阅读说明：本技术 一类手性4,5-二取代吡咯烷-2-酮化合物及其制备方法和应用 (Chiral 4, 5-disubstituted pyrrolidine-2-ketone compound and preparation method and application thereof ) 是由 王平安 张生勇 白育军 程美玲 姜茹 张东旭 李穆琼 于 2021-09-22 设计创作，主要内容包括：本发明属于有机合成技术领域,具体涉及一类手性4,5-二取代吡咯烷-2-酮化合物及其制备方法和应用。本发明首次以硝基取代烷(I)和反式α,β-不饱和3-甲基-4-硝基异噁唑(II)为原料,以手性超强碱催化I和II的不对称迈克尔加成反应为关键步骤,经水解、酯化和还原关环,合成一类手性3,4-二取代吡咯烷-2-酮化合物,包括光学纯芬克罗酮。本发明首次系统考察手性超强碱催化剂催化2-取代硝基乙烷(I)和反式α,β-不饱和3-甲基-4-硝基异噁唑(II)的不对称迈克尔加成反应,用以制备手性4,5-二取代吡咯烷-2-酮,为含有手性4,5-二取代吡咯烷-2-酮骨架的药物如光学纯芬克罗酮等的合成提供捷径。(The invention belongs to the technical field of organic synthesis, and particularly relates to chiral 4, 5-disubstituted pyrrolidine-2-ketone compounds, and a preparation method and application thereof. The invention firstly takes nitro-substituted alkyl (I) and trans-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole (II) as raw materials, takes asymmetric Michael addition reaction of I and II catalyzed by chiral superbase as a key step, and synthesizes chiral 3, 4-disubstituted pyrrolidine-2-ketone compounds including optical pure fenclorone through hydrolysis, esterification and reduction ring closing. The invention systematically considers the asymmetric Michael addition reaction of 2-substituted nitroethane (I) and trans-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole (II) catalyzed by a chiral superbase catalyst for the first time to prepare chiral 4, 5-disubstituted pyrrolidine-2-ketone, and provides a shortcut for the synthesis of medicaments containing chiral 4, 5-disubstituted pyrrolidine-2-ketone skeletons, such as optical pure fenclorone and the like.)

1. A preparation method of chiral 4, 5-disubstituted pyrrolidine-2-ketone compounds is characterized by comprising the following steps:

(1) using nitro-substituted alkyl and trans-beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole as raw materials, using chiral superbase as a catalyst, carrying out asymmetric Michael addition reaction in a solvent at room temperature for 2-4h to obtain an addition product compound III;

wherein the nitro-substituted alkyl is nitromethane or 2-substituted nitroethane, and the ratio of the amount of the nitro-substituted alkyl to the amount of the trans-beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole to the amount of the chiral superbase is 1-3: 1: 0.05-0.3;

(2) hydrolyzing the compound III prepared in the step (1) at room temperature for 2-8h under the condition of alkali or acid to obtain a hydrolysate compound IV;

wherein the mass ratio of the compound III to the alkali or acid is 1: 3-5;

(3) carrying out esterification reaction on the compound IV prepared in the step (2) and methanol in an acid environment for 2-4h to obtain an esterification product compound V;

(4) adding a reducing agent into the compound V prepared in the step (3) and carrying out reduction amine cyclization reaction to obtain a chiral 4, 5-disubstituted pyrrolidine-2-one compound, wherein the chiral 4, 5-disubstituted pyrrolidine-2-one compound comprises optically pure fenclolone.

2. The method for preparing chiral 4, 5-disubstituted pyrrolidine-2-one compounds according to claim 1, wherein in the step (1), the structural formula of the 2-substituted nitroethane is shown as formula (I):

wherein R is₁Selected from: H. n, O, S-containing five-membered or six-membered single heterocyclic compound, and C6-30 aromatic ring, which may be substituted by one or more substituents selected from C1-6 alkyl and OCH₃、CF₃Or a halogen.

3. The method for preparing chiral 4, 5-disubstituted pyrrolidin-2-one compound according to claim 1, wherein in the step (1), the structural formula of β -substituted α, β -unsaturated 3-methyl-4-nitroisoxazole is represented by formula (ii):

wherein R is₂Selected from: alkyl with 1-6 carbon atoms, aromatic ring with 6-30 carbon atoms, and five-membered or six-membered single heterocyclic compound containing N, O, S; the aromatic ring may be substituted by one or more substituents selected from C1-6 alkyl and OCH₃、OH、CF₃Or a halogen.

