Preparation method of nerofloxacin chiral piperidylamine intermediate

Abstract

The invention relates to a method for preparing a nerofloxacin chiral piperidylamine intermediate, which comprises the following steps of: carrying out condensation reaction on 5-hydroxy nicotinic acid which is simple and easy to obtain and is used as a raw material and different alcohols, screening through a series of asymmetric catalytic hydrogenation conditions to obtain optimal reaction conditions, and under the conditions, carrying out reaction on various 3, 3 '-dihydroxy nicotinic acid and 3, 3'-dihydroxy nicotinic acid to obtain the nerofloxacin chiral piperidylamine intermediate. The 2, 5-disubstituted pyridine quaternary ammonium salt is reduced into a tetrahydropyridine product, and the C5 site enantioselectivity of the product is excellent. The preparation method comprises the following steps: selecting methyl (R)-1-benzyl-5-hydroxy-1, 4, 5, 6-tetrahydropyridine-3-carboxylic acid methyl ester as a substrate, completely hydrogenating by using platinum dioxide hydrogen, and then carrying out methyl ester reduction, dehydroxylation, Mitsunobu reaction and protecting group removal to obtain a key chiral intermediate for industrial synthesis of a quinolone antibacterial drug nemonofloxacin with high enantioselectivity and high yield.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field, in particular to a preparation method of a nairoxacin chiral piperidine amine intermediate. BACKGROUND

[0002] The chiral piperidine ring as the core skeleton of natural alkaloids, synthetic bioactive molecules and drug molecules has important value in the chemical and pharmaceutical industries. For example, the quinolone antibacterial drug nairoxacin molecule contains a key chiral amino piperidine ring structure, which significantly improves the pharmacokinetic performance of the drug. At present, the chiral piperidine is mainly synthesized by asymmetric hydrogenation of substituted pyridine salt in industry, which has the advantages of high atom economy and simple steps. However, the existing technology for asymmetric hydrogenation of pyridine salt is mostly limited to C2 aryl-substituted substrates. For example, both the research groups of Zhou Yonggui (Angew. Chem. Int. Ed. 2012, 51, 10181-10184) and Zhang Xumou (Angew. Chem. Int. Ed. 2014, 53, 12761-12764) reported asymmetric hydrogenation methods for C2 aryl-substituted pyridine salt, but there is no report on asymmetric hydrogenation system for C3 and C5 double-substituted (especially C3 ester-substituted) pyridine salt. It is worth noting that the C3 ester-substituted piperidine structure widely exists in natural products, drugs (such as nairoxacin) and organic catalysts, and the development of efficient asymmetric hydrogenation technology for such substrates has important application prospects.

[0003] The current industrial synthesis route of the key intermediate of nairoxacin (such as TW200808729A) depends on the chiral source L-pyroglutamic acid, and needs to go through multiple functional group transformations and protection / deprotection operations. Specifically, the route involves steps such as carboxyl methyl esterification, Boc protection, palladium-carbon reduction of lactam ring opening, introduction of leaving groups (such as MsCl) in the dihydroxy compound intermediate, and benzylamine ring closure. This process has the following defects: first, the key reagent tert-butoxy bis(dimethylamino)methane is expensive and has insufficient domestic supply, resulting in high production cost; second, a large amount of MsCl and other highly toxic reagents are used, which puts pressure on production safety and environment; third, the total yield is limited due to multiple steps, and the dependence on chiral source reduces the process flexibility. SUMMARY

[0004] Therefore, it is necessary to provide a preparation method of a nairoxacin chiral piperidine amine intermediate to replace the existing chiral source process and solve the problems of raw material supply, environmental friendliness and process economy.

[0005] To achieve the above-mentioned purpose, the present application provides a technical solution:

[0006] A preparation method of a nairoxacin chiral piperidine amine intermediate, characterized in that it comprises the following steps:

[0007] S100. Compound I Compound II was prepared by the reaction

[0008] The specific steps of S100 include:

[0009] Compound I When dissolved in an organic solvent, and with the addition of an alcohol and a dehydrating agent, a dehydration or condensation reaction occurs to give compound II.

[0010] Specifically, in step S100, the organic solvent includes at least one of dichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, and tetrahydrofuran.

