A method for asymmetric catalytic synthesis of chiral nitrogen-containing quaternary carbon piperazinone

Abstract

The application discloses a method for asymmetrically catalytically synthesizing chiral nitrogen-containing quaternary carbon piperazinone; simple 1,2-diamine and 2,3-dicarbonyl ketone ester are used as starting materials, and under the catalysis of chiral phosphoric acid, a one-pot high-efficiency preparation of piperazine derivatives containing a chiral nitrogen quaternary carbon center with diversified structures is realized. The method has the advantages of high atom economy, mild reaction condition, green (water is the only by-product), low cost and high conversion rate, can provide rich material basis and strong theoretical support for the research and development of piperazine drugs, and has good theoretical value and application prospect. The target product obtained by the application can be further derivatized to synthesize various commercially available drug molecules and analogs thereof.

Description

Technical Field

[0001] This invention belongs to the technical field of organic synthesis and pharmaceutical synthesis, and relates to a method for synthesizing chiral nitrogen-containing quaternary piperazine ketones; specifically, it relates to a highly efficient asymmetric catalytic method for synthesizing chiral nitrogen-containing quaternary piperazine ketones. Background Technology

[0002] Chiral heterocyclic compounds are widely found in natural products and drug molecules. Among them, piperazine derivatives, as an important component of heterocyclic compounds, rank third among nitrogen-containing heterocyclic small molecule drugs. They possess unique physiological and pharmacological activities and are extremely common structural units in drug molecules, such as the anxiolytic drug vestipitant containing a chiral nitrogen-containing tertiary carbon structure, the antidiabetic drug evogliptin, and bioactive natural products containing a chiral nitrogen-containing quaternary carbon structure, such as Marcfortine B and Malbrancheamide. Therefore, the synthesis of chiral piperazines and their derivatives has attracted great interest from chemists.

[0003] Most reported synthetic methods for chiral piperazine derivatives start from chiral amino acid derivatives, involving steps such as condensation cyclization and amide reduction. These methods often suffer from problems such as high substrate costs and cumbersome synthetic routes. Asymmetric catalysis is one of the most ideal and direct methods for constructing chiral substances; however, there are few reported methods for constructing piperazine derivatives using asymmetric catalysis, and those that exist are mainly focused on the construction of chiral nitrogen-tertiary carbon centers.

[0004] Currently, methods for synthesizing chiral piperazine molecules via asymmetric catalysis in the literature include:

[0005] Merck scientist Rossen developed a hydrogenation method for constructing optically pure 2-tert-butylamine carbonylpiperazine compounds during the preparation of the anti-AIDS drug indinavir. ((a) Rossen, K.; Weissman, SA; Sager, J.; Reamer, RA; Askin, D.; Volante, RP; Reider, PJ Tetrahedron Lett. 1995, 36, 6419; (b) Pye, PJ; Rossen, K.; Reamer, RA; Tsou, NN; Volante, RP; Reider, PJ J Am. Chem. Soc. 1997, 119, 6207.)

[0006]

[0007] The asymmetric hydrogenation of pyrazine salts catalyzed by alkylammonium salts was achieved using an alkylammonium salt activation strategy (Huang, W.; Liu, L.; Wu, B.; Feng, G.; Wang, B.; Zhou, Y. Org. Lett. 2016, 18, 3082).

[0008]

[0009] A bi-asymmetric hydrogenation reaction of 3,6-bisalkylene-2,1-diketopiperazine derivatives using chiral iridium catalysis (Ge, Y.; Han, Z.; Wang, Z.; Ding, K. J. A. M. Chem. Soc. 2019, 141, 8981.)

[0010]

[0011] Due to steric hindrance, the synthesis of quaternary aza carbons is more difficult than the construction of tertiary aza carbon centers. Because of the limitations imposed by the substrate structure in the hydrogenation reaction, this method cannot prepare piperazine derivatives containing quaternary aza carbons. Furthermore, kinetic resolution methods are also difficult to achieve efficiently in preparing these molecules, hence there are few reports on their use in the literature.

