A method for synthesizing chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide

Abstract

The invention provides a method for synthesizing chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide (anti-inversion amine). The method uses N-(2-benzoyl-4-chlorophenyl)isonicotinamide as a raw material, uses a complex formed in situ by metal iridium and a phenylethylamine skeleton PNN ligand as a catalyst, methanol as a solvent, and potassium carbonate as an alkali additive. A hydrogenation reaction occurs under this homogeneous catalytic system, and N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide is obtained with a yield of >99% and an ee value of >99%. The method has high activity, mild conditions, and high industrial application value.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis method for preparing a chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide compound by asymmetric hydrogenation of N-(2-benzoyl-4-chlorophenyl)isonicotinamide. Background Art

[0002] N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide (antilodging amine) is a plant growth retardant that can inhibit the synthesis of gibberellins in rice plants and has a strong selective anti-lodging effect on rice. When this antilodging amine is used, the number of grains per ear of rice is reduced, but the grain maturity rate is increased, so that the actual yield is increased. Therefore, antilodging amines are widely used in rice production.

[0003] Studies have shown that the anti-lodging effect of the S-type of N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide is significantly greater than that of the R-type and the racemic form [(1) Kato, M.; Sasahara, K.; Ochi, K.; Akita, H.; Oishi, T. Chem. Pharm. Bull. 1991, 39, 2498-2501.]. Therefore, it is of great significance to synthesize chirally pure N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide.

[0004] At present, the synthesis of chirally pure N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide is mainly obtained by yeast-catalyzed reduction of the corresponding ketone [(1) Kato, M.; Sasahara, K.; Ochi, K.; Akita, H.; Oishi, T. Chem. Pharm. Bull. 1991, 39, 2498-2501. (2) Japan, JP60112771A1985-06-19]. However, these methods have low catalytic activity and require a long reaction time. Transition metal-catalyzed asymmetric hydrogenation of ketones is one of the most effective methods for the synthesis of chiral alcohols [(3) Xie, J.; Liu, X.; Xie, J.; Wang, L.; Zhou, Q. Angew. Chem. Int. Ed. 2011, 50, 7329. (4) Wu, U.; Xie, Y.; Li, P.; Li, X.; Liu, Y.; Dong, X.; Zhang, X. Org. Lett. 2016, 18, 2938. (5) Császár, Z.; Szabó, EZ; Bényei, AC; Bakos, J.; Farkas, G. Catal. Commun. 2020, 146, 2938.]. Therefore, the synthesis of chirally pure N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide by transition metal-catalyzed asymmetric hydrogenation of N-(2-benzoyl-4-chlorophenyl)isonicotinamide has very high research significance and industrial prospects. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing a chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide compound. The method uses hydrogen as a reducing agent, uses a cheap industrial base, is simple to operate, has high reaction activity, and has high industrial application value.

[0006] The present invention provides a method for synthesizing a chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide compound, wherein N-(2-benzoyl-4-chlorophenyl)isonicotinamide and hydrogen are used as raw materials, a metal iridium and a phenylethylamine skeleton PNN ligand in situ form a complex as a catalyst, and under the action of a base additive, asymmetric hydrogenation occurs to obtain N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide with high yield and high ee value. The specific steps are as follows:

[0007] Iridium metal and a PNN ligand with a phenyl skeleton are vigorously stirred in a reaction medium at a molar ratio of 1:1.1-1:2.2, and then a reaction medium solution of N-(2-benzoyl-4-chlorophenyl)isonicotinamide is added thereto, and an alkali additive is added, and the reaction medium is placed in a high-pressure reactor, which occupies less than 70% of the volume of the reactor, and the atmosphere in the reactor is replaced with hydrogen, and hydrogen is charged to 3-5MPa, and the reaction is carried out at 20-60°C for 1-24 hours. After cooling to room temperature, hydrogen is released, and the solvent is removed to separate and obtain chirally pure N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide.

[0008]

[0009] The reaction medium is at least one of toluene, benzene, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, carbon tetrachloride, ethyl acetate, ether, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide, preferably methanol.

[0010] The base additive is selected from KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, i Pr2NEt, i PrNMe2, NEt3, t BuOK, t BuONa, t One or more of BuOLi, MeONa, MeOK or K3PO4. Preferably K2CO3.

[0011] Iridium metal is selected from [Ir(COD)Cl]2, [Ir(COD)2]BF4, [Ir(PCy3)(COD)(Py)] + PF6 - At least one of them, preferably [Ir(COD)Cl]2.

