically, 2.5 mL / mmol may be selected.

[0022] In one embodiment of the present invention, the temperature of the second step reaction is 20-30°C and the reaction time is 4-10 hours. Specifically, the reaction can be carried out at room temperature for 6 hours.

[0023] In one embodiment of the present invention, the synthetic route of the method is:

[0024]

[0025] In one embodiment of the present invention, the 3-piperidone compound comprises the following structure:

[0026]

[0027] In one embodiment of the present invention, the method further comprises the following process: after the second step reaction is completed, saturated sodium bicarbonate is added for quenching, ethyl acetate is extracted, and the crude product is concentrated to obtain the target product, and then column chromatography is performed to obtain the target product.

[0028] In one embodiment of the present invention, the method specifically includes the following process:

[0029]

[0030] N-toluenesulfonylpiperidine shown in formula 1 is used as the reaction raw material, tert-butyl peroxide (DTBP, 2 equivalents) is used as the oxidant, NOBF4 (4 equivalents) is used as the nitrating agent, and acetonitrile is used as the reaction solvent. The reaction is carried out at 80°C in a nitrogen atmosphere for 6 hours. After the reaction is completed, a saturated sodium bicarbonate solution is added to quench the reaction, the aqueous phase is extracted with ethyl acetate three times, the organic phases are combined and washed once with saturated brine, and the solvent is removed by concentration under reduced pressure to obtain a crude product compound shown in formula 2; the crude product compound shown in formula 2 is used as the raw material, palladium carbon (5 mol%) is used as the catalyst, 2 equivalents of hydrochloric acid, and ethanol is used as the solvent. The reaction is carried out at room temperature under one atmosphere of hydrogen for 6 hours; after the reaction is completed, a saturated sodium bicarbonate solution is added to quench the reaction, the aqueous phase is extracted with ethyl acetate three times, the organic phases are combined and washed once with saturated brine, the solvent is removed by concentration under reduced pressure, and the target 3-piperidone derivative is obtained by column chromatography.

[0031] Beneficial effects:

[0032] The synthesis method of the invention does not require toxic metal catalysts and metal oxidants, and the reaction conditions are relatively mild. 3-piperidone is synthesized from N-p-toluenesulfonylpiperidine in two steps, and the yield can reach 64%. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is the H NMR spectrum of N-toluenesulfonyl-3-piperidone 3a obtained in Example 1;

[0034] Figure 2 This is the NMR carbon spectrum of N-toluenesulfonyl-3-piperidone 3a obtained in Example 1; DETAILED DESCRIPTION

[0035] The present invention will be further described below in conjunction with specific embodiments.

[0036] Embodiment 1:

[0037] Preparation method of product N-toluenesulfonyl-3-piperidone:

[0038]

[0039] The reaction raw material N-toluenesulfonylpiperidine 1a (480 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and repeated three times, the oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and reacted at 80°C for 6 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to remove the solvent to obtain a crude product 2a.

[0040] The crude product 2a and catalyst Pd / C (106 mg, 5 mmol% 1a) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1a) was mixed with 5 mL dry ethanol. The solution was then added to the Shrek tube with a syringe and reacted at room temperature for 6 h. TLC detection showed that the raw material disappeared. After the reaction was completed, the filtrate was filtered with diatomaceous earth. A saturated sodium bicarbonate solution was added to the filtrate. The aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine. The solvent was removed by concentration under reduced pressure. The target product N-toluenesulfonyl-3-piperidone 3a was obtained by column chromatography.

[0041] The target product N-toluenesulfonyl-3-piperidone 3a was a white solid, 323 mg, with an overall yield of 64% and a melting point of 102°C-103°C.

[0042] Data Characterization: 1 H NMR (400MHz, CDCl3): 7.60–7.58(m,2H),7.30-7.27(m,2H),3.53(s,2H),3.24–3.21(m,2H),2.37(s,3H),2.29(t,J=6.8Hz,2H),1.97–1.91(m,2H). 13 C NMR(100MHz, CDCl3):202.6,144.2,132.7,129.9,127.7,55.7,44.5,37.9,22.7,21.5.IR(cm -1 ):2926,2854,1735,1596,1447,1339,1164,1091,943,815,747,659.