[0012] In 2011, Stoltz's group achieved the first asymmetric catalytic synthesis of piperazine derivatives with nitrogen-containing heteroquaternary carbon centers using chiral palladium-catalyzed decarboxylation allylation. However, the reaction involves complex substrate structures, cumbersome synthetic steps, and the product types are limited to allyl-substituted piperazine compounds.

[0013]

[0014] Therefore, the current asymmetric catalytic synthesis methods for chiral piperazine derivatives are very limited, and are mainly concentrated on the synthesis of nitrogen-containing tertiary carbon centers. Methods for constructing nitrogen-containing quaternary carbon centers are rarely reported, resulting in a significant gap in the study of the bioactivity of related compounds and representing one of the bottleneck problems restricting the development of chiral heterocyclic drugs. Therefore, developing efficient and universal asymmetric synthesis methods for piperazine derivatives with nitrogen-containing quaternary carbon structures has significant application value and research significance. Summary of the Invention

[0015] Piperazine derivatives are widely found in drug molecules and bioactive natural products. However, chiral synthetic methods for these compounds are rarely reported, especially asymmetric catalytic methods for the construction of piperazine ketone derivatives with nitrogen-containing heterocyclic carbon centers, resulting in significant gaps in the study of the chemical properties and biological activities of these compounds. This invention provides an efficient asymmetric catalytic synthesis method for chiral nitrogen-containing heterocyclic piperazine ketones, aiming to solve the challenge of asymmetric catalytic synthesis of piperazine ketone derivatives with chiral nitrogen-containing heterocyclic carbon centers; it provides a simple, efficient, and low-cost synthetic technique for the construction of chiral nitrogen-containing heterocyclic piperazine ketone molecules, providing technical support and a material basis for the development of piperazine drug molecules.

[0016] To achieve the above-mentioned objectives, the technical solution of the present invention is as follows:

[0017] This invention relates to a method for synthesizing chiral nitrogen-containing heteroquaternary piperazine ketones. In a benzene-based solvent, 1,2-diamine and 2,3-dicarbonyl ketoester react under chiral acid and heating conditions to yield the chiral nitrogen-containing heteroquaternary piperazine ketone. The reaction can be carried out in nitrogen, argon, and air. Some non-benzene solvents can also yield the product, but the yield or ee value is reduced; for example, cyclohexane yields 41% with a 61% ee; methyl tert-butyl ether yields only 7%, and the ee was not determined.

[0018] As one embodiment, the benzene solvent includes at least one selected from toluene, xylene, chlorobenzene, and benzene. Toluene is more preferably preferred.

[0019] As one implementation scheme, the reaction temperature is 70-110℃ and the reaction time is 12-48 hours. More preferably, the reaction temperature is 80-140℃ and the reaction time is 14-48 hours.

[0020] As one embodiment, the chiral acid is chiral phosphoric acid, comprising... R = 2,4,6-iPr3C6H2, 2,3,4,1,6-(CH3)1C6, or 9-anthracenyl. R = 2,3,4,1,6-(CH3)1C6 and R = 9-anthracenyl can also yield ee values ​​above 81%, but the yield decreases. Other substituents result in chiral phosphoric acid with moderate ee values. Furthermore, the absolute configuration of the catalyst can be either R or S configuration.

[0021] As one embodiment, the molar ratio of 1,2-diamine, 2,3-diketoester, and chiral phosphoric acid is 1:1.0:0.1 to 1:1.1:0.2. More preferably, it is 1:1.2:0.1.

[0022] As one embodiment, the 2,3-dicarbonyl ketoester and its hydrate have the structure shown in Formula 1, and the 1,2-diamine has the structure shown in Formula 2:

[0023]

[0024] In Formula 1, R and R' are aryl or alkyl groups, or aryl or alkyl groups containing substituents; in Formula 2, Ar is an aromatic group.

[0025] As one embodiment, Ar is p-methoxyphenyl, p-ethylphenyl, or p-methylphenyl; the aryl group includes phenyl, naphthyl substituent, thiophene, furanyl, pyrrole, pyridyl, and indolyl; the alkyl group is a C1-C16 alkyl group; and the substituent includes cyano, phenyl, chlorine atom, trifluoromethyl, fluorine atom, bromine atom, alkyl, methoxy, ester, or nitro group.