4. The method for preparing chiral 4, 5-disubstituted pyrrolidin-2-one compounds according to claim 1, wherein in step (1), the chiral superbase is selected from one of the following compounds:

5. the method for preparing chiral 4, 5-disubstituted pyrrolidine-2-one compound according to claim 1, wherein the solvent in step (1) is one selected from dichloromethane, 1, 2-dichloroethane, chloroform, acetone, tetrahydrofuran, 1, 4-dioxane, ethyl acetate, acetonitrile, methanol, ethanol, toluene, N-dimethylformamide and N-methylpyrrolidone.

6. The method for preparing chiral 4, 5-disubstituted pyrrolidine-2-one compound of claim 1, wherein in the step (2), if the hydrolysis is performed under alkaline condition, the base is selected from organic base, 2-4mol/L sodium hydroxide aqueous solution or 2-4mol/L potassium hydroxide aqueous solution;

the organic base is triethylamine, diisopropylethylamine, One of (1);

if the hydrolysis is carried out under acidic conditions, the acid is selected from 2-4mol/L hydrochloric acid aqueous solution or 2-4mol/L sulfuric acid aqueous solution.

7. The method for preparing chiral 4, 5-disubstituted pyrrolidin-2-one compounds according to claim 1, wherein the acidic environment in step (3) is selected from one of thionyl chloride, acetyl chloride, oxalyl chloride, 1mol/L hydrochloric acid and 1mol/L sulfuric acid aqueous solution.

8. The method for preparing chiral 4, 5-disubstituted pyrrolidine-2-one compounds according to claim 1, wherein when the reducing agent in step (4) is 10% w.t. palladium on carbon/1.0-5.0 atm hydrogen, the reaction conditions are as follows: stirring for 24-36h at room temperature;

when the reducing agent in the step (4) is one of reduced zinc powder/1.0-3.0 mol/L diluted hydrochloric acid, reduced zinc powder/acetic acid, reduced iron powder/1.0-3.0 mol/L diluted hydrochloric acid, reduced iron powder/acetic acid, and reduced iron powder/1.0-3.0 mol/L ammonium chloride aqueous solution, the reaction conditions are as follows: reacting for 2-12h at 70-reflux temperature;

the mass ratio of the reduced zinc powder to the dilute hydrochloric acid and acetic acid is 3-5: 50; the mass ratio of the reduced iron powder to the dilute hydrochloric acid and acetic acid is 3-5: 50; the mass ratio of the reduced iron powder to the ammonium chloride aqueous solution is 3-5: 100.

when the reducing agent in the step (4) is NaBH₄/NiCl₂.6H₂When O is generated, the used solvent is methanol or ethanol, and the reaction conditions are as follows: reacting at 0-4 ℃ for 2-6 h, heating to room temperature after the reaction is finished, adding 4-6mol/L aqueous solution of LNaOH into the reaction solution, stirring for 1-2h, adding 1-2mol/L aqueous solution of hydrochloric acid, and stirring for 1-2 h; reducing agent NaBH₄/NiCl₂.6H₂The mass ratio of O is 10-20: 1-2.

9. Chiral 4, 5-disubstituted pyrrolidin-2-one compounds obtainable by the process according to any one of claims 1 to 8.

10. The use of a class of 4, 5-disubstituted pyrrolidin-2-one compounds as claimed in claim 9 in the preparation of a medicament comprising a chiral 4, 5-disubstituted pyrrolidin-2-one backbone.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to chiral 4, 5-disubstituted pyrrolidine-2-ketone compounds, a preparation method and application thereof, in particular to application in synthesis of optically pure fencrotone.

Background

4, 5-disubstituted pyrrolidin-2-one is an important structural unit constituting a drug. A study group of Heshoujiang in Kunming plant of Chinese academy of sciences takes clausenamide as a lead structure (shown in figure 1), designs and synthesizes a series of simplified analogs (4, 5-disubstituted pyrrolidine-2-ketone), performs activity screening, selects a compound with the best activity, namely, phenchlorobenpyrone (Phenchenpyrone), and researches the analogs to find that the analogs have the effects of improving the memory disorder of tested animals, and has the advantages of low dosage, low toxicity and long duration. In addition, the fenclorone has the effects of protecting and repairing nerve cell injury of tested animals, can be used for improving brain function, and particularly has obvious effect of improving behavioral and mental disorders of patients with senile dementia and cerebrovascular disease sequelae. Fenclorone entered phase IIb clinical trials in 2020.

