Synthesis and application of a novel bidentate nitrogen ligand palladium complex

Abstract

The application relates to a novel structure of a bidentate nitrogen ligand palladium complex and a preparation method and application thereof, and the bidentate nitrogen ligand palladium complex is obtained by heating reaction of 2-acetylpyridine, palladium chloride and a substituted aniline in an organic acid. Compared with the prior art, the novel structure of the palladium complex prepared by the application has the advantages of simple synthesis process, high catalytic activity, excellent reaction activity in a Heck reaction for synthesizing a key intermediate of montelukast, obvious reduction of the cost of the montelukast bulk drug, and good industrialization prospect.

Description

Technical Field

[0001] This invention relates to palladium catalysts with novel structures, their preparation and uses, and particularly to a novel bidentate nitrogen ligand palladium complex, its preparation, and its use in the Heck reaction. Background Technology

[0002] Montelukast, developed by Merck & Co. in the United States, is a novel, highly selective LTD4 receptor antagonist marketed under the brand name Singular. It was first launched in Finland and Mexico in February 1998. As a selective leukotriene LTD4 receptor antagonist, it selectively binds to leukotriene LTD4 receptors in the airways, blocking the action of allergic mediators, improving respiratory inflammation, and clearing the airways. It is a highly effective, low-toxicity, and safe anti-asthmatic, anti-inflammatory, and anti-allergic drug with broad application prospects.

[0003]

[0004] The Heck reaction is one of the mature methods for synthesizing montelukast intermediates. It was first reported in patent EP0480717 that (E)-1-(3-(2-(7-chloro-2-quinolinyl)vinyl)phenyl)-2-propen-1-ol and methyl o-iodobenzoate were reacted by the Heck reaction under Pd(OAc)2 catalysis to generate methyl (E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-oxopropyl]benzoate.

[0005]

[0006] Patent CN112430177 reports that (E)-1-(3-(2-(7-chloro-2-quinolinyl)vinyl)phenyl)-2-propen-1-ol and 2-(2-bromophenyl)-2-propanol undergo a Heck reaction under the catalysis of Pd(OAc)2 and phosphine ligands to generate (E)-1-(3-(2-(7-chloro-2-quinolinyl)vinyl)phenyl)-3-(2-(2-hydroxyisopropyl)phenyl)propanone.

[0007]

[0008] However, the amount of palladium acetate used in these Heck reactions is generally between 1-5%, and with the continuous rise in the price of precious metals, the cost proportion of palladium acetate is becoming increasingly high. Therefore, finding a simple-to-prepare and highly reactive Heck reaction catalyst can effectively reduce the synthesis cost of montelukast active pharmaceutical ingredient. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art by providing a novel bidentate nitrogen-ligand palladium complex, its preparation method, and its applications. This palladium complex uses readily available raw materials, involves few synthesis steps, has a simple process, and is suitable for mass production. As a catalyst, it exhibits high activity in the Heck reaction, allowing the palladium dosage to be reduced to below 0.1%.

[0010] The objective of this invention can be achieved through the following technical solutions:

[0011] Synthesize a bidentate nitrogen-ligand palladium complex of formula (I):

[0012] In formula (I), R1 is hydrogen, diphenylmethyl, diisopropyl, etc.;

[0013] R2 can be hydrogen, methyl, etc.

[0014]

[0015] I

[0016] The preparation method is as follows: 2-acetylpyridine, palladium chloride and substituted aniline are heated and reacted in an organic acid to obtain the target complex.

[0017]

[0018] The definitions of R1 and R2 in substituted aniline are the same as in formula (I).

[0019] In the preparation method described above, the molar ratio of 2-acetylpyridine, palladium chloride, and substituted aniline is 1~1.3:1:1~1.3.

[0020] The organic acid used in the preparation method is an organic carboxylic acid such as formic acid, acetic acid, and propionic acid.

[0021] The palladium complex is used as a catalyst in the Heck coupling reaction. Detailed Implementation

[0022] The present invention will be described in detail below with reference to specific embodiments:

[0023] Most of the reagents used in the experiment were commercially available industrial products, and the remaining compounds were synthesized with reference to the literature.