[0043] Embodiment 2:

[0044] Preparation method of product N-p-toluenesulfonyl-4-methyl-3-piperidone:

[0045]

[0046] The reaction raw material N-toluenesulfonyl-4-methylpiperidine 1b (506 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and repeated three times, the oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and reacted at 80°C for 6 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to remove the solvent to obtain a crude product 2b.

[0047] The crude product 2b and catalyst Pd / C (106 mg, 5 mmol% 1b) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1b) was mixed with 5 mL dry ethanol. The solution was then added to the Shrek tube with a syringe and reacted at room temperature for 6 h. TLC detection showed that the raw material disappeared. After the reaction was completed, the mixture was filtered through diatomaceous earth, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine, concentrated under reduced pressure to remove the solvent, and the target product N-toluenesulfonyl-4-methyl-3-piperidone 3b was obtained by column chromatography.

[0048] The target product N-toluenesulfonyl-4-methyl-3-piperidone 3b was a white solid, 304 mg, with an overall yield of 57% and a melting point of 113°C-114°C.

[0049] Data Characterization: 1 H NMR(400MHz, CDCl3):7.76–7.55(m,2H),7.35(d,J=8.0Hz,2H),3.90(dd,J=15.2,1.6Hz,1H),3.74–3.64(m,1H),3.28(d,J=15.2Hz,1H) ,2.95(td,J=11.6,3.9Hz,1H),2.44(s,3H),2.33(dp,J=12.7,6.4Hz,1H),2.17–2.07(m,1H),1.71–1.63(m,1H),1.06(d,J=6.6Hz,3H). 13 C NMR(100MHz, CDCl3):204.4,144.1,132.6,129.8,127.7,55.3,44.6,42.3,31.1,21.5,13.9.IR(cm -1 ):3043,2966,2929,2872,1721,1597,1450,1336,1158,1062,937,812,733,672.

[0050] Embodiment 3:

[0051] Preparation method of product N-p-toluenesulfonyl-5-methyl-3-piperidone:

[0052]

[0053] The reaction raw material N-toluenesulfonyl-3-methylpiperidine 1c (506 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and repeated three times, the oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and reacted at 80°C for 6 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to remove the solvent to obtain a crude product 2c.

[0054] The crude product 2c and catalyst Pd / C (106 mg, 5 mmol% 1c) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1c) was mixed with 5 mL dry ethanol. The solution was then added to the Shrek tube with a syringe and reacted at room temperature for 6 h. TLC detection showed that the raw material disappeared. After the reaction was completed, the mixture was filtered through diatomaceous earth, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine, concentrated under reduced pressure to remove the solvent, and the target product N-toluenesulfonyl-5-methyl-3-piperidone 3c was obtained by column chromatography.

[0055] The target product N-toluenesulfonyl-5-methyl-3-piperidone 3c was a white solid, 330 mg, with an overall yield of 62% and a melting point of 100°C-102°C.

[0056] Data Characterization: 1 H NMR(400MHz, CDCl3):7.62–7.55(m,2H),7.31–7.26(m,2H),3.76(d,J=15.5Hz,1H),3.57(dd,J=11.9,4.2Hz,1H),3.19(d,J=15.4Hz,1H) ,2.51(dd,J=11.9,9.4Hz,1H),2.46–2.39(m,1H),2.37(s,3H),2.22–2.11(m,1H),1.89(dd,J=15.9,10.4Hz,1H),0.96(d,J=6.7Hz,3H). 13 C NMR (100MHz, CDCl3):202.4,144.1,132.7,129.9,127.7,55.1,53.4,51.1,46.3,29.7,21.5,18.8.IR(cm -1):2961,2925,1727,1596,1457,1344,1165,1091,1006,926,813,773,664.

[0057] Embodiment 4:

[0058] Preparation method of product N-toluenesulfonyl-6-methyl-3-piperidone:

[0059]

[0060] The reaction raw material N-toluenesulfonyl-2-methylpiperidine 1d (506 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and repeated three times, the oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and reacted at 80°C for 6 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to remove the solvent to obtain a crude product 2d.