[0026] As one embodiment, the 2,3-diketoester 1 can be obtained by diazotization / oxidation of a 1,3-dicarbonyl compound.

[0027] As one embodiment, the diaryl-substituted 1,2-diamine 2 can be obtained by condensation / reduction of 1,2-dialdehyde with an aromatic amine.

[0028] As one implementation method, after the reaction is monitored by TLC to be complete, the solvent is evaporated to obtain the crude product; then, the product is purified by column chromatography to obtain the target product.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1) Previous methods were basically limited to the construction of nitrogen-containing tertiary carbon centers. This method enables the construction of piperazine derivatives containing nitrogen-containing quaternary carbon centers, providing a novel chiral skeleton with rich structures.

[0031] 2) It avoids the use of transition metals and adopts an organic catalytic mode, which reduces costs and does not cause heavy metal residues in the reaction process.

[0032] 3) A nitrogen-containing quaternary carbon center piperazine molecule was synthesized in one pot via a series reaction, which is highly efficient and fast.

[0033] 4) The reaction conditions are mild and the operation is simple, with good application prospects; therefore, this invention has great theoretical innovation value and practical application value. Detailed Implementation

[0034] This invention contains 2,3-dicarbonyl ketoester derivative 1, 1,2-diamine derivative 2, and chiral phosphate Cat. The toluene solution of molecular sieve was stirred at 120℃ for 24-48 hours and monitored by TLC. After the reaction was complete, the toluene was distilled off to obtain the crude product, which was then purified by column chromatography to obtain the target product.

[0035] In chemical formula 1, R and R' are aryl or alkyl, or aryl or alkyl containing substituents; in compound 2, Ar is p-methoxyphenyl, p-ethylphenyl, p-methylphenyl, or aromatic groups with similar structures.

[0036] The specific synthetic routes for the reactions involved are shown below:

[0037]

[0038] This invention directly and stereoselectively constructs chiral nitrogen-containing quaternary carbon centers through an asymmetric condensation cyclization / 1,2-carbon migration reaction involving 1,2-diamine and 2,3-diketoester esters induced by chiral phosphoric acid. Simultaneously, the ester group serves as an excellent functional group, enabling various transformations. This method achieves the synthesis of multi-substituted piperazinone molecules in a one-pot, highly efficient manner using readily available substrates and relatively mild reaction conditions—a type of chiral skeleton that is difficult to obtain using existing methods.

[0039] The present invention will be described in detail below with reference to embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make several adjustments and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention.

[0040] The raw materials were synthesized as follows in the following examples:

[0041] Synthesis of tricarbonyl compounds:

[0042]

[0043] Ethyl 3-oxo-3-phenylpropionate (10 mmol) and p-ABSA (12 mmol) were added to a 100 mL round-bottom flask. 10 mL of acetonitrile was added to the mixture, and the temperature was lowered to 0 °C. Et3N (11 mmol) was then introduced. The system was allowed to react at room temperature for 6 h, during which a large amount of white solid was generated, as monitored by TLC. After the reaction was complete, the solid was filtered off, and the organic phase was evaporated to dryness to obtain the crude product. This crude product was then purified by column chromatography to obtain a diazonium ketoester (91% yield).

[0044] A diazo compound (1 mmol) was added to a 100 mL round-bottom flask, followed by 20 mL of a CH3CN / H2O mixture (9:1 ratio). The mixture was cooled to 0 °C, and a low-valence t-BuOCl (1.1 mmol) was slowly added. The reaction mixture was then brought to room temperature and reacted for 30 minutes, monitored by TLC. After the reaction was complete, the reaction mixture was concentrated and then purified by column chromatography to obtain tricarbonyl compound 1a (yield 81%, including the monohydrate form 1a' and the anhydrous form 1a”, with a molar ratio of 1a' / 1a” = 1.7 / 1).

[0045] Spectral analysis of main component 1a': 1 H NMR (400MHz, Chloroform-d) δ8.09-8.01(m,2H),7.66-7.60(m,1H),7.41(t,J=7.6Hz,2H),1.31(s,2H),4.21(q,J=7.1Hz,2H),1.08(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ191.7,170.0,134.8,131.1,130.3,128.9,91.7,63.3,13.8.