The general method for preparing 4, 5-disubstituted pyrrolidine-2-ketone is not reported in the literature, only the synthesis of the fencroketone is disclosed in patents CN1191218A, CN1186071A and CN1120036A, and the preparation method of the CN119218A document is shown in figure 2;

the synthetic route disclosed by the prior art takes o-chlorobenzaldehyde, nitromethane and methyl cinnamate as raw materials, and the fenclorone is obtained with the total yield of 55% through 6 steps of aldol condensation, reduction, Michael addition, transformation, reductive amination and cyclization and the like. The route has the advantages that the raw materials are convenient and easy to obtain, the expensive organic base DBU can be recycled, and the total yield is good; the disadvantages are that the reaction steps are many-up to 6 steps, the reaction time is long-the reaction time of the key step is up to 3 days, the operation is complicated-recrystallization is needed for 2-3 times in the transformation step.

Disclosure of Invention

Aiming at the problems in the synthetic route, the invention provides a chiral 4, 5-disubstituted pyrrolidine-2-ketone compound, a preparation method and application thereof, in particular to application in the synthesis of optical pure fenclorone. The invention mainly provides a brand-new preparation method of chiral 4, 5-disubstituted pyrrolidine-2-one compounds, overcomes the technical defects of more reaction steps, long reaction time and complicated operation in the prior art, and obtains compounds which can be applied to medicaments containing chiral 4, 5-disubstituted pyrrolidine-2-one frameworks.

In order to solve the technical problems, the invention adopts the following technical scheme:

(1) asymmetric Michael addition reaction catalyzed by chiral superbase:

using nitro-substituted alkyl and trans-beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole as raw materials, using chiral superbase as a catalyst, carrying out asymmetric Michael addition reaction in a solvent at room temperature for 2-4h to obtain an addition product compound III;

wherein the nitro-substituted alkyl is nitromethane or 2-substituted nitroethane, and the mass ratio of the nitro-substituted alkyl to the trans-beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole to the chiral superbase is 1-3: 1: 0.05-0.3;

(2) hydrolysis-esterification reaction:

hydrolyzing the compound III prepared in the step (1) at room temperature for 2-8h under the condition of alkali or acid to obtain a hydrolysate compound IV;

wherein the mass ratio of the compound III to the alkali or acid is 1: 3-5;

heating the compound IV and methanol in an acid environment to reflux, and carrying out esterification reaction for 2-8h to obtain an esterification product compound V;

(3) reductive amination and ring closure reaction:

adding a reducing agent into the compound V prepared in the step (2) and carrying out reduction amine cyclization reaction to obtain a chiral 4, 5-disubstituted pyrrolidine-2-one compound, wherein the chiral 4, 5-disubstituted pyrrolidine-2-one compound comprises optically pure fencloketone.

Preferably, in the step (1), the structural formula of the 2-substituted nitroethane is shown as formula (I):

wherein R is₁Selected from: H. n, O, S-containing five-membered or six-membered single heterocyclic compound, and C6-30 aromatic ring, which may be substituted by one or more substituents selected from C1-6 alkyl and OCH₃、CF₃Or halogen, the N, O, S-containing five-membered or six-membered single heterocyclic compound can be furan, thiophene, pyrrole, pyridine, the 6-30 carbon atom aromatic ring can be a benzene ring, and further, the 2-substituted nitroethane is selected from one of the following compounds:

preferably, in the step (1), the structural formula of the beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole is shown as the formula (II):

wherein R is₂Selected from: alkyl with 1-6 carbon atoms, aromatic ring with 6-30 carbon atoms, and five-membered or six-membered single heterocyclic compound containing N, O, S; the aromatic ring may be substituted by one or more substituents selected from C1-6 alkyl and OCH₃、OH、CF₃Or halogen, the N, O, S-containing five-membered or six-membered single heterocyclic compound can be furan, thiophene, pyrrole, pyridine, the 6-30 carbon atom aromatic ring can be a benzene ring or a naphthalene ring, and further, the beta-substituted alpha, beta-unsaturated 3-methyl-4-nitroisoxazole is selected from one of the following compounds:

preferably, the chiral superbase is selected from one of the following compounds:

the invention also protects the chiral 4, 5-disubstituted pyrrolidine-2-ketone compound prepared by the preparation method.

The invention also protects the application of the 4, 5-disubstituted pyrrolidine-2-ketone compound in the preparation of chiral 4, 5-disubstituted pyrrolidine-2-ketone skeleton drugs, wherein the skeleton drugs comprise optical pure fenclorone.

Compared with the prior art, the invention has the following beneficial effects:

(1) the method takes 2-substituted nitroethane (I) and trans-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole (II) as raw materials for the first time, uses chiral superbase to catalyze the asymmetric Michael addition reaction of the 2-substituted nitroethane (I) and the trans-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole (II) as a key step to prepare chiral 4, 5-disubstituted pyrrolidine-2-ketone (VI), and the prepared chiral 4, 5-disubstituted pyrrolidine-2-ketone compound comprises fenclorone;

(2) the synthesis steps of the invention are only 4 steps, and can be completed in 48h, wherein the products obtained in the step (1) and the step (2) do not need to be separated and purified, and can be directly subjected to subsequent reaction; as the chiral superbase Catalyst (COSB) is used in the key step of the Michael addition reaction, a stereospecific trans (anti-) addition product is obtained without transformation, thereby saving a large amount of time and resources.

