Preparation method of chiral aryl(2-pyridyl)benzoylmethyl hydrazine derivatives

Abstract

The present invention relates to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative. The preparation method provided by the present invention comprises the following steps: mixing an aryl(2-pyridyl)hydrazone, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst and a solvent, and carrying out an asymmetric transfer hydrogenation reaction to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative. The preparation method does not require the substrate to contain an ortho-substituted benzene ring or a thiophene unit, and has excellent enantioselectivity.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a method for preparing a chiral aryl(2-pyridyl) benzoylmethylhydrazine derivative. Background Art

[0002] Chiral aryl(2-pyridyl) benzoylmethylhydrazine derivatives are an important class of nitrogen-containing molecules, and aryl(pyridin-2-yl) methanamine can also be obtained by cleavage of the nitrogen-nitrogen bond. The structures of such diarylmethanamines are widely present in some drug molecules. For example, Levocetirizine (levocetirizine, as shown in Formula 1) is commonly used in anti-allergic treatment. By antagonizing the binding of histamine to receptors, it inhibits allergic reactions caused by histamine, such as seasonal persistent allergic rhinitis, chronic idiopathic urticaria, etc. Piclopastine (as shown in Formula 1) is also an important antihistamine.

[0003]

[0004] In recent decades, methods for synthesizing chiral diarylmethanamines have been established, which can be roughly divided into three types: the first is the asymmetric addition of imine aldehydes to aryl metals or aryl borons; the second is the asymmetric C-H functionalization of diarylmethanamines; the third is the asymmetric hydrogenation of diarylimines. Among these methods, the asymmetric hydrogenation of the carbon-nitrogen double bond has good industrial application prospects due to its excellent enantioselectivity and high efficiency. So far, there are few reports on the asymmetric hydrogenation reaction of diarylimines. The established methods mainly use chiral phosphine ligands and precious metals. In addition, an ortho group is also required on the aryl group. For example, the Zhang Xumu research group reported the ruthenium-catalyzed asymmetric reductive amination of ortho-hydroxy-substituted diaryl ketones (Angew. Chem. Int. Ed. 2020, 59, 5321-5325). Recently, the Zhou Haifeng research group reported the stepwise asymmetric reductive amination of aryl(2-pyridyl) ketones with benzylamine catalyzed by iridium, but this catalytic system still requires an ortho group on the aryl group to obtain high enantioselectivity (Asian J. Org. Chem. 2021, 10, 2950-2953.).

[0005] Considering the requirements of sustainable development and green chemistry, it is very necessary to use metals with very abundant reserves on earth for the synthesis of such compounds. So far, only the Zhou Jianrong research group has reported an example of the asymmetric reductive amination reaction of diaryl ketones catalyzed by nickel, but the substrate still needs to contain an ortho-substituted benzene ring or thiophene unit to effectively distinguish the two aromatic rings (Angew. Chem. Int. Ed. 2019, 58, 292-296), and substrates containing 2-pyridyl groups are not involved. Summary of the Invention

[0006] The object of the present invention is to provide a preparation method of a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative, which does not require the substrate to contain an ortho-substituted benzene ring or thiophene unit and has excellent enantioselectivity.

[0007] To achieve the above object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a preparation method of a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative, comprising the following steps:

[0009] Mix an aryl(2-pyridyl)hydrazone having the structure shown in formula I, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst and a solvent, and carry out an asymmetric transfer hydrogenation reaction to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative; the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative has the structure shown in formula II;

[0010]

[0011] Wherein, Ar 1 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl;

[0012] R is hydrogen, halogen, aryl, C1-C6 alkyl or alkoxy.

[0013] Preferably, the Ar1 is a substituted aryl or a substituted heteroaryl; the number of substituents in the substituted aryl or substituted heteroaryl ≥ 1;

[0014] The substituents in the substituted aryl or substituted heteroaryl are independently C1-C6 alkyl, halogen or alkoxy;

[0015] The heteroaryl is furan, thiophene, benzothiophene or benzofuran.

[0016] Preferably, the Ar 1 is phenyl, p-chlorophenyl, m-chlorophenyl, p-tert-butylphenyl, p-methoxyphenyl or 3,5-dimethylphenyl;

[0017] The R is hydrogen or chlorine.

