WO2013105688A1 - Method for preparing 1-(1'-(carboxymethyl)cyclopropane methyl disulfonyl methyl)cyclopropane acetic acid and derivative thereof - Google Patents

Abstract

The present invention relates to a novel method for preparing 1-(1'-(carboxymethyl)cyclopropane methyl disulfonyl methyl)cyclopropane acetic acid and derivatives thereof which are precursors of 1-(mercaptomethyl)cyclopropane acetic acid, an important material for the synthesis of a pharmaceutical - especially Montelukast which is an antiasthmatic - in an industrially efficient way. The present invention provides a novel method for preparing 1-(1'-(carboxymethyl)cyclopropane methyl disulfonyl methyl)cyclopropane acetic acid and derivatives thereof characterized by reacting disodium disulfide salt with cyclopropane acetic acid derivatives appropriate for substitution by a mercapto group.

Description

1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid and its derivative

The present invention relates to 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl), which is a precursor of intermediate 1- (mercaptomethyl) cyclopropaneacetic acid, which is important in the synthesis of pharmaceuticals, in particular the asthma drug' Montelukast ' It relates to a method for producing cyclopropane acetic acid (1) and derivatives thereof ((2), (3)].

Conventional methods related to the preparation of 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid of the above formula (1) are described in US Pat. No. 6,512,140. As in 1, 1- (hydroxymethyl) cyclopropaneacetonitrile of formula (4) is stirred in the presence of an inorganic acid such as bromic acid to form an iminoester of formula (5) or a bromoamide compound of formula (6) These mixtures were reacted with thiourea to prepare and separate the 'carbaimidosulfanyl amide salt' of formula (7), alkali hydrolyze them, oxidize with hydrogen peroxide and neutralize the target compound 1- (1 '-(carboxymethyl). It was reported that cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid (1) can be prepared.

<Scheme 1>

However, in this manufacturing process, anhydrous reaction of bromic anhydride, which is difficult to apply industrially, is required to suppress the formation of by-products, and the overall manufacturing process is long, so that the yield is generally low. This is necessary.

In the present invention, in order to overcome the industrial difficulties of the existing process, the intermediate is reacted with disodium disulfide (Na ₂ S ₂ ) which can be manufactured very easily from the intermediate (8), which is easy to manufacture, as in Scheme 2. After the synthesis of the disulfide compound of (9), it was hydrolyzed to develop a novel production method for simply preparing the target compound (1).

<Scheme 2>

X in Scheme 2 includes halogen atoms such as chlorine, bromine, iodine or sulfonate groups such as methanesulfonate, toluenesulfonate that are easily released in substitution reaction with disodium disulfide.

In Scheme 2, Y is a carboxylic acid derivative such as a cyano group or an ester group, and the ester group includes ester groups which are easily hydrolyzed, such as methyl ester, lower alkyl ester such as ethyl ester or aryl ester such as phenyl ester if necessary.

The present invention provides an efficient precursor 1- (1 '-(carboxymethyl) cyclopropanemethyl that makes it easy to prepare 1- (mercaptomethyl) cyclopropaneacetic acid, which is a major ingredient in the manufacture of medicines such as montelukast. Disulfanylmethyl) cyclopropaneacetic acid and its derivatives are useful inventions that facilitate the industrial production of pharmaceuticals such as the asthma drug 'montelukast' by providing a novel manufacturing process that can effectively prepare them.

The present invention provides a disulfide compound of the following formula (9) by reacting a cyclopropaneacetic acid derivative of the following formula (8) with disodium disulfide (Na ₂ S ₂ ), and alkali hydrolysis of the formula (1) Process for the preparation of 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid:

Wherein X is a halogen atom such as chlorine, bromine or iodine or sulfonate groups such as methanesulfonate and toluenesulfonate which are easily released in substitution reaction with disodium disulfide, and Y is carboxy such as cyan group or ester group As the acid derivative, the ester group includes ester groups that are easily hydrolyzed, such as lower alkyl esters such as methyl ester and ethyl ester or aryl esters such as phenyl ester if necessary.

Solvents used in the substitution reaction of disodium disulfide include polar organic solvents such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, nitriles such as acetonitrile and ketones such as acetone. Or mixed solvents of these organic solvents or mixed solvents with water.

Compound (8) in Scheme 2, a raw material of the present invention, is first halogenated or sulfonated from 1- (hydroxymethyl) cyclopropaneacetonitrile of Structural Formula (4), which is commercially available, as shown in Scheme 3 below. The compound of formula 10 obtained by substitution with leaving group X, which is advantageous for the substitution reaction, is used as a raw material of Scheme 2, or the compound of formula (10) thus synthesized is alcoholized in an alcohol solution of hydrochloric acid and esterified by alkali neutralization. The compound of Structural Formula (11) can be prepared and used as a raw material of Scheme 2.