[0046] Spectral analysis of main components (1d'): 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J=7.8Hz,2H),7.70(d,J=8.4Hz,2H),7.63(d,J=7.1Hz,2H),7. 48(t,J=7.2Hz,2H),7.43(d,J=7.1Hz,1H),1.44(s,2H),4.21(q,J=7.1Hz,2H),1.12(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ191.3,170.1,147.4,139.1,130.9,130.2,129.2,128.8,127.44,127.41,91.9,63.4,13.8.

[0047] Spectral analysis of the main component 1e': 1 H NMR (400MHz, Chloroform-d) δ8.18(d,J=8.1Hz,2H),7.77(d,J=8.1Hz,2H),1.27(s,2H),4.22(q,J=7.1Hz,2H),1.10(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ191.0,169.3,134.8,132.6,130.6,117.8,117.6,92.1,63.6,13.8.

[0048] Spectral analysis of main component 1f': 1H NMR (400MHz, Chloroform-d) δ8.18(d,J=1.7Hz,1H),7.90(m,1H),7.11(d,J=8.4Hz,1H),1.31(s,2H),4.23(q,J=7.1Hz,2H),1.13(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ190.1,169.4,139.6,133.8,132.1,131.1,131.0,129.2,92.1,63.6,13.9.

[0049] Synthesis of diamine compound 2a:

[0050]

[0051] A 40% aqueous solution of glyoxal (3.11 g, 20 mmol) was dissolved in 4 mL of EtOH and 4 mL of H₂O. This solution was then added to a 20 mL ethanol solution of 4-methoxyaniline (1.11 g, 40 mmol). The mixture was stirred at room temperature, and a large amount of yellow solid was immediately formed. Stirring was continued at room temperature for 1 h, and the reaction was monitored by TLC. After the reaction was complete, the yellow solid was filtered to obtain the target product, washed with EtOH, dried, and used directly in the next step. An imine intermediate (2.7 g, 10 mmol) was dissolved in a mixed solution of 30 mL of THF and 3 mL of MeOH. The solution was cooled to 0 °C, and NaBH₄ (1.1 g, 40 mmol) was added in portions. The mixture was slowly heated to reflux and stirred overnight, and the reaction was monitored by TLC. After the reaction was complete, H₂O was added to quench the reaction, and the mixture was extracted with EtOAc. The organic phase was washed with 1 N HCl and saturated NaHCO₃, respectively. The solvent was evaporated to obtain the crude product, which was then purified by column chromatography to obtain the target product 2a. 1 H NMR (400MHz, Chloroform-d) δ6.18(d,J=8.1Hz,2H),6.46(d,J=2.6Hz,2H),6.41(dd,J=8.1,2.6Hz,2H),4.04(s,2H),3.82(s,6H),3.76(s,6H),3.37(s,4H). 13 C NMR (101MHz, Chloroform-d) δ 112.3, 148.3, 132.6, 110.6, 104.0, 99.4, 16.0, 11.6, 44.3.

[0052] Example 1

[0053] ethyl 1,4-bis(4-methoxyphenyl)-3-oxo-2-phenylpiperazine-2-carboxylate(3a):

[0054]

[0055] Three starting materials—tricarbonyl compound 1a (0.12 mmol), chiral phosphate Cat. (0.01 mmol), and diamine compound 2a (0.1 mmol)—were added to a dried reaction tube in a ratio of 1.2:0.1:1. Additionally, [the following was added] Molecular sieve (30 mg) was added to the mixture along with toluene (1.0 mL). The reaction system was stirred at 120 °C for 24 h under nitrogen atmosphere. TLC monitoring confirmed complete reaction. The solvent was then evaporated to obtain the crude product, which was subsequently purified by column chromatography to obtain the target product (yield 91%, ee value 92%). Spectroscopic analysis of the product: 1 H NMR(400MHz,Chloroform-d)δ7.91(d,J=6.9Hz,2H),7.44–7.34(m,3H),7.06(d,J=8.9Hz,2H),6.84(d,J=8.9Hz,2H) ,6.71–6.61(m,4H),4.12–3.90(m,4H),3.87–3.00(m,1H),3.76(s,3H),3.71–3.74(m,1H),3.71(s,3H),3.71(s,3H). 13 CNMR(101MHz,Chloroform-d)δ168.1,166.1,118.3,113.7,141.6,137.4,134.8,12 9.1,128.3,128.1,126.4,117.1,114.4,114.2,77.4,61.7,11.7,48.7,46.2,13.9.