[0011] In step S100, the alcohol includes methanol and ethanol.

[0012] In step S100, the dehydrating agent includes concentrated sulfuric acid.

[0013] In step S100, the dehydrating agent includes at least one selected from concentrated sulfuric acid, DCC (dicyclohexylcarbodiimide), DIC (N,N'-diisopropylcarbodiimide), and EDC (1-ethyl-(3-dimethylaminopropyl)carbodiimide). S200. Compound II is reacted with an aryl halide to prepare compound III.

[0014] The specific steps of S200 include:

[0015] Compound II was dissolved in an organic solvent, and an aryl halide was added to prepare compound III by reaction.

[0016] Specifically, in step S200, the aryl halogenated compound includes at least one of benzyl bromide, benzyl chloride, 4-methylbenzyl bromide, 3-methoxybenzyl bromide, 4-trifluoromethylbenzyl bromide, and 3,5-dimethylbenzyl bromide.

[0017] In step S200, the organic solvent includes at least one of acetonitrile, acetone, diethyl ether, and methyl tert-butyl ether.

[0018] S300. Compound III undergoes an asymmetric hydrogenation reaction to obtain compound IV under the catalysis of an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, with the addition of a basic additive. Or compound S-Ⅳ

[0019] Specifically, depending on the type and configuration of the chiral bisphosphine ligand used, the reaction products of the asymmetric hydrogenation reaction vary, and may specifically be compound IV. Or compound S-Ⅳ Due to the obtained compound S-Ⅳ The 5-hydroxyl group will undergo a stereoconfiguration flip in subsequent steps, and the resulting configuration will be the opposite of the final product. Therefore, S-IV will not be used in subsequent steps.

[0020] In some embodiments, in step S300, the molar ratio of compound III, the iridium metal catalyst, the chiral bisphosphine ligand, and the basic additive is 1:(0.001-0.1):(0.002-0.1):(0.1-1).

[0021] In some embodiments, in step S300, the alkaline additive includes at least one of pyridine, pyrrole, triethylamine, aniline, sodium bicarbonate, and potassium carbonate.

[0022] In some embodiments, in step S300, the reaction temperature range of the asymmetric hydrogenation reaction is -40°C to 20°C.

[0023] In some embodiments, the reaction time for the asymmetric hydrogenation reaction in step S300 ranges from 12 h to 72 h.

[0024] S400. The compound IV Compound V is prepared by a redox reaction between hydrogen and a metal catalyst.

[0025] The specific steps of S400 include:

[0026] The compound IV Compound V was prepared by dissolving it in an organic solvent, adding a metal catalyst, and reducing it in a hydrogen atmosphere.

[0027] In some embodiments, in step S400, the organic solvent includes at least one of methanol, ethanol, isopropanol, ethyl acetate, and acetic acid.

[0028] In some embodiments, in step S400, the metal catalyst comprises at least one of platinum dioxide, 10 wt.% palladium on carbon, palladium hydroxide on carbon, and Raney nickel.

[0029] S500. Compound V is reacted with a hydrogen-rich reagent to prepare compound VI.

[0030] The specific steps of S500 include:

[0031] Compound V was dissolved in an organic solvent, and a hydrogen-rich reagent was added to react and prepare compound VI.

[0032] In some embodiments, in step S500, the organic solvent includes at least one of tetrahydrofuran, diethyl ether, 1,4-dioxane, and methanol.

[0033] In some embodiments, in step S500, the hydrogen-rich reagent includes at least one of lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and dimethyl sulfide borohydride.

[0034] S600. Adding Barton's esterifying agent to compound VI yields a thioester intermediate, followed by the addition of a hydrogen donor and a free radical initiator to give compound VII.

[0035] The specific steps of S600 include:

[0036] Compound VI was dissolved in an organic solvent, and Barton's esterification reagent was added to give a thioester intermediate. Subsequently, a hydrogen donor was added to give compound VII.

[0037] In some embodiments, in step S600, the organic solvent includes at least one of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, and 1,2-dichloroethane.

[0038] In some embodiments, in step S600, the Barton esterification agent comprises phenyl thiochloroformate, or

[0039] A mixture of sodium hydride, carbon disulfide and iodomethane, wherein the mass ratio of compound VI: sodium hydride: carbon disulfide: iodomethane is 1:2:2:2.

