Compounds, methods of making montelukast sodium intermediates, and related compounds uses and methods of making montelukast sodium intermediates

Abstract

The present application relates to the field of pharmaceutical chemistry, and in particular to a compound for preparing montelukast sodium intermediate, a method and related compound use and a method for preparing montelukast sodium intermediate. The present application discloses a new compound for preparing montelukast sodium intermediate, which is obtained by catalyzing a compound of formula IV and a compound of formula V as raw materials, and then reacting with compound III to obtain the target compound. The whole preparation process is simple, and the yield of the synthesis route is high, the purity of the end product is high, the post-treatment is simple, compared with the synthesis method in the prior art, the production cost is significantly reduced, and the needs of industrial large-scale production are met.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, particularly to the synthesis of montelukast sodium, and more specifically to compounds, methods for preparing montelukast sodium intermediates, and the uses of related compounds and methods for preparing montelukast sodium intermediates. Background Technology

[0002] Montelukast sodium, chemically named [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropylacetate sodium, was developed by Merck & Co., Inc. and first marketed in Finland and Mexico in February 1998. Montelukast sodium is a selective leukotriene D4 receptor antagonist that selectively binds to leukotrienes in the airways, blocking the action of allergic mediators, improving respiratory inflammation, and clearing the airways. It is used for asthma relief, anti-inflammation, and anti-allergy purposes.

[0003] Methyl (E)-2-[3-[3-[2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-oxopropyl]benzoate is an important intermediate in the preparation of montelukast sodium. Patent WO2008058118 discloses a method for preparing the montelukast sodium intermediate, and its synthetic route is as follows:

[0004]

[0005] The above reaction uses isophthalaldehyde and 7-chloro-2-methylquinoline as starting materials, and proceeds through seven steps to obtain the target intermediate. This synthetic route is long and the reaction conditions are harsh. The method of obtaining the montelukast sodium intermediate compound using this synthetic route not only has a low yield and high cost, but also a long production cycle, making it unsuitable for industrial production. Summary of the Invention

[0006] The technical problem to be solved by this invention is that the synthesis of montelukast sodium intermediates in the prior art is hampered by long routes, high costs, and low yields, which affect the large-scale production of montelukast sodium intermediates.

[0007] To address the aforementioned technical problems, this invention discloses a novel compound for preparing montelukast sodium intermediates, as shown in Formula II:

[0008] .

[0009] Furthermore, this invention also discloses a method for preparing the above-mentioned intermediate montelukast sodium. This method involves reacting compound IV and compound V in the presence of a palladium catalyst, a phase transfer catalyst, and a base in a solvent environment to obtain compound II. The synthetic route is as follows:

[0010] ;

[0011] Where X is any one of Cl, Br, and I.

[0012] Preferably, the palladium catalyst is one of palladium acetate, palladium trifluoroacetate, or palladium on carbon.

[0013] Preferably, the phase transfer catalyst is one of benzyltriethylammonium bromide, tetrabutylammonium bromide, or tetrapropylammonium bromide.

[0014] Preferably, the base is one of triethylamine, hexahydropyridine, or pyrrolidine.

[0015] Preferably, the solvent is one of tetrahydrofuran, toluene, or 1,4-dioxane.

[0016] Preferably, the reaction temperature is 30–80°C.

[0017] Furthermore, this invention also discloses a method for preparing montelukast sodium intermediates using the aforementioned novel compounds. This method involves preparing the montelukast sodium intermediate of Formula I by combining the compound shown in Formula III with the aforementioned compound shown in Formula II in a solvent present in PdCl2. The synthetic route is as follows:

[0018] .

[0019] Preferably, the solvent is one of dimethyl sulfoxide, toluene, xylene, N,N-dimethylformamide, 1,4-dioxane, or N-methylpyrrolidone.

[0020] Preferably, the molar ratio of compound II, compound III, and PdCl2 is (3-7):1:(0.05-0.3).

[0021] Preferably, the reaction temperature is 80–160°C.

[0022] The present invention also discloses the use of the compound of formula II in the preparation of the sodium montelukast intermediate of formula I.

[0023] And the use of the compound of formula III in the preparation of the sodium montelukast intermediate shown in formula I.

[0024] This invention discloses a novel method for preparing sodium montelukast intermediate and the corresponding intermediate compound. The method involves using compounds of formula IV and V as starting materials, followed by catalytic reaction to obtain a new intermediate compound, which is then reacted with compound III to yield the target compound. The entire preparation process is simple, and experiments have shown that this synthetic route achieves high yields, high purity of the final product, and simple post-processing. Compared to existing synthetic methods, the production cost is significantly reduced, meeting the needs of large-scale industrial production. Detailed Implementation

[0025] To better understand the present invention, we will further elaborate on the present invention below with reference to specific embodiments.

[0026] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available products.