[0056] Example 2

[0057] ethyl 1,4-bis(4-methoxyphenyl)-2-methyl-3-oxopiperazine-2-carboxylate(3b):

[0058]

[0059] Except for replacing structural formula 1a in Example 1 with 1b, the remaining operating steps are the same as in Example 1. Yield: 91%, ee value: 91%. Product spectroscopic analysis: 1H NMR(400MHz,Chloroform-d)δ7.26(d,J=7.1Hz,2H),7.01(d,J=8.7Hz,2H),6.94(d,J=8.7Hz,2H),6.84(d,J=8.7Hz,2H),4.21(q,J= 7.0Hz,2H),4.00–3.87(m,2H),3.82(s,3H),3.79(s,3H),3.77–3.70(m,1H),3.38–3.28(m,1H),1.64(s,3H),1.27(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ170.7,168.3,118.4,117.0,140.9,131.1,127. 0,126.3,114.6,114.1,77.4,71.2,61.1,11.6,11.1,10.7,46.4,21.1,14.2.

[0060] Example 3

[0061] tert-butyl1,4-bis(4-methoxyphenyl)-3-oxo-2-phenylpiperazine-2-carboxylate(3c):

[0062]

[0063] Except for replacing structural formula 1a in Example 1 with 1c, the other operating steps are the same as in Example 1. Yield: 88%, ee value: 93%. Product spectral analysis: 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=7.1Hz,2H),7.41–7.33(m,3H),7.01(d,J=8.6Hz,2H),6.84(d,J=8.7Hz,2H),6.71–6. 61(m,4H),4.09–3.99(m,1H),3.96–3.87(m,1H),3.86–3.80(m,1H),3.76(s,3H),3.71–3.73(m,1H),3.71(s,3H),1.11(s,9H). 13C NMR(101MHz,Chloroform-d)δ167.1,166.7,118.2,113.6,142.0,137.6,134.9,129.6 ,128.2,128.0,126.3,117.2,114.4,114.2,81.9,77.8,11.8,11.6,48.6,46.3,27.6.

[0064] Example 4

[0065] ethyl 2-([1,1'-biphenyl]-4-yl)-1,4-bis(4-methoxyphenyl)-3-oxopiperazine-2-c arboxylate(3d):

[0066]

[0067] Except for replacing structural formula 1a in Example 1 with 1d, the other operating steps are the same as in Example 1. Yield: 81%, ee value: 91%. Product spectral analysis: 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=8.4Hz,2H),7.66–7.60(m,4H),7.41(t,J=7.1Hz,2H),7.31(t,J=7.3Hz,1H),7.09(d,J=8.9Hz,2H),6 .81(d,J=8.9Hz,2H),6.73(s,1H),4.14–3.94(m,4H),3.89–3.81(m,1H ),3.76(s,3H),3.71–3.73(m,1H),3.72(s,3H),0.91(d,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.1,166.1,118.4,113.8,141.7,141.1,140.9,136.6,134.8,129.9 ,128.9,127.1,127.3,126.8,126.4,117.6,114.1,114.2,77.4,61.8,16.0,11.6,48.8,46.2,13.9.