[0040] In some embodiments, in step S600, the hydrogen-donating agent includes at least one selected from tributyltin hydrogen, phenylsilane, diphenylsilane, and tris(trimethylsilane). More specifically, the free radical initiator includes AIBN (azobisisobutyronitrile).

[0041] S700. Compound VIII is prepared by reacting compound VII with azodicarboxylic acid ester, N-(tert-butoxycarbonyl)-p-toluenesulfonamide, and triphenylphosphine.

[0042] The specific steps of S700 include:

[0043] Compound VII was dissolved in an organic solvent, and then azodicarboxylic acid ester, N-(tert-butoxycarbonyl)-p-toluenesulfonamide, and triphenylphosphine were added. The reaction yielded compound VIII, which exhibited a configuration inversion at the C3 position.

[0044] In some embodiments, in step S700, the organic solvent includes at least one of tetrahydrofuran, dichloromethane, N,N-dimethylformamide, and 1,2-dichloroethane.

[0045] In some embodiments, in step S700, the azodicarboxylic acid ester includes isopropyl azodicarboxylic acid.

[0046] S800. Compound VIII is reacted with magnesium powder and ammonium chloride to prepare compound IX.

[0047] The specific steps of S800 include:

[0048] Compound VIII was dissolved in an organic solvent, and magnesium powder and ammonium chloride were added to react and prepare compound IX.

[0049] In some embodiments, in step S800, the organic solvent includes at least one of methanol, ethanol, isopropanol, and ethyl acetate.

[0050] S900. Compound IX and 10 wt.% palladium on carbon were deprotected under a hydrogen atmosphere to obtain the chiral piperidineamine intermediate X of nunofloxacin.

[0051] The specific steps of the S900 include:

[0052] Compound IX was dissolved in an organic solvent, and 10 wt.% palladium on carbon was added to remove the protecting group, yielding the chiral piperidineamine intermediate X of nunofloxacin. More specifically, the protecting group was removed under a hydrogen atmosphere.

[0053] In some embodiments, in step S900, the organic solvent includes at least one of methanol, ethanol, isopropanol, ethyl acetate, and acetic acid.

[0054] In some embodiments, in step S900, the metal catalyst comprises 10 wt.% palladium on carbon or 10 wt.% palladium hydroxide on carbon.

[0055] Wherein, R1 is any one of C1-C5 alkyl, aralkyl, aryl, or substituted aryl;

[0056] R2 is any one of alkyl, aralkyl, aryl, or substituted aryl;

[0057] X can be any one of chloride ion, bromide ion, or iodide ion.

[0058] In some embodiments, in step S300, the iridium metal catalyst comprises at least one of methoxy(cyclooctadiene)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, bis(cyclooctene)iridium chloride dimer, bis(1,5-cyclooctadiene iridium tetratetra[3,5-bis(trifluoromethyl)phenyl]boronic acid, and (1,5-cyclooctadiene)(pyrimidine)(tricyclohexylphosphine)iridium hexafluorophosphate.

[0059] In some embodiments, the chiral bisphosphine ligand includes at least one of (S,S)-f-Binaphane, (R,R)-Me-DUPHOS, (R,R)-QuinoxP*, (S,S)-Et-DUPHOS, (S)-SegPhos, 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene, 1,1'-Bis((2R,5R)-2,5-di-i-propylphospholano)ferrocene, (R)-(-)-DTBM-SegPhos, (S)-MeO-BIPHEP, (R,R)-BDPP, and CTH-(R)-P-Phos;

[0060] The chemical structural formula of the chiral diphosphine ligand is as follows:

[0061]

[0062] More specifically, the preparation process of the numonoxacin chiral piperidineamine intermediate is as follows:

[0063]

[0064] It is worth noting that:

[0065] Compound I It is 5-hydroxynicotinic acid.