(3) The preparation method of the 4, 5-disubstituted pyrrolidine-2-ketone developed by the invention has the advantages that the sources of reactants are wide, and the chiral 4, 5-disubstituted pyrrolidine-2-ketone has diversity in chemical structure;

(4) the preparation method of the 4, 5-disubstituted pyrrolidine-2-ketone, which is developed by the invention, can continuously operate the steps (1) to (3), and the products obtained in the steps (1) and (2) do not need to be separated and purified.

Drawings

FIG. 1 shows the structural formulas of clausenamide and fencroketone in the background art;

FIG. 2 is a scheme showing the synthesis scheme of fenclorone reported in the prior art CN119218A patent in the background art;

FIG. 3 is a NMR chart of I-A obtained in example 1(¹H NMR)；

FIG. 4 is the NMR spectrum of I-A obtained in example 1: (¹³C NMR)；

FIG. 5 is a NMR chart of II-A obtained in example 1(¹H NMR)；

FIG. 6 is a NMR chart of II-A obtained in example 1: (¹³C NMR)；

FIG. 7 shows the NMR spectrum of COSB-5 catalytic product III-A obtained in example 1: (¹H NMR)；

FIG. 8 is a NMR chart of addition product III-A obtained in example 1: (¹³C NMR)；

FIG. 9 is a high resolution mass spectrum of addition product III-A obtained in example 1;

FIG. 10 is a chiral HPLC plot of the COSB-5 catalytic product III-A prepared in example 1;

FIG. 11 is a chiral HPLC plot of the COSB-7 gram-scale catalytic product III-A prepared in example 3;

FIG. 12 is a NMR chart of esterified product V-A obtained in example 1(¹H NMR)；

FIG. 13 is a NMR chart of esterified product V-A obtained in example 1(¹³C NMR)；

FIG. 14 is a high resolution mass spectrum of esterification product V-A obtained in example 1;

FIG. 15 is a structural view of an X-single crystal diffraction pattern of esterification product V-A obtained in example 1;

FIG. 16 is a chiral HPLC plot of esterification product V-A prepared in example 1;

FIG. 17 is a NMR chart of the final product VI-A obtained in example 1(¹H NMR)；

FIG. 18 shows the NMR spectrum of the final product VI-A obtained in example 1(¹³C NMR)；

FIG. 19 is a chiral HPLC plot of the final product VI-A prepared in example 1;

FIG. 20 is a reaction scheme of the present invention.

Detailed Description

In order to make the technical solutions of the present invention better understood and implemented by those skilled in the art, the present invention is further described below with reference to the following specific embodiments and the accompanying drawings, but the embodiments are not meant to limit the present invention.

The following experimental methods and detection methods, unless otherwise specified, are conventional methods; the following reagents and starting materials are all commercially available unless otherwise specified.

Example 1

A preparation method of chiral 4, 5-disubstituted pyrrolidine-2-ketone compounds comprises the following steps:

(1) synthesis of 2-o-chlorophenyl nitroethane:

14.1g (0.1mol) of o-chlorobenzaldehyde are weighed into a 250mL single-necked round-bottomed flask, a magnetic stirrer is placed, 100mL of ethanol and 15mL of nitromethane (CH) are added₃NO₂0.3mol), stirring and cooling to 0 ℃, dropwise adding 20mL of 10% NaOH aqueous solution, continuously stirring at 0 ℃ for 1h, moving to room temperature, continuously stirring and reacting for 2h, detecting the reaction process by a Thin Layer Chromatography (TLC) method, cooling the reaction solution to 0 ℃ after o-chlorobenzaldehyde disappears, slowly adding about 10mL of 2mol/L hydrochloric acid aqueous solution to ensure that the pH of the reaction solution is 3, continuously stirring, precipitating a large amount of light yellow solid completely, standing for 1h, performing suction filtration, washing a filter cake with absolute ethyl alcohol (3X 10mL), collecting the filter cake, and performing vacuum drying to obtain 16.2g (89%) of light yellow powdery solid; the solid was suspended in methanol, cooled to 0 ℃ and 12.0g (3.3eq.) NaBH added in three portions with vigorous stirring₄Solid, after addition, reacted at 0 ℃ for 5h, at room temperature for 3h, the solvent was removed under reduced pressure and the residue obtained was suspended in 100ml of CH₂Cl₂The solid was removed by suction filtration, the filtrate was washed with water (2X 30mL) and saturated brine (3X 20mL) in that order, dried over anhydrous sodium sulfate for 1h, and evaporated to dryness13.8g (75%) of a yellow clear oil, the product I-A obtained was used directly in the next reaction; nuclear magnetic resonance hydrogen spectrum of I-A (¹HNMR) and carbon Spectroscopy (¹³CNMR) see fig. 3 and 4;