[0012] The complex formed in situ by the metal iridium and the phenylethylamine skeleton PNN ligand is a catalyst, and the general structure formula of the PNN ligand is as follows:

[0013]

[0014] Where:

[0015] Ar is phenyl, 2-substituted, 3-substituted, 4-substituted, 2,6-disubstituted, 2,4,6-trisubstituted aryl, etc. The number of carbon atoms on the aromatic ring is C6-C 60 (preferably C6-C 30 , more preferably C6-C 24 ) is an aromatic group; the substituent is C1-C 40 (preferably C1-C 30, more preferably C1-C6) alkane, C1-C 40 (preferably C1-C 30 , more preferably C1-C6) one or more of alkoxy, halogen, nitro, ester or cyano;

[0016] R 1 , R 2 are the same or different groups, are hydrogen, C1-C 40 (preferably C1-C 30 , more preferably C1-C6) alkane; the number of carbon atoms on the aromatic ring is C6-C 60 (preferably C6-C 30 , more preferably C6-C 24 ) aromatic group, the aromatic ring contains one or more N, S, O, P heteroatoms, and the number of carbon atoms on the aromatic ring is C3-C 60 Aromatic group (preferably C3-C 30 , more preferably C3-C 24 );

[0017] R 1 , R 2 It can form a cyclic group as shown below together with the N atom, wherein n is a natural number of 1-6 (preferably 1-5, more preferably 3-5);

[0018]

[0019] The chiral phenylphosphine-1,2-diphenylethylenediamine ligand, the cycloalkyl group and cycloalkyl derivative group are preferably a six-membered piperidine ring L-1a;

[0020]

[0021] The molar ratio of the substrate to the catalyst is 100-50000:1;

[0022] The molar ratio of the substrate to the base additive is 10-10000:1;

[0023] The catalytic reaction conditions are:

[0024] Temperature: room temperature - 100°C, preferably 20°C;

[0025] Pressure: 3-5MPa;

[0026] Time: 0.1-24 hours, preferably 12 hours.

[0027] The present invention has the following advantages:

[0028] 1. High reaction activity, mild reaction conditions and high yield;

[0029] 2. Using hydrogen as raw material and methanol as solvent, the reaction system is green and environmentally friendly;

[0030] 3. The catalyst preparation is simple and efficient, and the entire process is suitable for industrial production; BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the hydrogen nuclear magnetic resonance spectrum of N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide;

[0032] Figure 2 This is the carbon nuclear magnetic resonance spectrum of N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide. DETAILED DESCRIPTION

[0033] The following examples will further illustrate the present invention, but are not intended to limit the present invention. Nuclear magnetic resonance was measured using a Bruker 400 nuclear magnetic resonance instrument.

[0034] Example 1

[0035] Chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was prepared from N-(2-benzoyl-4-chlorophenyl)isonicotinamide.

[0036]

[0037] In a glove box, [Ir(COD)Cl]2 (0.001mmol) and ligand L-1a (0.0022mmol) were stirred vigorously in 1ml methanol (0.001M) at a molar ratio of 1:2.2 for 1h, and then N-(2-benzoyl-4-chlorophenyl)isonicotinamide (0.2mmol) methanol solution (0.1M) was added thereto, and K2CO3 (0.02mmol) was added, and then placed in a 500mL high-pressure reactor, the atmosphere in the reactor was replaced with hydrogen, and hydrogen was filled to 3MPa, and the reaction was carried out at 20°C for 12 hours. After the reaction was completed and cooled to room temperature, hydrogen was slowly released, the solvent was removed, and the residue was separated by column chromatography with a yield of 99% and >99%ee to obtain (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide. The absolute configuration of the product was determined by optical rotation [α] D 15 =-14.0 (c 1, MeOH), literature value [α] D 22 =+16.4 (c 1, MeOH), S configuration [(1) Kato, M.; Sasahara, K.; Ochi, K.; Akita, H.; Oishi, T. Chem. Pharm. Bull. 1991, 39, 2498-2501.];

[0038] The product structure was determined by H NMR and C NMR spectra (e.g. Figure 1 and 2 and confirmed by high-resolution mass spectrometry. 1 H NMR (700MHz, CD3OD): δ8.58-7.09(m,12H),5.86(s,1H).; 13 C NMR (176MHz, CD3OD): δ163.7,149.8,142.2,142.0,137.8,134.2,130.6,128.1,128.0,127.7,127.4,126.2,125.5,121.2,73.5.HRMS cal.for C 19 H 16 ClN2O2 + [M+H] + :339.0895,found:339.0893.

[0039] (The characterization method of the following examples is the same as that of Example 1)

[0040] Example 2

[0041] The PNN ligand L-1a in Example 1 was replaced by L-1b in an equal molar amount, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 98%ee.

[0042]

[0043] Example 3

[0044] The [Ir(COD)Cl]2 in Example 1 was replaced by [Ir(COD)2]BF4 in an equal molar amount, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 95%ee.

[0045] Example 4

[0046] The K2CO3 in Example 1 was used t BuOk was substituted in an equal molar amount and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 98%ee.

[0047] Example 5

[0048] The [Ir(COD)Cl]2 (0.001 mmol) and ligand L-1a (0.0022 mmol) in Example 1 were replaced by [Ir(COD)Cl]2 (0.0001 mmol) and ligand L-1a (0.00022 mmol) and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained in a yield of 99% and 98%ee.

[0049] Example 6

[0050] The methanol in Example 1 was replaced by toluene and the rest was the same as Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 90%ee.