[0066] Nemonoxacin (XIII) is a non-fluoroquinolone antibiotic with advantages over previous generations of quinolones, including a broader antibacterial spectrum, stronger bactericidal effect against Gram-positive bacteria, better pharmacokinetic properties, and less cross-resistance. Nemonoxacin was initially developed and manufactured by TaiGen Biotechnology Co., Ltd. in Taiwan under license from Procter & Gamble (P&G). The finished drug primarily uses its malate, known as nemonoxacin malate. Its oral capsule formulation was first launched in March 2014 and subsequently received drug approval from the China National Medical Products Administration (NMPA) in 2016. The main method for synthesizing nemonoxacin active pharmaceutical ingredient (API) involves the chiral piperidineamine intermediate X. It is prepared by a substitution reaction with non-fluoroquinolone building blocks.

[0067] According to patent TW200808729A, chiral piperidineamine intermediate X was successfully prepared. Subsequently, it undergoes a substitution reaction with compound XI from another synthetic module to obtain compound XII. Then, by successively removing the borate ester protecting group and the tert-butyloxycarbonyl (Boc) protecting group, the quinolone antibacterial drug nemonoxacin (XIII) can be prepared relatively conveniently.

[0068]

[0069] The beneficial effects of this invention are:

[0070] This invention provides a method for using compound I Using 5-hydroxynicotinic acid as a raw material, the chiral piperidine amine intermediate of nemonoxacin was prepared by asymmetric catalytic hydrogenation. The key chiral intermediate of nemonoxacin chiral piperidine amine, a quinolone antibacterial drug, was obtained with high enantioselectivity and high yield through condensation reactions with different alcohols, reactions with different aryl halides, asymmetric hydrogenation, methyl ester reduction, dehydroxylation, Mitsunobu reaction, and deprotection.

[0071] Asymmetric hydrogenation reactions exhibit high enantioselectivity, good atom economy, and high yield.

[0072] The route of this invention does not rely on chiral raw materials, does not use toxic or harmful substances, is simple to operate, and has a high overall yield. Attached Figure Description

[0073] Figure 1 The hydrogen spectrum of compound IIa;

[0074] Figure 2 This is the carbon spectrum of compound IIa;

[0075] Figure 3 The hydrogen spectrum of compound IIIa;

[0076] Figure 4 This is the carbon spectrum of compound IIIa;

[0077] Figure 5 This is the proton NMR spectrum of compound IVa;

[0078] Figure 6 This is the carbon spectrum of compound IVa;

[0079] Figure 7 The hydrogen spectrum of compound VIa;

[0080] Figure 8 The carbon spectrum of compound VIa;

[0081] Figure 9The hydrogen spectrum of compound Xa;

[0082] Figure 10 This is the carbon spectrum of compound Xa. Detailed Implementation

[0083] To better illustrate the purpose, technical solution, and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0084] In the embodiments, unless otherwise specified, the experimental methods used are conventional methods, and the materials and reagents used are commercially available unless otherwise specified.

[0085] Example 1

[0086] Synthesis of compound IIa

[0087]

[0088] 5-hydroxynicotinic acid (compound I, 5.0 g, 35.9 mmol, 1.0 eq) was uniformly dispersed in 40 mL of methanol and stirred at room temperature. 10 mL of concentrated sulfuric acid was slowly added dropwise. The mixture was then transferred to a 70 °C oil bath with a spherical condenser and refluxed with flowing water for 12 h.

[0089] After TLC monitoring showed complete consumption of the raw materials, the oil bath was removed, and the mixture was allowed to cool to room temperature. A saturated sodium bicarbonate solution was then slowly added with stirring until the reaction system was alkaline as measured by a wide-range pH test paper. Methanol was removed by vacuum concentration. 40 mL of water was added to the system, and the mixture was sonicated for 0.5 h to ensure uniform dispersion of the precipitated solid. The mixture was filtered, and the filter cake was washed successively with anhydrous ethanol and diethyl ether to obtain product compound IIa, which was 5.3 g of a white solid, with a yield of 96%.

[0090] 1H NMR (400MHz, Methanol-d4) δ8.59(d,J=1.7Hz,1H),8.28(d,J=2.8Hz,1H),7.74(dd,J=2.9,1.7Hz,1H),3.93(s,3H).

[0091] 13C NMR (101MHz, Methanol-d4) δ165.47,154.29,141.16,140.43,127.13,122.86,51.54.