[0018] Preferably, the ammonia borane compound includes one or more of ammonia borane complex, dimethylamine borane, diisopropylamine borane and morpholine borane.

[0019] Preferably, the molar ratio of the aryl(2-pyridyl)hydrazone having the structure shown in formula I to the ammonia borane compound is 1:(0.1-3).

[0020] Preferably, the chiral amino benzimidazole manganese catalyst has the structure shown in Formula 1 or Formula 2:

[0021]

[0022] Wherein, R 1 is tert-butyl, isopropyl, phenyl, benzyl or adamantyl; R 2 is methyl, ethyl, isopropyl or benzyl; R 3 is hydrogen, aryl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl; R 4 is substituted aryl.

[0023] Preferably, the chiral amino benzimidazole manganese catalyst comprises:

[0024] Preferably, the molar ratio of the chiral amino benzimidazole manganese catalyst to the aryl(2-pyridyl)hydrazone having the structure shown in Formula I is (0.01-5):100.

[0025] Preferably, the solvent comprises one or more of methanol, ethanol, isopropanol, ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether and water.

[0026] Preferably, the temperature of the asymmetric transfer hydrogenation reaction is room temperature and the time is 12 h.

[0027] The present invention provides a method for preparing a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative, comprising the following steps:

[0028] Mixing an aryl(2-pyridyl)hydrazone having the structure shown in Formula I, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst and a solvent, and carrying out an asymmetric transfer hydrogenation reaction to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative; the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative has the structure shown in Formula II;

[0029]

[0030] Wherein, Ar 1 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0031] R is hydrogen, halogen, aryl, C1-C6 alkyl or alkoxy.

[0032] Due to the metal-catalyzed hydrogen transfer reaction using ammonia borane compounds as hydrogen sources, metal hydride active intermediates are often formed during the reaction. In the present invention, a chiral amino benzimidazole manganese catalyst is used, and the Mn-H therein is used as the active catalytic center of the catalytic system. The hydrogen transfer step of the Mn(I)-H species is the key step determining the stereoselectivity. The π-π stacking between the benzimidazole part and the benzene ring of the ligand in the catalyst plays a key role in controlling the enantioselectivity, thereby enabling the obtaining of chiral products with high enantioselectivity. Therefore, the preparation method does not require the substrate to contain an ortho-substituted benzene ring or a thiophene unit, and has excellent enantioselectivity; meanwhile, the preparation method is simple to operate, has a wide substrate scope, high yield, excellent enantioselectivity, and can also achieve gram-scale synthesis, having good industrial application value. Detailed implementation mode

[0033] The present invention provides a method for preparing a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative, comprising the following steps:

[0034] Mix an aryl(2-pyridyl)hydrazone having the structure shown in formula I, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst, and a solvent, and carry out an asymmetric transfer hydrogenation reaction to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative; the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative has the structure shown in formula II;

[0035]

[0036] wherein, Ar 1 is a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl;

[0037] R is hydrogen, halogen, aryl, C1-C6 alkyl or alkoxy.

[0038] In the present invention, unless otherwise specified, all preparation raw materials are commercially available products well-known to those skilled in the art.

[0039] In the present invention, the Ar 1 is preferably a substituted aryl or a substituted heteroaryl; the number of substituents in the substituted aryl or substituted heteroaryl is preferably ≥1; the substituents in the substituted aryl or substituted heteroaryl are independently preferably C1-C6 alkyl, halogen or alkoxy; the heteroaryl is preferably furan, thiophene, benzothiophene or benzofuran.

[0040] In the present invention, the Ar 1 is preferably phenyl, p-chlorophenyl, m-chlorophenyl, p-tert-butylphenyl, p-methoxyphenyl or 3,5-dimethylphenyl; the R is hydrogen or chlorine.

[0041] In the present invention, the ammonia borane compound includes one or several of ammonia borane complex, dimethylamine borane, diisopropylamine borane and morpholine borane; when the ammonia borane compound is more than two of the above specific selections, the present invention has no special limitation on the ratio of the above specific substances, and they can be mixed in any ratio.

[0042] In the present invention, the molar ratio of the aryl(2-pyridyl)hydrazone having the structure shown in Formula I to the ammonia borane compound is preferably 1:(0.1 - 3), more preferably 1:(0.5 - 2.5), and most preferably 1:(1.0 - 2.0).