[0051] Example 7

[0052] The H2 (3 MPa) in Example 1 was replaced by H2 (5 MPa) and the rest was the same as Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and >99%ee.

[0053] Example 8

[0054] K2CO3 (0.02 mmol) in Example 1 was replaced by K2CO3 (0.002 mmol) and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained in a yield of 99% and 98%ee.

[0055] Example 9

[0056] The 20° C. in Example 1 was replaced by 60° C. and the rest was the same as Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and >99%ee.

[0057] Example 10

[0058] The reaction time of 12 h in Example 1 was replaced by 24 h, and the rest was the same as Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and >99% ee.

[0059] Embodiment 11

[0060] The PNN ligand L-1a in Example 1 was replaced by L-2a in an equal molar amount, and the rest was the same as in Example 1.

[0061] (S)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained in 99% yield, >99% ee.

[0062]

[0063] Example 12

[0064] [Ir(COD)Cl]2 (0.001 mmol) in Example 1 was replaced by [Ir(COD)Cl]2 (0.002 mmol) and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 96%ee.

[0065] Embodiment 13

[0066] The K2CO3 in Example 1 was removed and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 16% and >99%ee.

[0067] Embodiment 14

[0068] The Ir(COD)Cl]2 in Example 1 was replaced by [Rh(COD)2]BF4 in an equal molar amount, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 90%ee.

[0069] Embodiment 14

[0070] The Ir(COD)Cl]2 in Example 1 was replaced by RuCl3 in an equal molar amount, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 55%ee.

[0071] Embodiment 15

[0072] The PNN ligand L-1a in Example 1 was replaced by the diphosphine ligand L-3a in an equal molar amount, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 33%ee.

[0073]

[0074] Example 16

[0075] The PNN ligand L-1a in Example 1 was replaced by an equal molar amount of the diphosphine ligand L-4a, and the rest was the same as in Example 1. (R)-N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide was obtained with a yield of 99% and 10%ee.

[0076]

[0077] The above-mentioned implementation cases only express the implementation methods of the present invention, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for synthesizing chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide, characterized in that: N-(2-benzoyl-4-chlorophenyl)isonicotinamide and hydrogen are used as raw materials, a complex formed in situ using metal iridium and a phenylethylamine skeleton PNN ligand is used as a catalyst, and a hydrogenation reaction is carried out under a base additive catalytic system to generate chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide; The N-(2-benzoyl-4-chlorophenyl)isonicotinamide compound has the following structure: ， The iridium compound used in the catalyst synthesis is one or two of [Ir(COD)Cl]2 and [Ir(COD)2]BF4; The PNN ligand is one or more of L-1a, L-2a, and L-1b, ， The reaction medium is one or more of methanol, ethanol and isopropanol; The chiral N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide compound has the following structure: 。 2. The synthesis method according to claim 1, characterized in that: The iridium compound used in the catalyst synthesis is [Ir(COD)Cl]2; the molar ratio of the iridium compound to the PNN ligand is 1:1.1-1:2.

2.

3. The synthesis method according to claim 1, characterized in that: The base additive is selected from KOH, NaOH, Na2CO3, Cs2CO3, K2CO3, NaHCO3, i Pr2NEt, i PrNMe2, NEt3, t BuOK, t BuONa, t One or more of BuOLi, MeONa, MeOK or K3PO4.

4. The synthesis method according to claim 1, characterized in that: The reaction medium is methanol.

5. The synthesis method according to claim 1, characterized in that: The molar ratio of the iridium compound to the PNN ligand is 1:1.5-1:2.2, and the base additive is selected from K2CO3.

6. The synthesis method according to claim 1, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the catalyst is 100-50000:1 based on the iridium compound.

7. The synthesis method according to claim 6, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the iridium compound in the catalyst is 100-5000:

1.

8. The synthesis method according to claim 6, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the iridium compound in the catalyst is 100-1000:

1.

9. The synthesis method according to claim 1, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the base additive is 1-1000:

1.

10. The synthesis method according to claim 9, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the base additive is 10-1000:

1.

11. The synthesis method according to claim 9, characterized in that: The molar ratio of the substrate (N-(2-benzoyl-4-chlorophenyl)isonicotinamide) to the base additive is 10-100:

1.

12. The synthesis method according to any one of claims 1 to 11, characterized in that: The method is as follows: The metal iridium and the PNN ligand are stirred in a reaction medium according to a desired molar ratio, and then a reaction medium solution containing N-(2-benzoyl-4-chlorophenyl)isonicotinamide is added thereto. Add an alkali additive, place it in a high-pressure reactor, occupy less than 70% of the volume of the reactor, replace the atmosphere in the reactor with hydrogen, fill it with hydrogen to 3-5 MPa, react at 20-60 ° C for 1-24 hours, release hydrogen after cooling to room temperature, remove the solvent, separate and purify to obtain chirally pure N-(4-chloro-2-(hydroxy(phenyl)methyl)phenyl)isonicotinamide.

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