[0092] Example 2

[0093] Synthesis of compound IIa

[0094]

[0095] Compound IIa (5.0 g, 32.6 mmol, 1.0 eq) was dispersed in 180 mL of acetone and refluxed in an oil bath at 60 °C with stirring until the solution was clear. Benzyl bromide (8.4 g, 48.9 mmol, 1.5 eq) was added dropwise, and stirring and reflux were continued for 24 h, during which a white solid gradually precipitated. TLC monitoring confirmed complete consumption of the feed. The mixture was filtered, and the filter cake was washed three times with diethyl ether to obtain the desired compound IIIa, which was a white solid of 12.4 g, with a yield of 95%.

[0096] 1H NMR(400MHz, Methanol-d4)δ8.32(t,J=1.5Hz,1H),7.88(dd,J=2.7,1.6Hz,1H),7.80 (dd,J=2.7,1.3Hz,1H),7.44(tdd,J=4.2,3.1,2.1Hz,5H),5.58(s,2H),4.85(s,3H).

[0097] 13C NMR (101MHz, Methanol-d4) δ168.14,163.51,136.51,133.94,133.34,130.69,129.28,129.12,128.30,126.59,63.83,52.11

[0098] Example 3

[0099] Synthesis of compound IVa

[0100]

[0101] Weigh 213 mg (0.02 mmol, 0.005 eq) of 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl] and 21 mg (0.04 mmol, 0.01 eq) of chiral bisphosphine ligand 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene into 50 mL of toluene that has been pre-deoxygenated by sonication. Stir at room temperature for 0.5 h. Add 1.56 g (3.90 mmol, 1.0 eq) of substrate IIIa and 313 μL (3.90 mmol, 1.0 eq) of pyridine. Transfer to a high-pressure hydrogenation reactor. After checking the airtightness, pressurize to 20 atm and then depressurize. Repeat the atmosphere replacement process three times. Pressurize to 80 atm and stir at 0 °C for 48 h. Hydrogen was slowly released to depressurize the system. TLC monitoring showed that the raw material was completely consumed. After filtering the system with diatomaceous earth, the solvent was removed by vacuum evaporation. The solution was then separated by rapid silica gel column chromatography to obtain 870 mg of transparent oil IVa, with a yield of 90% and an ee of 93%.

[0102] 1H NMR(400MHz,Chloroform-d)δ7.58(d,J=1.0Hz,1H),7.39–7.17(m,5H),4.31(q,J=15.1Hz,2H),4.13(qt,J=6.0,2.7Hz,1H),3.67(s,3H),3.0 8(dddd,J=12.5,3.2,2.3,1.1Hz,1H),2.95(dddd,J=12.5,5.1,2.4,0.7Hz,1H),2.50(dddd,J=16.2,4.4,2.1,0.9Hz,1H),2.42–2.33(m,1H).

[0103] 13C NMR (101MHz, Chloroform-d) δ168.15,144.82,135.47,127.84,126.96,126.54,90.32,61.81,61.76,58.83,50.30,49.75,28.00.

[0104] Screening experiments were conducted on the reaction conditions in Example 2. Other reaction conditions were the same as in Example 2. The differences and experimental results are shown in Table 1.

[0105] Table 1. Screening experiment results in Example 2

[0106]

[0107]

[0108] Note: In Table 1, DIPEA (N,N-Diisopropylethylamine) is N,N-diisopropylethylamine;

[0109] DMEDA (N,N'-dimethylethylenediamine) is N,N'-dimethylethylenediamine;

[0110] DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) is 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0111] DMAP (4-dimethylaminopyridin) is 4-dimethylaminopyridine;

[0112] TMG (Tetramethylguanidin) is tetramethylguanidine;

[0113] DCE (dichloroethan) is 1,2-dichloroethane;

[0114] THF (tetrahydrofuran) is tetrahydrofuran;

[0115] DCM (dichloromethane) is dichloromethane.