[0043] In the present invention, the chiral amino benzimidazole manganese catalyst preferably has the structure shown in Formula 1 or Formula 2:

[0044]

[0045] Among them, R 1 is preferably tert-butyl, isopropyl, phenyl, benzyl or adamantyl; R 2 is preferably methyl, ethyl, isopropyl or benzyl; R 3 is preferably hydrogen, aryl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl; R 4 is preferably substituted aryl.

[0046] In the present invention, R 1 is more preferably tert-butyl; R 3 is more preferably hydrogen, 3,5-di-tert-butylphenyl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl; R 4 is more preferably 3,5-di-tert-butylphenyl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl.

[0047] In the present invention, the chiral amino benzimidazole manganese catalyst preferably includes:

[0048]

[0049] In the present invention, the chiral amino benzimidazole manganese catalyst is preferably prepared, and the preparation method of the chiral amino benzimidazole manganese catalyst preferably includes the following steps:

[0050] Mix the organic ligand, manganese pentacarbonyl bromide and toluene, and carry out a coordination reaction in a protective atmosphere to obtain the chiral amino benzimidazole manganese catalyst.

[0051] In the present invention, the organic ligand is preferably Among them, R 1 is preferably tert-butyl, isopropyl, phenyl, benzyl or adamantyl; R 2Preferably methyl, ethyl, isopropyl or benzyl; R 3 Preferably hydrogen, aryl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl; R 4 Preferably substituted aryl.

[0052] In the present invention, R 1 More preferably tert-butyl; R 3 More preferably hydrogen, 3,5-di-tert-butylphenyl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl; R 4 More preferably 3,5-di-tert-butylphenyl, 3,5-dimethyl-4-methoxyphenyl or 4-tert-butylphenyl.

[0053] In the present invention, the molar ratio of the organic ligand to manganese pentacarbonyl bromide is preferably 1:1.

[0054] In the present invention, the concentration of the mixed solution obtained after mixing is preferably 0.1 mol / L.

[0055] In the present invention, the protective atmosphere is preferably an argon atmosphere.

[0056] In the present invention, the coordination reaction is preferably carried out under reflux conditions; the reflux temperature is preferably 110 °C and the time is preferably 4 h.

[0057] After the coordination reaction is completed, the present invention preferably further includes post-treatment, which preferably includes cooling to room temperature, adding n-hexane until no more yellow solid precipitates, stirring and washing, waiting for the precipitate to settle to the bottom of the bottle, separating out the supernatant, adding n-hexane for washing again, repeating twice, and finally drying.

[0058] In the present invention, the molar ratio of the chiral amino benzimidazole manganese catalyst to the aryl(2-pyridyl)hydrazone having the structure shown in Formula I is preferably (0.01-5):100, more preferably (0.5-4.5):100, and most preferably (2-3):100.

[0059] In the present invention, the solvent preferably includes one or more of methanol, ethanol, isopropanol, ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether and water; when the solvent is two or more of the above specific selections, the present invention has no special limitation on the ratio of the above specific substances, and they can be mixed in any ratio.

[0060] The present invention has no special limitation on the amount of the solvent used, and the amount well known to those skilled in the art can be used to enable the asymmetric transfer hydrogenation reaction to proceed normally.

[0061] In the present invention, the mixing is preferably carried out in a protective atmosphere; the protective atmosphere is preferably an argon atmosphere; the present invention has no special limitation on the order of the mixing, and the process well-known to those skilled in the art can be adopted.

[0062] In the present invention, the temperature of the asymmetric transfer hydrogenation reaction is preferably room temperature, and the time is preferably 12 h.

[0063] After the completion of the asymmetric transfer hydrogenation reaction, the present invention preferably further includes post-treatment, and the post-treatment preferably includes adding dichloromethane to the obtained product system for extraction, then combining the organic phases, drying with anhydrous sodium sulfate, adding silica gel and performing rotary evaporation under reduced pressure to remove the solvent, and then purifying by column chromatography.

[0064] The following examples are used to illustrate in detail the preparation method of the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative provided by the present invention, but they should not be construed as limiting the protection scope of the present invention.