[0024] Example 1

[0025] Synthesis of palladium complex 1

[0026]

[0027] Under nitrogen protection, 12.0 g (67.8 mmol) palladium chloride, 8.6 g (71.0 mmol) 2-acetylpyridine, 32.7 g (74.4 mmol) 2,6-bis(diphenylmethyl)-4-methylaniline, and 600 mL acetic acid were added to a 1 L four-necked flask, and the mixture was stirred and refluxed for 22 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was collected. The filter cake was dissolved in 500 mL dichloromethane, filtered to remove a small amount of insoluble matter, and the filtrate was collected and concentrated to obtain a yellow solid. The solid was recrystallized from 150 mL toluene, filtered, and the filter cake was collected and dried under vacuum to obtain 45.8 g of bright yellow solid, which was the target product (yield 94%).

[0028] Example 2

[0029] Heck reaction in which palladium complex 1 acts as a catalyst

[0030]

[0031] Under nitrogen protection, 50 g (155.4 mmol) of (E)-1-(3-(2-(7-chloro-2-quinolinyl)vinyl)phenyl)-2-propen-1-ol, 36.8 g (171.1 mmol) of 2-(2-bromophenyl)-2-propanol, 45 g (230.4 mmol) of dicyclohexylmethylamine, 110 mg (0.15 mmol) of palladium complex 1, and 200 mL of N,N-dimethylacetamide were added to a 1 L four-necked flask. The mixture was heated to 125 °C and reacted for 16 hours. After cooling to room temperature, 200 mL of 2M sodium hydroxide aqueous solution was added, and the mixture was stirred for 30 minutes. The mixture was extracted three times with 200 mL of dichloromethane. The organic phases were combined, washed once with 200 mL of brine, separated, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was collected and distilled to remove the solvent, yielding a gray solid. Add 180 mL of toluene for recrystallization, filter, collect the filter cake, and vacuum dry to obtain 60.2 g of off-white solid, which is the target product (yield 85%, liquid phase purity 98.5%).

[0032] Example 3

[0033] Synthesis of palladium complex 2

[0034]

[0035] Under nitrogen protection, 6.0 g (33.9 mmol) palladium chloride, 4.3 g (35.5 mmol) 2-acetylpyridine, 6.6 g (37.2 mmol) 2,6-diisopropylaniline, and 150 mL acetic acid were added to a 250 mL four-necked flask, and the mixture was stirred and refluxed for 20 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was collected. The filter cake was dissolved in 150 mL of dichloromethane, filtered to remove a small amount of insoluble matter, and the filtrate was collected and concentrated to obtain a yellow solid. The solid was recrystallized from 60 mL of toluene, filtered, and the filter cake was collected and dried under vacuum to obtain 13.8 g of bright yellow solid, which was the target product (yield 89%).

[0036] Example 4

[0037] Heck reaction in which palladium complex 2 acts as a catalyst

[0038]

[0039] Under nitrogen protection, 10 g (31.1 mmol) of (E)-1-(3-(2-(7-chloro-2-quinolinyl)vinyl)phenyl)-2-propen-1-ol, 7.4 g (34.4 mmol) of 2-(2-bromophenyl)-2-propanol, 9 g (46.1 mmol) of dicyclohexylmethylamine, 71 mg (0.16 mmol) of palladium complex 2, and 40 mL of N,N-dimethylacetamide were added to a 250 mL four-necked flask. The mixture was heated to 125 °C and reacted for 16 hours. After cooling to room temperature, 40 mL of 2M sodium hydroxide aqueous solution was added, and the mixture was stirred for 30 minutes. The mixture was extracted three times with 40 mL of dichloromethane. The organic phases were combined, washed once with 40 mL of brine, separated, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was collected and distilled to remove the solvent, yielding a gray solid. Add 150 mL of toluene for recrystallization, filter, collect the filter cake, and vacuum dry to obtain 11.3 g of off-white solid, which is the target product (yield 80%, liquid phase purity 98.3%).

[0040] The above description is only a part of the embodiments of the present invention and does not limit the patent scope of the present invention. Any equivalent structural or process transformations made using the content of this specification, or direct or indirect applications in other related technical fields, are similarly included in the patent protection scope of the present invention.

Claims

1. The use of a bidentate nitrogen-ligand palladium complex, characterized in that, The structure of the bidentate nitrogen-ligand palladium complex, used as a catalyst in the Heck coupling reaction, is as follows: ； The Heck coupling reaction is as follows: 。

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