characterization data for I-A:¹HNMR(400MHz,CDCl₃)7.33-7.31(m,1H),4.58(t,J＝7.2Hz,2H),3.38(t,J＝7.2Hz,2H)；¹³CNMR(400MHz,CDCl₃)ppm 134.0,133.3,131.1,129.9,129.1,127.3,77.3,77.2,77.0,76.7,74.2,31.4；HRMS(ESI):Exact mass calcd for C₈H₈ClNO₂[M+H]⁺,186.0322.Found 186.0317.

the preparation method of other 2-substituted nitroethane is the same as that of the example 1, and only other aromatic aldehyde needs to be replaced;

(2) synthesis of trans-beta-phenyl-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole:

weighing 5.35g (0.05mol) of benzaldehyde and 7.1g (0.051mol) of 3, 5-dimethyl-4-nitroisoxazole into a 250mL single-neck round-bottom flask, adding a magnetic stirrer, adding 100mL of ethanol and 5mL of tetrahydropyrrole (0.005mol), heating to 75 ℃, stirring for 8 hours, and separating out a large amount of yellow solid; monitoring the reaction process by a Thin Layer Chromatography (TLC) method, cooling the reaction liquid to 0 ℃ after benzaldehyde disappears, standing for 1h, performing suction filtration, washing a filter cake with absolute ethyl alcohol (3X 10mL), collecting the filter cake, and performing vacuum drying to obtain 10.5g (91%) of a light yellow granular solid; the obtained product can be directly used for the next reaction; II-A nuclear magnetic resonance hydrogen spectrum (¹H NMR) and carbon Spectroscopy (¹³C NMR) see fig. 5 and 6;

characterization data for II-A:¹HNMR(400MHz,CDCl₃)7.74(d,J＝16.4Hz,2H),7.70-7.66(m,3H),7.46-7.45(m,3H),2.61(s,3H)；¹³CNMR(400MHz,CDCl₃)ppm167.1,156.1,143.1,134.4,131.1,129.1,128.4,110.9,11.8；HRMS(ESI):Exact mass calcd for C₁₂H₁₀N₂O₃[M+H]⁺,213.0770.Found 213.0765.

the preparation method of other trans-beta-substituted-alpha, beta-unsaturated 3-methyl-4-nitroisoxazoles is the same as that of the example 1, and only other aromatic aldehydes are needed to be replaced;

(3) COSB-5 catalyzed asymmetric Michael addition to prepare Compound III:

weighing 0.12g (0.5mmol) of alpha, beta-unsaturated nitroisoxazole and 95mg (0.51mmol) of 2-o-chlorophenyl nitroethane into a 10mL reaction tube, putting a magnetic stirrer, adding 5mL of toluene and 33mg of COSB-5(0.05mmol), stirring at room temperature for 24h, monitoring the reaction progress by a Thin Layer Chromatography (TLC) method, removing the solvent under reduced pressure after the raw materials disappear, and performing flash column chromatography on the obtained residue (eluent: petroleum ether/ethyl acetate: 5/1, volume ratio) to obtain white powdery solid III-A0.20g (95%); its nuclear magnetic resonance hydrogen spectrum (¹H NMR), nuclear magnetic resonance carbon spectrum (C¹³C NMR), high resolution mass spectrometry, chiral HPLC are shown in FIGS. 7-10;

characterization data for III-A:¹H NMR(400MHz,CDCl₃)7.38(d,J＝8.0Hz,1H),7.29-7.23(m,4H),7.21-7.12(m,4H),5.21-5.16(m,1H),3.94(q,J＝8.0Hz,1H),3.83(d,J＝6.8Hz),3.57(dd,J₁＝2.8Hz,J₂＝14.4Hz,1H),3.32(dd,J₁＝11.2Hz,J₂＝14.4Hz,1H),2.46(s,3H)；¹³C NMR(400MHz,CD₃COCD₃)ppm 171.3,155.5,133.7,132.6,131.4,129.8,129.4,129.0,128.7,127.8,127.5,91.2,46.7,35.6,30.2,11.5；HRMS(ESI):Exact mass calcd for C₂₀H₁₈ClN₃O₅[M+H]⁺,416.1013.Found 416.1003.