[0065] Example 1

[0066] According to a molar ratio of 1:1, the organic ligand and manganese pentacarbonyl bromide were added to a reaction flask, and after adding toluene (the concentration of the obtained mixed solution was 0.1 mol / L) under argon protection, the temperature was raised to 110 °C and refluxed for 4 h. After the system was cooled to room temperature, n-hexane was added until no more yellow solid was precipitated, followed by stirring, washing, standing, separating the upper clear liquid, and then adding n-hexane for washing. After repeating twice, drying was carried out to obtain the chiral amino benzimidazole manganese catalyst ( denoted as Mn-1);

[0067] Under argon protection, 0.5 mmol of aryl(pyridin-2-yl)methylhydrazone (1a), 0.5 mol% of Mn-1 relative to the aryl(pyridin-2-yl)methylhydrazone, 1.0 mmol of ammonia borane, 1 mL of methyl tert-butyl ether (MTBE) and 1 mL of water were mixed, and after reacting at room temperature for 12 h, dichloromethane was added for extraction, then the organic phases were combined, dried with anhydrous sodium sulfate, added with silica gel and rotary evaporated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2a);

[0068]

[0069] The enantioselectivity of the 2a was determined by high performance liquid chromatography, and the test results were: White solid, 74% isolated yield. (c 1.13 in CHCl3), 1H NMR(400 MHz, CDCl3) δ 8.60 (d, J = 4.4 Hz, 1H), 8.13 (s, 1H), 7.69–7.55 (m, 3H), 7.46 (t, J = 7.6 Hz, 3H), 7.40–7.28 (m, 5H), 7.26–7.22 (m, 1H), 7.16 (dd, J = 7.0, 5.3 Hz, 1H), 5.46 (s, 1H). 13C NMR(101 MHz, CDCl3) δ 167.00, 160.45, 149.19, 139.98, 136.69, 133.03, 131.69, 128.74, 128.58, 128.11, 126.91, 122.59, 122.33, 69.31. HRMS(ESI) Calcd. for C 19 H 18 N3O [M + H] + : 304.1444, found: 304.1440. HPLC - separation conditions: Chiralcel OD - H column, 254 nm, hexane / i - PrOH = 70:30; flow rate 1.0 mL / min; t1 = 8.298 min, t2 = 9.442 min, tR = 8.160 min (major), tR = 9.450 min (minor); 99% ee.

[0070] Example 2

[0071] The preparation method of the chiral amino - benzimidazole manganese catalyst refers to the example, with the difference that: the organic ligand is The structural formula of the prepared chiral amino - benzimidazole manganese catalyst is (denoted as Mn - 2);

[0072] The preparation method of the chiral aryl(2 - pyridyl) benzoyl methyl hydrazide derivative (2a) refers to Example 1, with the difference that Mn - 1 is replaced by Mn - 2, and the enantioselectivity of the 2a is determined by high - performance liquid chromatography. The yield of the 2a is 72%, 97% ee.

[0073] Example 3

[0074] The preparation method of the chiral amino - benzimidazole manganese catalyst refers to the example, with the difference that: the organic ligand is The structural formula of the prepared chiral amino - benzimidazole manganese catalyst is (denoted as Mn - 3);

[0075] The preparation method of the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2a) refers to Example 1, except that Mn-1 is replaced by Mn-3, and the enantioselectivity of the 2a is determined by high performance liquid chromatography. The yield of the 2a is 78%, 92% ee.

[0076] Example 4

[0077] The preparation method of the chiral amino benzimidazole manganese catalyst refers to the reference example, except that: the organic ligand is The structural formula of the prepared chiral amino benzimidazole manganese catalyst is (denoted as Mn-5);

[0078] The preparation method of the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2a) refers to Example 1, except that Mn-1 is replaced by Mn-5, and the enantioselectivity of the 2a is determined by high performance liquid chromatography. The yield of the 2a is 82%, 96% ee.