[0027] Example 1

[0028] Under nitrogen protection, compound IV (X is I, 46 g, 0.2 mol), compound V (61.5 g, 0.32 mol), benzyltriethylammonium bromide (70.8 g, 0.26 mol), anhydrous magnesium sulfate (24.1 g, 0.2 mol), and 500 mL of tetrahydrofuran were added to a reaction flask and stirred. Then, palladium acetate (11.2 g, 0.05 mol) and triethylamine (24.3 g, 0.24 mol) were added. The reaction mixture was heated to 50 °C, and the reaction proceeded under TLC monitoring until the reactants were fully reacted. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate, washed with 300 mL of saturated sodium chloride, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1). The concentrate yielded compound II, with a yield of 93.6% and a purity of 99.4%.

[0029] Example 2

[0030] Under nitrogen protection, compound IV (X is Br, 36.6 g, 0.2 mol), compound V (61.5 g, 0.32 mol), tetrabutylammonium bromide (83.8 g, 0.26 mol), anhydrous magnesium sulfate (24.1 g, 0.2 mol), and 500 mL of toluene were added to a reaction flask and stirred. Then, palladium trifluoroacetate (16.6 g, 0.05 mol) and hexahydropyridine (20.4 g, 0.24 mol) were added. The reaction mixture was heated to 80 °C, and the reaction proceeded under TLC monitoring until the reactants were fully reacted. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate, washed with 300 mL of saturated sodium chloride, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1). The concentrate yielded compound II, with a yield of 90.4% and a purity of 99.2%.

[0031] Example 3

[0032] Under nitrogen protection, compound IV (X is Cl, 27.7 g, 0.2 mol), compound V (61.5 g, 0.32 mol), tetrapropylammonium bromide (69.2 g, 0.26 mol), anhydrous magnesium sulfate (24.1 g, 0.2 mol), and 500 mL of 1,4-dioxane were added to a reaction flask and stirred. Palladium acetate (11.2 g, 0.05 mol) and pyrrolidine (17.1 g, 0.24 mol) were then added. The reaction mixture was heated to 30 °C, and the reaction proceeded under TLC monitoring until the reactants were fully reacted. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate, washed with 300 mL of saturated sodium chloride, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1). The concentrate yielded compound II, with a yield of 88.5% and a purity of 99.1%.

[0033] Example 4

[0034] Under nitrogen protection, compound III (18 g, 100 mmol) and PdCl2 (2.66 g, 15 mmol) were added to a reaction flask, followed by compound II (132.5 g, 450 mmol) and 200 mL of dimethyl sulfoxide. The reaction mixture was stirred and heated to 120 °C, and the reaction proceeded under TLC monitoring until the starting materials were fully reacted. After the reaction was complete, the mixture was cooled to room temperature, diluted with 500 mL of ethyl acetate, and washed with 500 mL of water. The aqueous layer was extracted twice with 250 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by rapid column chromatography (silica gel, hexane:EtOAc = 8:1) to give compound I, with a yield of 91.7% and a purity of 99.2%.

[0035] Example 5

[0036] Under nitrogen protection, compound III (18 g, 100 mmol) and PdCl2 (0.89 g, 5 mmol) were added to a reaction flask, followed by compound II (206 g, 700 mmol) and 300 mL xylene. The reaction mixture was stirred and heated to 160 °C, and the reaction proceeded under TLC monitoring until the starting materials were fully reacted. After the reaction was complete, the mixture was cooled to room temperature, diluted with 500 mL of ethyl acetate, and washed with 500 mL of water. The aqueous layer was extracted twice with 250 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by rapid column chromatography (silica gel, hexane:EtOAc = 8:1) to give compound I, with a yield of 87.4% and a purity of 98.8%.

[0037] Example 6

[0038] Under nitrogen protection, compound III (18 g, 100 mmol) and PdCl2 (5.3 g, 30 mmol) were added to a reaction flask, followed by compound II (88.3 g, 300 mmol) and 200 mL of 1,4-dioxane. The reaction mixture was stirred and heated to 80 °C, and the reaction proceeded under TLC monitoring until the starting materials were fully reacted. After the reaction was complete, the mixture was cooled to room temperature, diluted with 500 mL of ethyl acetate, and washed with 500 mL of water. The aqueous layer was extracted twice with 250 mL of ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified by rapid column chromatography (silica gel, hexane:EtOAc = 8:1) to give compound I, with a yield of 85.6% and a purity of 98.5%.

[0039] The above describes specific embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A novel compound for preparing sodium montelukast intermediate, characterized in that, The compound is shown in Formula II: 。 2. A method for preparing montelukast sodium intermediate using the novel compound of claim 1, characterized in that, This method involves preparing the sodium montelukast intermediate of Formula I by combining the compound shown in Formula III with the aforementioned compound shown in Formula II in a solvent present in PdCl2. The synthetic route is as follows: ； The molar ratio of compound II, compound III, and PdCl2 is (3~7):1:(0.05~0.3).

3. The method according to claim 2, characterized in that, Choose from any one or more of the following conditions: (1) The solvent is one of dimethyl sulfoxide, toluene, xylene, N,N-dimethylformamide, 1,4-dioxane or N-methylpyrrolidone; (2) The reaction temperature is 80~160℃.

4. Use of the compound of formula II as described in claim 1 in the preparation of the sodium montelukast intermediate of formula I; ， 。

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