Process for the preparation of a leukotriene antagonist and intermediates thereof

A solvate, phase transfer catalyst technology, applied in the preparation of montelukast sodium salt, a new intermediate, the international non-proprietary name field of propane acetic acid, can solve the problem of lengthy chromatographic purification, not suitable for large-scale production, intermediate The problem of low yield of body and final product, etc., to achieve the effect of high chemical and optical purity and high yield

Inactive Publication Date: 2008-12-10
ESTEVE QUIMICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method is less suitable for large-scale production as it requires lengthy chromatographic purification of methyl ester intermediates and / or final products and yields low yields of intermediates and final products

Method used

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  • Process for the preparation of a leukotriene antagonist and intermediates thereof
  • Process for the preparation of a leukotriene antagonist and intermediates thereof
  • Process for the preparation of a leukotriene antagonist and intermediates thereof

Examples

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Effect test

preparation example Construction

[0054] The preparation of compounds of formula (VIII) involves the reaction of compounds of formula (XI) with potassium ethanethioate to give compounds of formula (X). Typically, this reaction is carried out using an excess of potassium thioacetate in a suitable solvent. Examples of suitable solvents include dimethylsulfoxide, dimethylformamide, ethyl acetate, acetonitrile or mixtures thereof. Preferably, the reaction is carried out at a temperature between room temperature and 70°C. After isolation of the compound of formula (X), it is hydrolyzed using an acid or base catalyst to give the compound of formula (VIII). Examples of suitable acids are hydrochloric acid, sulfuric acid, acetic acid and formic acid. Examples of suitable bases are hydroxides, carbonates and alkoxylates of alkali metals and alkaline earth metals. An example of a suitable solvent is (C 1 -C 6 )-alcohol, (C 6 -C 8 )-aromatic hydrocarbons, dimethylformamide, dimethylsulfoxide or mixtures thereof. ...

Embodiment 1

[0058] Embodiment 1: the preparation of S-(1-(hydroxymethyl) cyclopropyl) methyl thioacetate (X)

[0059] 200 g of 5,7-dioxa-6-thiaspiro[2.5]octane 6-oxide was dissolved in 1.2 liters of dimethylsulfoxide, and 308 g of potassium thioacetate was poured into the solution. The suspension was then heated at 40 °C for 5. Once the reaction was complete, a combination of 3.6 liters of ethyl acetate and 3.6 liters of water was added. The organic phase was separated, washed with water and concentrated to dryness in vacuo. 200 g of S-(1-(hydroxymethyl)cyclopropyl)methylthioacetate were recovered. Yield corrected by GC: 78%. 1 H NMR (400MHz, CDCl 3 ): 3.45 (2H, d, J: 6.4 Hz); 3.01 (2H, s); 2.53 (OH, broad triplet, J: 6.4 Hz); 2.39 (3H, s); 0.54 (4H, m).

Embodiment 2

[0060] Embodiment 2: the preparation of (1-(mercaptomethyl) cyclopropyl) methanol (VIII)

[0061] 200 g of S-(1-(hydroxymethyl)cyclopropyl)methylthioacetate were dissolved in 2 liters of methanol. Then 111 ml of concentrated HCl were added under nitrogen atmosphere and the solution was stirred at room temperature for 10. The solvent was distilled off and the residue was redissolved in 1.5 liters of dimethylformamide for the preparation of 2-((R)-3-(3-((E)-2-(7-chloroquinoline-2- yl)vinyl)phenyl)-3-(((1-(hydroxymethyl)cyclopropyl)methyl)thio)propyl)methyl benzoate. Yield: 100%. 1 H NMR (400MHz, CDCl 3 ): 3.57 (2H, s); 2.63 (2H, d, J: 8.0 Hz); 2.45 (OH, broad singlet); 1.43 (SH, t, J: 8.0 Hz); 0.52 (4H, m).

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Abstract

It comprises a preparation process of Montelukast from an intermediate compound of formula (V), which is previously prepared by reaction of the corresponding sulfonate with 1-(mercaptomethyl)cyclopropyl)methanol. Compound (V) is reacted with a Grignard reactant to convert the ester group into a tertiary alcohol, followed by conversion of the primary alcohol into a sulfonate, substitution of the sulfonate group by a cyano group, and finally transforming the cyano compound to the carboxilic acid compound by a hydrolysis reaction to afford Montelukast. Montelukast can also be prepared by a hydrolysis reaction of the corresponding amide. It also comprises intermediate compounds useful in such preparation process.

Description

[0001] The present invention relates to a process for the preparation of montelukast, as well as certain novel intermediates useful in this process. Background technique [0002] Montelukast is (1-[[[(1R)-1-[3-[(1E)-2-(7-chloro-2-quinolinyl)vinyl]phenyl]-3-[2- International Nonproprietary Name of (1-Hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid with CAS Registry No. 158966-92-8.Montelukast monosodium Salt (CAS Registry No. 151767-02-1) is currently used in the treatment of asthma, inflammation, angina, cerebral spasm, glomerulonephritis, hepatitis, endotoxemia, uveitis, and allograft rejection. [0003] The structure of montelukast monosodium salt is formula (I): [0004] [0005] Different synthetic strategies are known for the preparation of montelukast and its salts. EP 480.717 discloses certain substituted quinolone compounds including montelukast sodium salt, processes for their preparation, and pharmaceutical compositions using these compou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18
CPCA61P1/16A61P7/00A61P9/10A61P11/06A61P13/12A61P25/00A61P27/02A61P29/00A61P37/06C07D215/18
Inventor L·考彼M·巴特拉桑玛特提Y·加桑斯古伦M·蒙萨尔瓦特吉拉古斯特拉P·塔拉维拉埃斯卡萨尼
Owner ESTEVE QUIMICA
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