[0079] Example 5

[0080] Referring to Example 1, except that 1a is replaced by 1b, the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2b) is prepared;

[0081]

[0082] The enantioselectivity of the 2b is determined by high performance liquid chromatography. The test results are: White solid, 80% isolated yield. (c 1.36in CHCl3), 1 1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.46(s,1H),7.65(d,J = 7.6Hz,2H),7.57(t,J = 7.4Hz,1H),7.42(t,J = 7.2Hz,1H),7.39–7.28(m,4H),7.23(d,J = 8.0Hz,3H),7.12(t,J = 4.8Hz,1H),5.72(s,1H),5.43(s,1H). 13 13C NMR(101MHz,CDCl3)δ167.40,159.97,149.22,138.61,136.76,133.82,132.87,131.74,129.88,128.80,128.52,127.05,122.53,122.48,68.61.HRMS(ESI)Calcd.for C 19 H 16 N3NaO[M+Na]+ : 360.0874, found: 360.0877. HPLC separation conditions: Chiralcel IC column, 254 nm, hexane / i-PrOH = 85 / 15; flow rate 1.0 mL / min; t1 = 24.646 min, t2 = 32.018 min, t R = 24.376 min (major), t R = 32.225 min (minor); 99% ee.

[0083] Example 6

[0084] Referring to Reference Example 1, with the difference that 1a is replaced by 1c, the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2c) is prepared;

[0085]

[0086] The enantioselectivity of the 2c is determined by high performance liquid chromatography, and the test results are: Light yellow solid, 85% isolated yield. (c 1.53 in CHCl3), 1 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.39 (d, J = 4.0 Hz, 1H), 7.75–7.64 (m, 2H), 7.53 (td, J = 8.0, 1.6 Hz, 1H), 7.43–7.33 (m, 3H), 7.32–7.25 (m, 5H), 7.05 (dd, J = 7.2, 5.6 Hz, 1H), 5.63 (s, 1H), 5.46 (s, 1H), 1.26 (s, 9H). 13 13C NMR (101 MHz, CDCl3) δ 167.26, 160.73, 150.81, 148.99, 136.96, 136.60, 133.12, 131.54, 128.45, 128.13, 127.13, 125.57, 122.70, 122.27, 69.13, 34.51, 31.33. HRMS (ESI) Calcd. for C 23 H 26 N3O [M + H] +: 360.2070, found: 360.2072. HPLC separation conditions: Chiralcel IC column, 254 nm, hexane / i-PrOH = 70 / 30; flow rate 1.0 mL / min; t1 = 13.441 min, t2 = 17.892 min, t R = 13.328 min (major), t R = 18.095 (minor); 97% ee.

[0087] Example 7

[0088] Referring to Reference Example 1, except that 1a was replaced with 1d, the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2d) was prepared;

[0089]

[0090] The enantioselectivity of the 2d was determined by high performance liquid chromatography, and the test results were: Light yellow solid, 79% isolated yield. (c 1.27 in CHCl3), 1 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.56 (td, J = 7.6, 1.2 Hz, 1H), 7.47–7.37 (m, 2H), 7.35–7.27 (m, 3H), 7.25–7.14 (m, 3H), 7.09 (dd, J = 6.8, 5.2 Hz, 1H), 5.55 (s, 1H), 5.42 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 167.47, 159.68, 149.21, 142.13, 136.85, 134.47, 132.78, 131.76, 129.94, 128.53, 128.48, 128.20, 127.07, 126.79, 122.63, 122.51, 68.78. HRMS (ESI) Calcd. for C 19 H 17 ClN3O [M + H] +: 338.1055, found: 338.1053. HPLC - separation conditions: Chiralcel IC column, 254 nm, hexane / i - PrOH = 70 / 30; flow rate 1.0 mL / min; t1 = 12.092 min, t2 = 23.144 min, t R = 12.055 min (major), t R = 23.316 min (minor); 98% ee.

[0091] Example 8

[0092] Referring to Reference Example 1, with the difference that 1a is replaced by 1e, the chiral aryl(2 - pyridyl)benzoylmethylhydrazine derivative (2e) is prepared;

[0093]

[0094] The enantioselectivity of the 2e is determined by high - performance liquid chromatography, and the test results are: White solid, 89% isolated yield. (c 1.29 in CHCl3), 1 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.48 (d, J = 4.4 Hz, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.56 (td, J = 7.6, 1.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.38–7.28 (m, 4H), 7.23 (d, J = 8.0 Hz, 1H), 7.10 (dd, J = 6.8, 5.2 Hz, 1H), 6.81 (d, J = 8.7 Hz, 2H), 5.57 (d, J = 8.8 Hz, 1H), 5.40 (s, 1H), 3.73 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 167.11, 160.76, 159.33, 149.06, 136.65, 133.05, 132.12, 131.62, 129.72, 128.52, 127.02, 122.56, 122.25, 114.04, 68.71, 55.23. HRMS (ESI) Calcd. for C 20 H 20 N3O2 [M + H] +: 334.1550, found: 334.1538. HPLC-separation conditions: Chiralcel OD-H column, 254 nm, hexane / i-PrOH = 70 / 30; flow rate 1.0 mL / min; t1 = 12.278 min, t2 = 15.261 min, t R = 12.893 min (major), t R = 15.132 min (minor); 99% ee.