[0061] The crude product 2d and catalyst Pd / C (106 mg, 5 mmol% 1d) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1d) was mixed with 5 mL dry ethanol. The solution was then added to the Shrek tube with a syringe and reacted at room temperature for 6 h. TLC detection showed that the raw material disappeared. After the reaction was completed, the mixture was filtered through diatomaceous earth and quenched with a saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine. The solvent was removed by concentration under reduced pressure and column chromatography to obtain the target product N-toluenesulfonyl-6-methyl-3-piperidone 3d.

[0062] The target product N-toluenesulfonyl-6-methyl-3-piperidone 3d was a colorless liquid, 288 mg, with an overall yield of 54%.

[0063] Data Characterization: 1H NMR(400MHz, CDCl3):7.79–7.51(m,2H),7.30(d,J=7.8Hz,2H),4.25–4.03(m,2H),3.75–3.61(m,1H),2.42 (s,3H),2.28–2.20(m,1H),2.12–2.03(m,1H),1.79–1.71(m,1H),1.61–1.51(m,1H),1.29(d,J=6.6Hz,3H). 13 C NMR(100MHz, CDCl3):205.9,143.8,136.3,129.9,127.0,50.3,48.9,35.4,28.1,21.4,19.4.IR(cm -1 ):2965,1730,1595,1342,1159,992,907,817,711,661.

[0064] Embodiment 5:

[0065] Preparation method of product N-toluenesulfonyl-4-phenyl-3-piperidone:

[0066]

[0067] The reaction raw material N-toluenesulfonyl-4-phenylpiperidine 1e (630 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and repeated three times, the oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and reacted at 80°C for 6 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and concentrated under reduced pressure to remove the solvent to obtain a crude product 2e.

[0068] The crude product 2e and catalyst Pd / C (106 mg, 5 mmol% 1e) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1e) was mixed with 5 mL dry ethanol. The solution was then added to the Shrek tube with a syringe and reacted at room temperature for 6 h. TLC detection showed that the raw material disappeared. After the reaction was completed, the mixture was filtered through diatomaceous earth, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine, concentrated under reduced pressure to remove the solvent, and the target product N-toluenesulfonyl-4-phenyl-3-piperidone 3e was obtained by column chromatography.

[0069] The target product N-toluenesulfonyl-4-phenyl-3-piperidone 3e was a white solid, 322 mg, with an overall yield of 49% and a melting point of 107°C-108°C.

[0070] Data Characterization: 1 H NMR(400MHz, CDCl3):7.65–7.59(m,2H),7.30(d,J=7.8Hz,2H),7.25–7.18(m,3H),7.02–6.86(m,2H),3.98(d,J= 13.9Hz,1H),3.80–3.72(m,1H),3.47–3.36(m,2H),3.08–3.00(m,1H),2.39(s,3H),2.21(dq,J=7.3,3.5Hz,2H). 13 C NMR (100MHz, CDCl3):201.9,144.3,136.7,132.8,130.0,128.6,128.4,127.8,127.5,55.8,54.2,44.8,30.9,21.5.IR(cm -1 ):3030,2928,2863,1726,1596,1450,1347,1162,1091,980,916,815,734,658.

[0071] Embodiment 6:

[0072] Preparation method of product N-toluenesulfonyl-4-benzyl-3-piperidone:

[0073]

[0074] The reaction raw material N-toluenesulfonyl-4-benzylpiperidine 1f (658 mg, 2 mmol) was added to a 50 mL dry Shrek tube, a magnetic stirrer was added, the tube was sealed with a stopper, vacuum was evacuated and then filled with N2, and the process was repeated three times. The oxidant DTBP (584 mg, 2 eq) was injected into the Shrek tube, and the nitration reagent NOBF4 (932 mg, 4 eq) was mixed and dissolved in 20 mL dry acetonitrile, and then the above solution was slowly added dropwise to the Shrek tube with a syringe, and the reaction was carried out at 80°C for 6 h. After the reaction was completed, a saturated sodium bicarbonate solution was added to quench the reaction, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, washed once with saturated brine, and the solvent was removed by concentration under reduced pressure to obtain a crude product 2f.