(4) hydrolysis reaction with 3mol/L aqueous sodium hydroxide solution:

weighing 1.05g (2.5mmol) of addition product III-A in a 100mL single-neck round-bottom reaction bottle, putting a magnetic stirrer, adding 20mL of dichloromethane to fully dissolve the addition product III-A, cooling to 0 ℃, dropwise adding 10mL of 3mol/L NaOH aqueous solution, moving to room temperature and stirring for 3 hours; monitoring the reaction progress by a Thin Layer Chromatography (TLC) method, adjusting the pH of the reaction solution to 3-4 by using 6mol/L HCl aqueous solution after the raw materials disappear, transferring the reaction solution into a separating funnel, standing for layering, extracting an aqueous phase by using dichloromethane (3X 15mL), combining organic phases, washing by using saturated saline solution (2X 15mL), drying by using anhydrous sodium sulfate, and removing a solvent to obtain 0.61g (73%) of a tan oily residue which can be directly used for the next reaction;

(5) methanol/thionyl chloride (SOCl)₂) And (3) participating in esterification reaction:

0.67g (2.0mmol) of hydrolysate IV-A was weighed into a 50mL single-necked round-bottomed reaction flask, placed with a magnetic stirrer, dissolved thoroughly by adding 15mL of methanol, cooled to 0 ℃ and added dropwise with 1.0mL of OCCl₂Moving to room temperature, stirring for 1h, and heating and refluxing for 3 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), after disappearance of the starting material, the solvent was removed and the residue obtained was dissolved in 30mL of CH₂Cl₂And cooled to 0 ℃, 10mL of water was carefully added dropwise, the mixture was stirred at room temperature for 30min, the mixture was allowed to stand for separation, the organic phase was washed with saturated brine (2 × 15mL), dried over anhydrous sodium sulfate, the solvent was removed, and flash column chromatography was performed on the residue (eluent: petroleum ether/ethyl acetate 5/1, volume ratio) to obtain 0.65g (95%) of a white powdery solid V-a; NMR spectrum of esterification product V-A: (¹H NMR), nuclear magnetic resonance carbon spectrum (C¹³C NMR), high resolution mass spectrum, X-single crystal diffraction structure diagram, and chiral HPLC diagram shown in figures 12-16;

characterization data for esterification product V-A:¹H NMR(400MHz,CDCl₃)7.41-7.28(m,6H),7.19(m,2H),7.03-7.02(m,1H),5.11-5.05(m,1H),3.81-3.75(m,1H),3.52(s,3H),3.07-3.00(m,1H),2.86-2.66(m,2H)；¹³C NMR(400MHz,CDCl₃)ppm 170.7,137.3,133.7,133.1,131.2,129.7,129.1,128.3,128.2,127.2,91.7,51.8,46.0,37.7,36.3；HRMS(ESI):Exact mass calcd for C₁₈H₁₈ClNO₄[M+H]⁺,348.1003.Found 348.1002.

(6) reductive amination of a closed ring with 10 mol% palladium on carbon/5.0 atmospheres of hydrogen/methanol

Weighing 0.87g (2.5mmol) of esterification product V-A in a 50mL single-neck long tube reaction bottle, putting a magnetic stirrer, adding 15mL of methanol to fully dissolve the esterification product V-A, adding 1.0g of 10% w.t.Pd-C, placing the whole reaction bottle in a 500mL stainless steel autoclave with an opening, replacing hydrogen for 3 times, pressurizing to 5atm, and stirring at room temperature for reaction for 24 hours; after the reaction was completed, the hydrogen was carefully purged, filtered (caution: carefully Pd-C on fire), washed with methanol (3X 5mL), the filtrate was collected and evaporated to dryness under reduced pressure to give a white powdery solid VI-A0.56g (78%); nuclear magnetic resonance hydrogen spectrum of product VI-A (¹HNMR), carbon nuclear magnetic resonance spectrum (C:)¹³C NMR) and chiral HPLC patterns are shown in FIGS. 17-19;

characterization data for the final product VI-A:¹H NMR(400MHz,CDCl₃)7.29-7.26(m,3H),7.22-7.17(m,3H),7.13-7.12(m,3H),5.22-5.17(m,1H),3.92-3.86(m,2H),3.52(s,3H),3.41-3.36(m,1H),3.10-3.04(m,2H),2.42(s,1H)；¹³C NMR(400MHz,CDCl₃)ppm 176.2,141.1,135.0,134.1,131.1,130.0,128.9,128.6,127.3,127.1,61.4,46.8,39.1,39.0；HRMS(ESI):Exact mass calcd for C₁₇H₁₆ClNO[M+H]⁺,286.0999.Found 286.1002。

example 2

The same procedure as in example 1 was followed, except that COSB-5 in step (3) was replaced with COSB-7, and the reaction was as follows:

COSB-7 catalyzed asymmetric Michael addition

Weighing 0.24g (1mmol) of alpha, beta-unsaturated nitroisoxazole and 0.20g (1.1mmol) of 2-o-chlorophenyl nitroethane in a 10mL reaction tube, putting a magnetic stirrer, adding 10mL of ethyl acetate and 20mg of COSB-7(0.05mmol), and stirring at room temperature for 3 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after disappearance of the starting material, the solvent was removed under reduced pressure and the residue obtained was subjected to flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1, vol.) to give white powdery solid III-A0.42g (97%).