[0116] As shown in Table 1, when the catalyst is fixed as 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl]2 (0.1 equivalent), the solvent is dichloroethane, and the base is sodium bicarbonate, under a hydrogen pressure of 80 atm at room temperature, using ligands 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene (0.2 equivalent) and 1,1'-Bis((2R,5R)-2,5-di-i-propylphospholano)ferrocene (0.2 equivalent), two products with opposite configurations and good enantioselectivity can be obtained, with yields of 60% ee and -61% ee, respectively. The yields are 64% and 66%, respectively. As shown in the experiments of groups 12-19 in the table, when the catalyst is fixed as 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl]2 (0.1 equivalent), the ligand is 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene (0.2 equivalent), and the base is sodium bicarbonate, at room temperature and under a hydrogen pressure of 80 atm, using toluene as the solvent, the enantioselective product IVa can be obtained, achieving 90% ee and a yield of 85%.

[0117] As shown in the experiments of groups 20-30 in the table, when the catalyst is fixed as 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl]2 (0.1 equivalent), the ligand is 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene (0.2 equivalent), and the solvent is toluene, under hydrogen pressure of 80 atm at room temperature and with pyridine as the base, the enantioselective product IVa can be obtained, achieving 92% ee and 88% yield.

[0118] Comparing experiments 30 and 31 in the table, it can be seen that when the catalyst is fixed as 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl]2 (0.1 equivalents), the ligand is 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene (0.2 equivalents), the solvent is toluene, and the base is pyridine, the reaction can improve the enantioselectivity and yield to a certain extent by charging the hydrogen at 80 atm and cooling to 0℃, and the product IVa reaches 93% ee and 90% yield.

[0119] As shown in the experiments of groups 31-33 in the table, under the conditions of fixed solvent (toluene), base (pyridine), and reaction temperature (0℃), gradually decreasing the amount of catalyst 1,5-cyclooctadiene iridium chloride dimer [Ir(COD)Cl]2 (from 0.1 equivalents to 0.005 equivalents) and ligand 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene (from 0.2 equivalents to 0.01 equivalents) did not change the reaction effect. The resulting product IVa maintained 93% ee and 90% yield.

[0120] Example 4

[0121] Synthesis of compound Va

[0122]

[0123] Compound IVa (1.0 g, 4.04 mmol) was dissolved in 10 mL of methanol, and 0.1 g of platinum dioxide was added. The mixture was transferred to a high-pressure hydrogenation reactor. After checking the airtightness, the reactor was pressurized to 20 atm with hydrogen and then depressurized. This process of purging the system atmosphere was repeated three times. The reactor was then pressurized to 40 atm and stirred at room temperature for 24 h. Hydrogen was slowly released to depressurize the reactor. TLC monitoring showed that the feedstock was completely consumed. After filtering the system through a diatomaceous earth liner, the solvent was removed by vacuum distillation. The crude product, a transparent oily substance (Va), yielded 970 mg, with a crude yield of 97%, and could be directly used for the next reaction.

[0124] Example 5

[0125] Synthesis of compound VIa

[0126]

[0127] Compound Va (1.0 g, 4.01 mmol, 1.0 eq) was dissolved in 20 mL of anhydrous tetrahydrofuran. The solution was stirred in an ice bath, and lithium aluminum hydride powder (609 mg, 16.00 mmol, 4.0 eq) was added in portions. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 5 h. TLC monitoring showed complete consumption of the starting material. The mixture was then stirred in an ice bath, and 20 mL of saturated potassium sodium tartrate solution was slowly added until the system became clear. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The solvent was removed under reduced pressure to obtain product Via, a pale yellow oil, 807 mg in yield (91%).

[0128] 1H NMR (400MHz, Methanol-d4) δ7.39–7.21(m,5H),3.74–3.60(m,1H),3.58(q,J=12.8Hz,2H),3.48–3.33(m,2H),3.00(tdd ,J=12.4,4.1,1.9Hz,2H),2.08–1.95(m,1H),1.87–1.76(m,1H),1.69(dt,J=34.3,10.7Hz,2H),0.87(q,J=11.8Hz,1H).

[0129] 13C NMR (101MHz, Methanol-d4) δ136.97,129.33,127.90,127.04,66.47,64.62,62.56,60.29,56.07,37.28,36.10.