[0068] Example 5

[0069] ethyl 2-(4-cyanophenyl)-1,4-bis(4-methoxyphenyl)-3-oxopiperazine-2-carbo xylate(3e):

[0070]

[0071] Except for replacing structural formula 1a in Example 1 with 1e, the other operating steps are the same as in Example 1. Yield: 87%, ee value: 81%. Product spectral analysis: 1 H NMR (400MHz, Chloroform-d) δ8.11(d,J=8.1Hz,2H),7.69(d,J=8.1Hz,2H),7.01(d,J=8.9Hz,2H),6.81(d,J=8.9Hz,2H),6.72(d,J=9.1H z,2H),6.61(d,J=9.1Hz,2H),4.08–3.92(m,4H),3.88–3.82(m,1H),3.81–3.79(m,1H),3.77(s,3H),3.71(s,3H),0.91(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ167.8,161.1,118.6,143.1,140.9,134.4,131.8,130.4 ,126.3,118.9,117.6,114.6,114.3,112.3,77.4,62.1,11.6,48.9,46.0,29.8,13.8.

[0072] Example 6

[0073]

[0074] Except for replacing structural formula 1a in Example 1 with 1f, the other operating steps are the same as in Example 1. Yield: 82%, ee value: 88%. Product spectroscopic analysis: 1 H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.73(d,J=8.1Hz,1H),7.37(d,J=8.6Hz,1H),6.98(d,J=8.3Hz,2H),6.76(d,J=8.3Hz,2H),6.63(d,J=8.7H z,2H),6.11(d,J=8.7Hz,2H),4.01–3.81(m,4H),3.71–3.69(m,1H),3.73( s,3H),3.67(s,3H),3.66–3.64(m,1H),3.62(s,3H),0.80(t,J=6.9Hz,3H). 13C NMR(101MHz,Chloroform-d)δ167.9,161.7,118.1,114.2,141.1,138.2,134.1,132.7,132.2 ,131.4,130.0,129.1,126.3,117.8,114.6,114.3,77.4,62.0,11.7,48.8,46.1,29.8,13.9.

[0075] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A method for synthesizing chiral nitrogen-containing heterocyclic piperazine ketones, characterized in that, In the presence of a 5 Å molecular sieve, 1,2-diamine and 2,3-dicarbonyl ketoester react under chiral acid and heating conditions in a benzene solvent to give a chiral nitrogen-containing heterocyclic piperazine ketone. The chiral acid is chiral phosphoric acid. R=2,4,6- i Pr3C6H2, 2,3,4,5,6-(CH3)5C6 or 9-anthrayl; the benzene solvent is selected from at least one of toluene, xylene, chlorobenzene, and benzene; The 2,3-dicarbonyl ketoester and its hydrate have the structure shown in Formula 1; in Formula 1, R and R' are thienyl, furanyl, pyrroleyl, pyridyl, indolyl, aryl, or alkyl, or are aryl or alkyl containing substituents; wherein the aryl group is phenyl or naphthalene substituent; the alkyl group is a C1-C16 alkyl group; and the substituent is cyano, phenyl, chlorine atom, trifluoromethyl, fluorine atom, bromine atom, alkyl, methoxy, ester, or nitro group; The 1,2-diamine is as shown in Formula 2; Ar is p-methoxyphenyl, p-ethylphenyl, or p-methylphenyl; The chiral nitrogen-containing heteroquaternary piperazine ketone is shown in Formula 3; 、 。 2. The method for synthesizing chiral nitrogen-containing quaternary piperazine ketones according to claim 1, characterized in that, The reaction temperature is 70-150 ℃, and the reaction time is 12-48 hours.

3. The method for synthesizing chiral nitrogen-containing heterocyclic piperazine ketones according to claim 1, characterized in that, The molar ratio of the 1,2-diamine, 2,3-dicarbonyl ketoester and chiral phosphoric acid is 1:1.0:0.1 to 1:1.5:0.

2.

4. The method for synthesizing chiral nitrogen-containing heterocyclic piperazine ketones according to claim 1, characterized in that, The 1,2-diamine is obtained by condensation / reduction of 1,2-dialdehyde with aromatic amine.

5. The method for synthesizing chiral nitrogen-containing quaternary piperazine ketones according to claim 1, characterized in that, The 2,3-diketoester is obtained by diazotization / oxidation of a 1,3-dicarbonyl compound.

6. The method for synthesizing chiral nitrogen-containing heterocyclic piperazine ketones according to claim 1, characterized in that, After the reaction was monitored by TLC until it was complete, the solvent was evaporated to obtain the crude product; then it was purified by column chromatography to obtain the target product.

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