Example 3

The same procedure as in example 2 was followed, except that a gram-scale operation was carried out:

weighing 2.4g (10.0mmol) of alpha, beta-unsaturated nitroisoxazole and 2.1g (11.0mmol) of 2-o-chlorophenyl nitroethane in a 250mL single-neck round-bottom reaction flask, adding a magnetic stirrer, adding 100mL of ethyl acetate and 200mg of COSB-7(0.5mmol), and stirring at room temperature for 3 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), after the starting material disappeared, the solvent was removed under reduced pressure, and the residue was recrystallized 2 times from petroleum ether/ethyl acetate (5/1 vol%) to give white granular crystals III-a3.6g (86%); its chiral HPLC is shown in FIG. 11.

Example 4

The same procedure as in example 1 was followed, except that COSB-5 in step (3) was replaced with COSB-11, and the reaction was as follows:

COSB-11 catalyzed asymmetric Michael addition

0.12g (0.5mmol) of alpha, beta-unsaturated nitroisoxazole and 95mg (0.51mmol) of 2-o-chlorophenyl nitroethane are weighed into a 10mL reaction tube, a magnetic stirrer is placed, 5mL of Tetrahydrofuran (THF) and 7.3mg of COSB-11(0.05mmol) are added, and the mixture is stirred at room temperature for 8 hours; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after the starting material had disappeared, the solvent was removed under reduced pressure, and the resulting residue was subjected to flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1, volume ratio) to obtain white powdery solid III-A0.19g (90%).

Example 5

The same procedure as in example 1 was followed, except that COSB-5 in step (3) was replaced with COSB-16, and the reaction was as follows:

COSB-16 catalyzed asymmetric Michael addition

Weighing 0.12g (0.5mmol) of alpha, beta-unsaturated nitroisoxazole and 95mg (0.51mmol) of 2-o-chlorophenyl nitroethane in a 10mL reaction tube, putting a magnetic stirrer, adding 5mL of dichloromethane and 62mg of COSB-16(0.015mmol), and stirring at room temperature for 1 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after disappearance of the starting material, the solvent was removed under reduced pressure, and the resulting residue was subjected to flash column chromatography (eluent: petroleum ether/ethyl acetate 5/1, volume ratio) to give 0.15g (74%) of a white powdery solid III-A.

The operation steps of the asymmetric Michael addition reaction of other 2-substituted nitroethane (I) and trans-alpha, beta-unsaturated 3-methyl-4-nitroisoxazole (II) are the same as those in example 7, and only different reaction substrates need to be replaced.

Example 6

The same procedure as in example 1 was followed, except that the hydrolysis reaction with the aqueous sodium hydroxide solution of step (4) was replaced with a hydrolysis reaction with the amount of 7 substances DABCO:

7 amount of substance DABCO involved in the hydrolysis reaction:

weighing 1.05g (2.5mmol) of addition product III-A in a 100mL single-neck round-bottom reaction bottle, adding a magnetic stirrer, adding 20mL of dichloromethane to fully dissolve the addition product, adding 2.0g (7.0eq.) of DABCO, and stirring at room temperature for 24 hours; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after disappearance of the starting material, the pH of the reaction mixture was adjusted to 3-4 with 6mol/LHCl aqueous solution, the reaction mixture was transferred to a separatory funnel, allowed to stand for separation, the aqueous phase was extracted with dichloromethane (3X 15mL), the organic phases were combined, washed with saturated brine (2X 15mL), dried over anhydrous sodium sulfate, and the solvent was removed to give 0.77g (93%) of a tan oily residue which was used directly in the next reaction.

Example 7

The same procedure as in example 1 was followed, except that the hydrolysis reaction with the aqueous sodium hydroxide solution of step (4) was replaced with a hydrolysis reaction with a 1.5mol/L aqueous sulfuric acid solution:

hydrolysis reaction with 1.5mol/L sulfuric acid aqueous solution:

weighing 1.05g (2.5mmol) of addition product III-A in a 100mL single-neck round-bottom reaction flask, adding a magnetic stirrer, adding 20mL of dichloromethane to fully dissolve, cooling to 0 ℃, and dropwise adding 1.5mol/LH₂SO₄5mL of aqueous solution, moving to room temperature and stirring for 3 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), and after the starting material had disappeared, the reaction solution was transferred to a separatory funnel, allowed to stand for separation, the aqueous phase was extracted with methylene chloride (3X 15mL), the organic phases were combined, washed with saturated brine (2X 15mL), dried over anhydrous sodium sulfate, and the solvent was removed to give 0.72g (86%) of a tan oily residue which was used directly in the next reaction.