[0130] Example 6

[0131] Synthesis of compound VIIa

[0132]

[0133] Compound VIa (500 mg, 2.26 mmol, 1.0 eq) was dissolved in 20 mL of dichloromethane. Phenyl thiocarbamate (390 mg, 2.26 mmol, 1.0 eq) was added dropwise, followed by N,N-diisopropylethylamine (380 mg, 2.94 mmol, 1.3 eq) and p-dimethylaminopyridine (28 mg, 0.23 mmol, 0.1 eq). The mixture was stirred at room temperature for 4 h, and the reaction mixture was monitored by TLC until the reactants were completely consumed. The solvent was evaporated, and the mixture was reconstituted with 20 mL of toluene. Tributyltin hydrogen (786 mg, 2.71 mmol, 1.2 eq) was then added dropwise with stirring, followed by azobisisobutyronitrile (37 mg, 0.23 mmol, 0.1 eq). The mixture was then heated to 110 °C and refluxed for 8 h. After quenching with 10% potassium fluoride solution, add an appropriate amount of water and extract three times with dichloromethane. Combine the organic phases, concentrate under slight reduced pressure, and then wash the organic phase with saturated citric acid aqueous solution, saturated sodium bicarbonate solution, and saturated brine solution, respectively. After drying with anhydrous sodium sulfate, evaporate the solvent to obtain the crude product of compound VIIa, which is a colorless oily substance of 376 mg, with a crude yield of 81%. It can be used directly in the next step without purification.

[0134] Example 7

[0135] Synthesis of compound VIIIa

[0136]

[0137] Compound VIIa (350 mg, 1.70 mmol, 1.0 eq) was dissolved in 10 mL of tetrahydrofuran. Triphenylphosphine (581 mg, 2.22 mmol, 1.3 eq), N-(tert-butyloxycarbonyl)-p-toluenesulfonamide (601 mg, 2.22 mmol, 1.3 eq), and diisopropyl azodicarboxylate (449 mg, 2.22 mmol, 1.3 eq) were added sequentially. The mixture was then purged with nitrogen under protection and stirred at room temperature for 12 h. After complete consumption of the starting material was monitored by TLC, the system was directly concentrated. The crude product was reconstituted with 5 mL of ethanol, and 350 mg of zinc chloride powder was added. The mixture was stirred for 2 h, resulting in the precipitation of a white solid. The filter cake was washed with dichloromethane after filtration, and the filtrate was concentrated to obtain 703 mg of a yellow solid crude product, with a crude yield of 90%. This product could be directly used for the next step.

[0138] Example 8

[0139] Synthesis of compound IXa

[0140]

[0141] Compound VIIIa (200 mg, 0.44 mmol, 1.0 eq) was dissolved in 10 mL of methanol and added to a reaction flask. Magnesium powder pretreated with dilute hydrochloric acid (106 mg, 4.4 mmol, 10.0 eq) and ammonium chloride powder (235 mg, 4.4 mmol, 10.0 eq) were added sequentially. The reaction flask was then sonicated for 6 hours, and TLC monitoring confirmed complete consumption of the reactants. Insoluble matter was removed by filtration, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to obtain 128 mg of a colorless oily crude product, with a crude yield of 96%, which can be directly used for the next step.

[0142] Example 9

[0143] Synthesis of compound Xa

[0144]

[0145] Compound IXa (100 mg, 0.33 mmol) was dissolved in 10 mL of methanol, and 10 mg of 10% palladium on carbon was added. The mixture was transferred to a high-pressure hydrogenation reactor. After checking the airtightness, the reactor was pressurized to 20 atm with hydrogen and then depressurized. This process of purging the system was repeated three times. The reactor was then pressurized to 40 atm and stirred at room temperature for 24 h. Hydrogen was slowly released to depressurize the reactor. TLC monitoring showed that the feedstock was completely consumed. The system was filtered through a diatomaceous earth filter, and the solvent was removed under reduced pressure. The product was then separated by rapid silica gel column chromatography to obtain 50 mg of white solid Xa, with a yield of 74%.

[0146] 1H NMR(400MHz,Chloroform-d)δ5.31(s,1H),3.75(s,1H),2.93(ddt,J=11.6,3.4 ,1.4Hz,1H),2.86(ddt,J=11.9,3.2,1.5Hz,1H),2.69(dd,J=11.9,2.6Hz,1H),2 .20(dd,J=11.6,10.0Hz,1H),1.76(dddd,J=24.9,14.3,5.7,2.9Hz,2H),1.58( s,1H),1.43(s,9H),1.19(ddd,J=13.0,11.3,3.6Hz,1H),0.83(d,J=6.5Hz,3H).