<Scheme 3>

X in Scheme 3 includes halogen atoms such as chlorine, bromine and iodine or sulfonate groups such as methanesulfonate and toluenesulfonate that are easily released in substitution with disodium disulfide.

In Scheme 3, Y refers to derivatives of organic acids such as esters and cyan groups, and esters include alkyl esters and aryl esters which are easily hydrolyzed as inorganic bases such as caustic soda, sodium carbonate, potassium hydroxide and potassium carbonate.

In the case of alkyl esters, industrially easy to handle alkyl esters having 1 to 6 carbon atoms are advantageous, and in the case of aryl esters, industrially easy to handle phenyl or substituted phenyl esters are advantageous.

In the hydrolysis reaction in Reaction Scheme 2, which is a simple description of the present invention, when Y is an ester substituent in the compound of Structural Formula (9), it is an inorganic base that is easily commercially available such as caustic soda, sodium carbonate, potassium hydroxide, and potassium carbonate. Hydrolysis yields 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid of Structural Formula (1) as a target compound.

In the hydrolysis reaction of Scheme 2, when Y is a cyan group in the compound of formula (9), after alcoholation reaction in an alcohol solution of hydrochloric acid, it is hydrolyzed by inorganic base such as caustic soda, sodium carbonate, potassium hydroxide, potassium carbonate, etc. 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid of formula (1) is obtained.

Sodium disulfide used in the present invention is a commercially available sodium sulfide hydrate (Na ₂ S ₂ .7H ₂ 0) and sulfur using the manufacturing method mentioned in 'Journal of the chemical society 1930. 1473 ~ 1497'. It was prepared by heating the reaction under ethanol solvent.

Hereinafter, the present invention will be described in detail with reference to Examples, but the following Examples are merely illustrative of the present invention and are not intended to limit the present invention.

Hereinafter, the present invention will be described in detail with reference to Examples, but the following Examples are merely illustrative of the present invention and are not intended to limit the present invention.

Example 1.

Preparation of 1- (1'-cyanocyclopropanemethyldisulfanylmethyl) cyclopropaneacetonitrile

27.8 g (0.25 mole) of 1- (hydroxymethyl) cyclopropaneacetonitrile and 31.4 g (0.275 mole) of methanesulfonyl chloride were added to 150 ml of dichloromethane, and 37.9 g (0.375 mole) of triethylamine was added dropwise with stirring at 0 ° C. After stirring at 0 ° C. for about 2 hours. When the reaction is completed by gas chromatography analysis, the reaction solution is adjusted to pH 3 or below with 5% aqueous hydrochloric acid solution and the layers are separated. The organic layer was neutralized to pH 7-8 with 5% aqueous sodium hydroxide solution, the layers were separated, the organic layer was washed with 100 ml of H ₂ O, the organic layer was removed with anhydrous forget-me-not, filtered and the filtrate was concentrated under reduced pressure. 23.4 g (0.124 mol) of 1- (methanesulfonyloxymethyl) cyclopropaneacetonitrile as a light off-white liquid were obtained.

 22.7 g (0.12 mole) of this concentrate was dissolved in 100 ml of DMF, 5.45 g (0.05 mole) of disodium disulfide was added, followed by stirring at 90 ° C. for about 8 hours to confirm completion of the reaction by gas chromatography analysis. The reaction solution was adjusted to pH 3 or less with 5% aqueous hydrochloric acid solution, and extracted with 100 ml of dichloromethane. The organic layer was neutralized to pH 7-8 with 5% aqueous sodium hydroxide solution, and then the organic layer was separated. The organic layer was removed with anhydrous forget-me-not, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.4 g (0.045 mol) of pale brown liquid 1- (1'-cyanocyclopropanemethyldisulfanylmethyl) cyclopropaneacetonitrile.

1 H NMR (CDCl ₃ , 300 MHz): δ 0.52-0.57 (8H, m); 2.49 (4H, s); 3.42 (4H, s)

Example 2.

Preparation of 1- (1 '-(carbomethoxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid methyl ester

11.4 g (0.045 mol) of 1- (1'-cyanocyclopropanemethyldisulfanylmethyl) cyclopropaneacetonitrile obtained in Example 1 was added to 100 ml of a methanol solution in which 6.48 g of hydrochloric acid was dissolved, followed by stirring at 70 ° C. for 8 hours. . After completion of the reaction by gas chromatography analysis, the solvent is concentrated and dissolved in 100 ml of dichloromethane. After neutralizing the pH of the reaction to 7-8 with an aqueous 5% caustic soda solution, the organic layer was separated and the separated organic layer was washed with 100 ml of water. The organic layer was dried over anhydrous forget-me-not, filtered, and the filtrate was concentrated under reduced pressure to give 25.2 g (0.036 mol) of 1- (1 '-(carbomethoxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid methyl ester as a pale brown liquid. Got.

