Synthesis method of montelukast sodium intermediate

A technology of montelukast sodium and its synthesis method, which is applied in the field of pharmaceutical chemical synthesis, can solve the problems of cumbersome process steps, no treatment of three wastes, and low yield, and achieve the effects of simple process steps, high industrial value and low cost

Pending Publication Date: 2021-03-02
SHENZHEN CATALYS SCI & TECH CO LTD +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The embodiment of the present invention provides a method for synthesizing the intermediate of montelukast sodium, aiming to solve the common problems in the synthesis method o

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  • Synthesis method of montelukast sodium intermediate
  • Synthesis method of montelukast sodium intermediate
  • Synthesis method of montelukast sodium intermediate

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preparation example Construction

[0022] In the embodiment of the present invention, the synthesis method of the intermediate of montelukast sodium includes:

[0023] 1,2-dibromobenzene, 1,2-diiodobenzene, 1,2-dichlorobenzene or methyl 2-bromobenzoate, methyl 2-iodobenzoate, methyl 2-chlorobenzoate in tetrahydrofuran Under the action of , react at the temperature of -88°C ~ -68°C and -10°C ~ 10°C respectively to generate compound II, the reaction is as follows:

[0024]

[0025] Compound IV and compound V are condensed under the action of acetic anhydride and triethylamine to obtain compound VI, wherein the reaction temperature is 100°C to 120°C, and toluene or xylene is used as a solvent for 8 to 12 hours. The reaction is as follows:

[0026]

[0027] Compound VI is reacted with tetrahydrofuran as a solvent under the action of vinylmagnesium bromide at a temperature of -30°C to -10°C to generate compound VII, and the reaction is as follows:

[0028]

[0029] Compound VII and the compound II are cond...

Embodiment 1

[0065] Embodiment 1: Preparation of compound II (taking 1,2-dibromobenzene as an example)

[0066] Add 1,2-dibromobenzene (118g, 0.5mol) into anhydrous tetrahydrofuran (1L), stir and cool down to -78°C, add n-butyllithium (220mL, 2.5mol / L n-hexane as solvent) dropwise, continue After stirring for 1 h, anhydrous acetone (29 g) was added dropwise. After the dropwise addition was completed, the temperature was slowly raised to -30° C., and stirring was continued for 3 h. The reaction was quenched by adding water, and the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 100 g (yield 93%) of a nearly colorless liquid, which was compound II.

Embodiment 2

[0067] Embodiment 2: the preparation of compound II (taking 2-bromobenzoic acid methyl ester as example)

[0068] Methyl 2-bromobenzoate (226g, 1.05mol) was dissolved in THF (1.6L), and 3MCH was added dropwise in an ice-water bath 3 MgBr (1.05 L, 3.15 mol) was added dropwise to form an off-white slurry liquid, which was slowly raised to room temperature and stirred until the reaction was completed. Under ice-water bath conditions, use HCl (4.5L, 0.5 M, 2.25mol) to slowly quench the reaction, after the addition is complete, continue stirring for 0.5h, then add 2N HCl (0.5 L, 1.00mol) to make the pH value 5-6 . Add MTBE (1L), separate the organic phase, then extract the aqueous phase with MTBE (2×0.5L), combine the organic phases, wash with sodium bicarbonate solution (2×0.3L), dry over anhydrous sodium sulfate, filter, and concentrate , 222 g (98.2% yield) of compound II was obtained as a solid.

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Abstract

The invention is applicable to the technical field of medicine synthesis, and provides a synthesis method of a montelukast sodium intermediate. The method comprises the following steps of: generatinga compound II from halogenated benzene under the action of tetrahydrofuran, condensing a compound IV and a compound V under the action of acetic anhydride and triethylamine to obtain a compound VI, and generating a compound VII from the compound VI under the action of vinyl magnesium bromide, condensing the compound VII and the compound II under the action of tris(o-methylphenyl)phosphorus, palladium acetate and triethylamine to obtain a compound VIII, and reacting the compound VIII under the action of a catalyst, a reaction solvent and alkali to generate the montelukast sodium intermediate IX. The synthesis method has the advantages of simple process steps, improvement of the synthesis route, shortening of the reaction steps, low cost, extremely high conversion rate and selectivity, highatom economy, environmental protection, and extremely high industrial value.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a synthesis method of a montelukast sodium intermediate. Background technique [0002] Montelukast sodium is an orally effective leukotriene receptor antagonist, which can specifically inhibit the cysteinyl leukotriene (CysLT1) receptor in the airway, block the action of allergic mediators, improve respiratory inflammation, It can unblock the airway and is a safe, efficient, and low-toxic antiasthmatic and antiallergic drug. [0003] The preparation of montelukast sodium usually requires the conversion of aryl ketones into chiral alcohols. At present, the conventional method for the preparation of the key intermediate chiral alcohol of montelukast sodium is as follows: [0004] [0005] That is, compound 4 was prepared by condensation of 7-chloroquinaldine and m-phthalaldehyde through conventional reaction, followed by Grignard reaction with ...

Claims

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Application Information

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IPC IPC(8): C07C29/143C07C33/48
CPCC07C29/143C07C45/512C07D215/18C07C33/486C07C49/835
Inventor 郑勇鹏赵金辉刘创基
Owner SHENZHEN CATALYS SCI & TECH CO LTD
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