[0075] The crude product 2f and catalyst Pd / C (106 mg, 5 mmol% 1f) were weighed and added to a 10 mL dry Shrek tube. A magnetic stirrer was added and the tube was sealed with a stopper. The tube was evacuated and filled with H2 for three times. Concentrated hydrochloric acid (0.33 mL, 2 eq 1f) was mixed with 5 mL dry ethanol and then the solution was added to the Shrek tube with a syringe. The reaction was carried out at room temperature for 6 hours. TLC detection showed that the raw material disappeared. After the reaction was completed, the diatomaceous earth was filtered, saturated sodium bicarbonate solution was added, and the aqueous phase was extracted with ethyl acetate three times. The organic phases were combined and washed once with saturated brine, concentrated under reduced pressure to remove the solvent, and the target product N-toluenesulfonyl-4-benzyl-3-piperidone 3f was obtained by column chromatography.

[0076] The target product N-toluenesulfonyl-4-benzyl-3-piperidone 3f was a white solid, 356 mg, with an overall yield of 52% and a melting point of 114°C-115°C.

[0077] Data Characterization: 1 H NMR(400MHz, CDCl3):7.57(d,J=8.3Hz,2H),7.26(d,J=8.1Hz,2H),7.20–7.1 6(m,2H),7.14–7.08(m,1H),7.00(d,J=6.7Hz,2H),3.85(dd,J=15.3,1.6Hz, 1H),3.62–3.52(m,1H),3.25(d,J=15.3Hz,1H),3.18(dd,J=13.3,3.7Hz,1H) ,2.83–2.74(m,1H),2.44–2.30(m,5H),1.95–1.86(m,1H),1.57–1.50(m,1H). 13 C NMR (100MHz, CDCl3):203.4,144.1,138.7,132.6,129.9,129.0,128.5,127.7,126.4,55.5,49.1,44.6,34.5,28.2,21.5.IR(cm -1 ):3026,2924,2858,1724,1597,1494,1449,1348,1161,1091,955,812,749,666.

[0078] Example 7: Exploring preparation conditions

[0079] According to the preparation method of Example 1, the oxidant was changed in the first step reaction, and other reaction parameters remained unchanged. The effects on the yield are shown in Table 1.

[0080] Table 1 Effect of the type of oxidant on the reaction during the reaction

[0081]

[0082] Example 8: Exploring preparation conditions

[0083] According to the preparation method of Example 1, the amount of the nitrating agent and the amount of the oxidant in the first step of the reaction were changed, and other reaction parameters remained unchanged. The effects on the yield are shown in Table 2.

[0084] Table 2 Effect of the amount of nitrating agent and oxidant on the reaction during the reaction

[0085]

Claims

1. A method for preparing a 3-piperidone compound, characterized in that: The method comprises the following steps: adding a compound of formula 1, an oxidant, and a nitrating agent NOBF4 into an organic solvent acetonitrile to react and obtain a nitroalkene intermediate shown in formula 2; then, the nitroalkene intermediate shown in formula 2 undergoes a reduction hydrolysis reaction of the nitroalkene under the catalysis of palladium carbon to synthesize a 3-piperidone compound shown in formula 3; Wherein, R is mono- to tri-substituted and can be selected from H, C1-8 alkyl, phenyl, benzyl, -COOR'; R' is H, C1-8 alkyl.

2. The method according to claim 1, characterized in that In the first step of the reaction, the oxidant is selected from any one or more of tert-butyl peroxide (TBHP), tert-butyl peroxide (DTBP), and tert-butyl perbenzoate (TBPB).

3. The method according to claim 1, characterized in that In the first step of the reaction, the molar ratio of the oxidant to the compound of formula 1 is 2:

1.

4. The method according to claim 1, characterized in that: In the first step of the reaction, the molar ratio of the nitrating agent to the compound of formula 1 is 4:1-3:

1.

5. The method according to claim 1, characterized in that In the first step reaction, the amount of the solvent used relative to the compound of formula 1 is 8-15 mL / mmol.

6. The method according to claim 1, characterized in that The amount of the palladium carbon catalyst used in the second step reaction is 5-10 mol% of the compound of formula 1.

7. The method according to any one of claims 1 to 6, characterized in that: The compound shown in formula 2 is used as a raw material, palladium carbon is used as a catalyst, ethanol is used as a solvent, and hydrochloric acid is added to carry out a reduction hydrolysis reaction.

8. The method according to claim 7, characterized in that In the second step reaction, the molar ratio of hydrochloric acid to the compound of formula 1 is (1.5-3):1; the amount of ethanol relative to the compound of formula 1 is 2-5 mL / mmol.

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