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Process for the preparation of leukotriene antagonists

A vinyl and crystallization technology, applied in the field of preparing 1-cyclopropylacetic acid precursor, can solve problems such as low yield, not particularly suitable for large-scale production, and unsatisfactory pharmaceutical preparations

Inactive Publication Date: 2007-12-05
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is not particularly suitable for large-scale production, as it requires lengthy chromatographic purification of the methyl ester intermediate and / or final product, and its yields are low
Also, the end products as sodium salts are obtained as amorphous solids, which are generally not ideal for pharmaceutical formulations

Method used

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  • Process for the preparation of leukotriene antagonists
  • Process for the preparation of leukotriene antagonists
  • Process for the preparation of leukotriene antagonists

Examples

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[0060] Scheme 3 depicts an improved process for the preparation of compounds of formula (I) contemplated by the present invention. In step (3a), the dilithium salt of 1-(mercaptomethyl)cyclopropylacetic acid is coupled with a sulfonate of formula (II). Thus, 1-(mercaptomethyl)cyclopropylacetic acid (VIII) was first converted to the dilithium dianion. This transformation is carried out by contacting the former with a lithium base such as n-butyllithium in hexane or heptane and the like. The reaction is carried out in an inert organic solvent such as THF, toluene or a mixture thereof at a temperature below 0°C, usually at about -5°C or lower.

[0061] The sulfonate (II) is then added to the solution of the dilithium dianion. The sulfonate can be added directly as a solid, or as a solution in an inert organic solvent such as THF or toluene, preferably THF. Due to the limited stability of the sulfonate (II) in solution, the sulfonate solution is preferably prepared just prior t...

Embodiment 1

[0080] 1,1-cyclopropyldimethanol cyclic sulfite

[0081] Method A:

[0082]To a 1 liter round bottom flask equipped with a stirrer, thermocouple, nitrogen inlet and syringe pump was added dichloromethane (645ml) and 1,1-cyclopropyldimethanol (10.64g; 97.93mmol). The mixture was stirred for 10 minutes to ensure complete dissolution. N,N-Diisopropylethylamine (34.21ml; 195.86mmol) was added and the solution was cooled to 0-5°C. Thionyl chloride (7.01 ml; 96.04 mmol) was added subsurface via a Teflon tube via a syringe pump over 60 minutes. The reaction solution was transferred to a separatory funnel containing cold (0-5°C) phosphate buffer (pH = 7.2, 650ml). After equilibration the layers were separated. The product solution in dichloromethane was washed with 2 wt % sodium chloride solution (650 ml), then the product solution was azeotropically dried and concentrated to 50 ml at 35-40° C. under atmospheric pressure. Assay yield of title compound = 13.07 g (90%)

[0083] Me...

Embodiment 2

[0087] 1-(Hydroxymethyl)cyclopropylacetonitrile

[0088] Method A:

[0089] A solution of the cyclic sulfite of Example 1 in dichloromethane (61 ml; 158.9 mg / ml; 9.69 g ) The solution was concentrated to about 20 ml by distillation at atmospheric pressure. Isopropyl acetate (2 x 30ml) was added and distillation continued to a final volume of 13ml. Dimethylformamide (21 ml) was added to the solution above 55°C and the solution was cooled to room temperature.

[0090] Add 40ml of cyclic sulfite (9.28g; 62.6mmol) in DMF:IPAc (isopropyl acetate) (4:1 ) in the above solution. Sodium cyanide (4.61 g; 94 mmol) and sodium iodide (3.75 g; 25.0 mmol) were added at room temperature. The reaction mixture was heated to 70±3°C and maintained at this temperature until the reaction was complete. The reaction mixture was allowed to cool to room temperature and diluted with cold (0-5°C) isopropyl acetate (187ml). The dark yellow slurry (218ml) was transferred to a separatory funnel conta...

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Abstract

The present invention relates to a process for the preparation of a compound of formula (I) or a sodium salt thereof, wherein HET is 7-chloroquinolin-2-yl or 6,7-difluoroquinolin-2-yl, which comprises: reacting the dilithium dianion of 1-(mercapto-methyl)cyclopropaneacetic acid with a compound of formula (II), wherein HET is as defined above and L is arylsulfonyl or alkylsulfonyl. The invention further provides the dicyclohexylamine salt of a compound of formula (I), an intermediate falling within (II) and a 1-(Mercaptomethyl)cyclopropaneacetic acid intermediate.

Description

[0001] This application is a divisional application of an invention patent application with a filing date of December 22, 1994, an application number of 98118381.6, and an invention title of "Preparation Method of a Leukotriene Antagonist". [0002] cross reference [0003] This application is a continuation-in-part of U.S.S.N. 08 / 174931 filed December 28, 1993, which application is incorporated herein by reference in its entirety. Background of the invention [0004] Leukotrienes constitute a group of locally acting hormones produced from arachidonic acid in living systems. The major leukotriene is leukotriene B 4 (abbreviated to LTB 4 ), LTC 4 ,LTD 4 and LTE 4 . The biosynthesis of these leukotrienes is initiated by the action of 5-lipoxygenase on arachidonic acid to produce known epoxides such as leukotriene A 4 (LTA 4 ), which are converted into other leukotrienes by subsequent enzymatic steps. More detailed biosynthesis and metabolism of leukotrienes can be found...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/18C07D215/14A61K31/47A61P11/06A61P29/00A61P37/08C07C215/14C07C313/02C07C323/53C07D215/12
CPCC07D215/14C07C323/53C07C2101/02C07C2601/02A61P11/06A61P29/00A61P37/08
Inventor M·布帕斯J·M·麦南马拉D·R·西德勒R·P·沃兰蒂J·J·伯根
Owner SCHERING AG
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