[0095] Example 9

[0096] Referring to Reference Example 1, except that 1a was replaced with 1e, the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative (2e) was prepared;

[0097]

[0098] The enantioselectivity of the 2e was determined by high performance liquid chromatography. The test results were: White solid, 79% isolated yield. (c 1.19 in CHCl3), 1 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.42 (d, J = 4.0 Hz, 1H), 7.80–7.63 (m, 2H), 7.54 (td, J = 7.6, 2.0 Hz, 1H), 7.45–7.35 (m, 1H), 7.35–7.23 (m, 3H), 7.05 (s, 3H), 6.87 (s, 1H), 5.68 (s, 1H), 5.39 (s, 1H), 2.21 (s, 6H). 13 13C NMR (101 MHz, CDCl3) δ 167.10, 160.74, 148.99, 139.88, 138.16, 136.63, 133.03, 131.59, 129.72, 128.47, 127.10, 126.21, 122.63, 122.26, 69.44, 21.29. HRMS (ESI) Calcd. for C 21 H 22 N3O [M+H] +: 332.1757, found: 332.1751. HPLC - separation conditions: Chiralcel IC column, 254 nm, hexane / i - PrOH = 70 / 30; flow rate 1.0 mL / min; t1 = 15.528 min, t2 = 19.955 min, t R = 15.481 (major), t R = 20.182 min (minor); 98% ee.

[0099] Example 10

[0100] Referring to Example 1, with the difference that 1a is replaced by 1g, the chiral aryl(2 - pyridyl) benzoylmethylhydrazine derivative (2g) is prepared;

[0101]

[0102] The enantioselectivity of the 2g is determined by high - performance liquid chromatography, and the test results are: Light yellow solid, 69% isolated yield. (c 1.17 in CHCl3), 1 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.50–7.39 (m, 3H), 7.37–7.27 (m, 6H), 7.13 (d, J = 4.0 Hz, 1H), 5.70 (s, 1H), 5.43 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 167.47, 162.38, 150.07, 144.73, 139.31, 132.79, 131.80, 128.87, 128.57, 128.48, 128.34, 127.06, 122.80, 122.75, 69.25. HRMS(ESI) Calcd. for C 19 H 17 ClN3O [M + H] + : 338.1055, found: 338.1053. HPLC - separation conditions: Chiralcel IC column, 254 nm, hexane / i - PrOH = 70 / 30; flow rate 1.0 mL / min; t1 = 15.126 min, t2 = 26.314 min, t R= 15.216 min (major), t R = 27.229 (minor); 99% ee.

[0103] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing a chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative, characterized in that, Comprising the following steps: Mix an aryl(2-pyridyl)hydrazone having the structure shown in Formula I, an ammonia borane compound, a chiral amino benzimidazole manganese catalyst and a solvent, and conduct an asymmetric transfer hydrogenation reaction to obtain the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative; the chiral aryl(2-pyridyl)benzoylmethylhydrazine derivative has the structure shown in Formula II; Among them, Ar 1 is phenyl; R is hydrogen or a halogen; The chiral amino benzimidazole manganese catalyst is as follows: The ammonia borane compound is ammonia borane.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the aryl(2-pyridyl)hydrazone having the structure shown in Formula I to the ammonia borane compound is 1:(0.1 - 3).

3. The preparation method according to claim 1, characterized in that, The molar ratio of the chiral amino benzimidazole manganese catalyst to the aryl(2-pyridyl)hydrazone having the structure shown in Formula I is (0.01 - 5):

100.

4. The preparation method according to claim 1, characterized in that The solvent is one or more of methanol, ethanol, isopropanol, ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether and water.

5. The preparation method according to claim 1, characterized in that, The temperature of the asymmetric transfer hydrogenation reaction is room temperature and the time is 12 h.

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