Example 8

The same procedure as in example 1 was repeated except that methanol/thionyl chloride (SOCl) of step (5)₂) The esterification reaction was replaced with methanol/oxalyl chloride [ (COCl)₂]And (3) participating in esterification reaction:

methanol/oxalyl chloride [ (COCl)₂]And (3) participating in esterification reaction:

0.67g (2.0mmol) of hydrolyzate IV-A was weighed into a 50mL single-necked round-bottomed flaskThe flask was charged with a magnetic stirrer, 15mL of methanol was added to dissolve the mixture sufficiently, the mixture was cooled to 0 ℃ and 1.0mL of (COCl) was added dropwise₂Moving to room temperature, stirring for 1h, and heating and refluxing for 3 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC) and, after disappearance of the starting material, the residue obtained was dissolved in 30mL of CH₂Cl₂And cooled to 0 deg.c, 10mL of water was carefully added dropwise, stirred at room temperature for 30min, allowed to stand for separation, the organic phase was washed with saturated brine (2 × 15mL), dried over anhydrous sodium sulfate, the solvent was removed, and flash column chromatography was performed on the residue (eluent: petroleum ether/ethyl acetate 5/1, volume ratio) to give V-a0.62g (90%) as a white powdery solid.

Example 9

The same procedure as in example 1 was repeated except that methanol/thionyl chloride (SOCl) of step (5)₂) The esterification reaction is replaced by reductive amination ring closing reaction under the condition that the amount of substances is 3.0-5.0, the amount of the reduced zinc powder is 3.0mol/L of dilute hydrochloric acid:

3.0-5.0 amount of substance reduced zinc powder/50 amount of substance 3.0mol/L diluted hydrochloric acid:

weighing 1.0g (15.0mmol) of reduced zinc powder and 1.05g (3.0mmol) of esterification product V-A into a 100mL single-neck round-bottom flask, adding a magnetic stirrer, adding 30mL of methanol, dropwise adding 30mL of 3.0mol/L HCl aqueous solution under stirring at room temperature, stirring at room temperature for reaction for 4h, and heating for reflux reaction for 8 h; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), after the starting material had disappeared, it was filtered with suction, the filter cake was washed with methanol (3X 5mL), the filtrate was collected, methanol was removed under reduced pressure, the residue was extracted with ethyl acetate (3X 20mL), the ethyl acetate layers were combined, washed with saturated brine (2X 15mL), dried over anhydrous sodium sulfate, the solvent was removed, and the residue was subjected to flash column chromatography (eluent: petroleum ether/ethyl acetate: 1/1, volume ratio) to give VI-A0.64g (75%) as a white flaky solid.

Example 10

The same procedure as in example 1 was followed, except that,the methanol/sulfoxide chloride (SOCl) of the step (5)₂) The esterification reaction is replaced by reductive amination ring closing reaction under the condition that the amount of the substances is 3.0-5.0, the amount of the reduced iron powder is 3.0mol/L of the ammonium chloride aqueous solution:

amount of 3.0-5.0 substance reduced iron powder/amount of 100 substance 3.0mol/L ammonium chloride aqueous solution:

0.9g (15.0mmol) of reduced iron powder and 1.05g (3.0mmol) of esterification product V-A are weighed into a 100mL single-neck round-bottom flask, a magnetic stirrer is placed, 30mL of methanol is added, and 30mL of 3.0mol/LNH is added dropwise with stirring at room temperature₄Stirring Cl aqueous solution at room temperature for 4 hours, and heating and refluxing for 8 hours; the progress of the reaction was monitored by Thin Layer Chromatography (TLC), after the starting material had disappeared, filtration was carried out, the filter cake was washed with methanol (3X 5mL), the filtrate was collected, methanol was removed under reduced pressure, the residue was extracted with ethyl acetate (3X 20mL), the ethyl acetate layers were combined, washed with saturated brine (2X 15mL), dried over anhydrous sodium sulfate, the solvent was removed, and flash column chromatography was carried out on the residue (eluent: petroleum ether/ethyl acetate: 1/1, volume ratio) to give VI-A0.67g (75%) as a white flaky solid.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention; thus, it is intended that such changes and modifications be included within the scope of the appended claims and their equivalents.