[0147] 13C NMR (101MHz, Chloroform-d) δ154.33,77.88,53.31,49.87,44.34,36.93,27.45,26.13,18.22.

[0148] It should be noted that the specific parameters or reagents in the above embodiments are specific or preferred embodiments under the concept of the present invention, and not limitations thereof; those skilled in the art can make adaptive adjustments within the concept and protection scope of the present invention.

Claims

1. A method for preparing a chiral piperidineamine intermediate containing nemonoxacin, characterized in that, Including the following steps: S100. Compound I Compound II was prepared by the reaction S200. Compound II is reacted with an aryl halide to prepare compound III. S300. Compound III undergoes an asymmetric hydrogenation reaction to obtain compound IV under the catalysis of an iridium complex formed by an iridium metal catalyst and a chiral bisphosphine ligand, with the addition of a basic additive. S400. The compound IV Compound V is prepared by a redox reaction between hydrogen and a metal catalyst. S500. Compound V is reacted with a hydrogen-rich reagent to prepare compound VI. S600. Adding Barton's esterifying agent to compound VI yields a thioester intermediate, followed by the addition of a hydrogen donor and a free radical initiator to give compound VII. S700 reacted compound VII with azodicarboxylic acid ester, N-(tert-butoxycarbonyl)-p-toluenesulfonamide, and triphenylphosphine to prepare compound VIII. S800. Compound VIII is reacted with magnesium powder and ammonium chloride to prepare compound IX. S900. Compound IX and a metal catalyst are deprotected to obtain the chiral piperidineamine intermediate X of nunofloxacin. Wherein, R1 is any one of C1-C5 alkyl, aralkyl, aryl, or substituted aryl; R2 is any one of alkyl, aralkyl, aryl, or substituted aryl; X can be any one of chloride ion, bromide ion, or iodide ion.

2. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S300, the iridium metal catalyst comprises at least one of methoxy(cyclooctadiene)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, bis(cyclooctene)iridium chloride dimer, bis(1,5-cyclooctadiene iridium tetratetra[3,5-bis(trifluoromethyl)phenyl]boronic acid, and (1,5-cyclooctadiene)(pyrimidine)(tricyclohexylphosphine)iridium hexafluorophosphate.

3. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, The chiral bisphosphine ligands include at least one of (S,S)-f-Binaphane, (R,R)-Me-DUPHOS, (R,R)-QuinoxP*, (S,S)-Et-DUPHOS, (S)-SegPhos, 1,1'-Bis((2S,5S)-2,5-di-i-propylphospholano)ferrocene, 1,1'-Bis((2R,5R)-2,5-di-i-propylphospholano)ferrocene, (R)-(-)-DTBM-SegPhos, (S)-MeO-BIPHEP, (R,R)-BDPP, and CTH-(R)-P-Phos; The chemical structural formula of the chiral diphosphine ligand is as follows:

4. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S300, the molar ratio of compound III, the iridium metal catalyst, the chiral bisphosphine ligand and the basic additive is 1:(0.001~0.1):(0.002~0.1):(0.1~1).

5. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S300, the alkaline additive includes at least one of pyridine, pyrrole, triethylamine, aniline, sodium bicarbonate, and potassium carbonate.

6. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S300, the reaction temperature range for the asymmetric hydrogenation reaction is -40℃ to 20℃.

7. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S300, the reaction time range for the asymmetric hydrogenation reaction is 12h to 72h.

8. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S400, the metal catalyst comprises at least one of platinum dioxide, 10 wt.% palladium on carbon, palladium hydroxide on carbon, and Raney nickel.

9. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S500, the hydrogen-rich reagent includes at least one of lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and dimethyl sulfide borohydride.

10. The method for preparing the chiral piperidineamine intermediate of nemonoxacin according to claim 1, characterized in that, In step S600, the Barton esterification agent comprises phenyl thiochloroformate, or A mixture of sodium hydride, carbon disulfide, and iodomethane.

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