1 H NMR (CDCl ₃ , 300 MHz): δ 0.50-0.62 (8H, m); 2.41 (4H, s); 2.86 (4H, s); 3.64 (6H, s)

Example 3.

Preparation of 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid

The 1- (1 '-(carbomethoxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid methyl ester concentrate obtained in Example 2 was dissolved in 70 ml of methanol, and caustic soda 3.1 g (0.078 mol) was added to reflux for 6 hours. Stirring reaction. When gas chromatography confirmed that the reaction product was consumed, 100 ml of ethyl acetate and 200 ml of water were added thereto, stirred for 30 minutes, and the layers were separated. 150 ml of dichloromethane was added to the separated water layer and neutralized with 5% aqueous hydrochloric acid solution to pH 3-4. The organic layer was separated, dried over anhydrous forget-me-not, filtered and the filtrate was concentrated under reduced pressure to give an off-white solid 1- (1 '-(carboxymethyl). 8.7 g (0.03 mol) of cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid was obtained.

1 H NMR (CDCl ₃ , 300 MHz): δ 0.52-0.57 (8H, m); 2.27 (4H, s); 2.90 (4H, s); 12.14 (2H, s)

Example 4.

Preparation of 1- (1 '-(carbomethoxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid methyl ester via methyl 1- (bromomethyl) cyclopropaneacetate

11.1 g (0.1 M) of 1- (hydroxymethyl) cyclopropaneacetonitrile is dissolved in 33 ml of dichloromethane and 27.9 g (0.102 M) of phosphorus tribromide is slowly added dropwise while stirring at 10 ° C, followed by stirring at 10 ° C for 4 hours. Confirm the reaction completion by gas chromatography analysis and neutralize the reaction solution with 5% aqueous sodium carbonate solution. The separated organic layer was washed with 50 ml of water, the organic layer was dried with anhydrous anhydrous forage, filtered and the filtrate was concentrated under reduced pressure to give 15.6 g (0.089 mol) of pale brown 1- (bromomethyl) cyclopropaneacetonitrile. Obtained in the liquid phase.

   Dissolve 25.8 g of hydrochloric acid in 135 ml of anhydrous methanol, add 15.6 g (0.89 mole) of 1- (bromomethyl) cyclopropaneacetonitrile obtained above, stir at 70 ° C. for 12 hours, and exhaust the reaction product by gas chromatography analysis. Check it. The reaction solution is concentrated in vacuo, dissolved in 180 ml of dichloromethane and neutralized to pH 7-8 with 5% aqueous sodium hydroxide solution. The organic layer was separated, dried with anhydrous forget-me-not, filtered, and the filtrate was concentrated under reduced pressure to obtain 13.1 g (0.063 mol) of methyl 1- (bromomethyl) cyclopropane acetate as a pale brown liquid.

This methyl 1- (bromomethyl) cyclopropane acetate concentrate and 3.3 g (0.03 mol) of disodium disulfide were added to 130 ml of DMF and stirred at 90 ° C. for about 8 hours. Confirm the completion of the reaction by gas chromatography analysis, adjust the pH to 3-4 with 5% hydrochloric acid aqueous solution, and neutralize the separated organic layer to pH 7-8 with 5% aqueous sodium hydroxide solution. The organic layer was separated, dried over anhydrous forget-me-not, filtered, and the filtrate was concentrated under reduced pressure to give 7.56 g of 1- (1 '-(carbomethoxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid methyl ester of a liquid. 0.024 mole).

1 H NMR (CDCl ₃ , 300 MHz): δ 0.50-0.62 (8H, m); 2.41 (4H, s); 2.86 (4H, s); 3.64 (6H, s)

Preparation of Disodium Disulfide

50 g of sodium sulfide hexahydrate (Aldrich, 98%) was dissolved in 500 ml of ethanol, and 7.5 g of sulfur was added thereto, followed by heating under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and 500 ml of ethanol was further added thereto, followed by concentration under reduced pressure to remove moisture. The resulting solid compound disodium disulfide was added to the required reaction.

Preparation of 1- (mercaptomethyl) cyclopropaneacetic acid

8.7 g (0.03 mol) of 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropane acetic acid obtained in Example 3 and 3.8 g (0.06 M) of powdered zinc were added to 45 ml of methanol, followed by stirring. 4.5g, 0.09M) was added slowly, followed by vigorous stirring at room temperature for 12 hours, followed by gas chromatography analysis. The reaction solution was filtered, concentrated under reduced pressure, dissolved in 100 ml of dichloromethane and neutralized to pH 7-8 with 5% aqueous hydrochloric acid solution. The organic layer is separated and the separated organic layer is dried with anhydrous forget-me-not. Filtration and concentration of the filtrate under reduced pressure afforded 3.5 g (0.024 mol) of 1- (mercaptomethyl) cyclopropane acetic acid as a pale brown solid.

1 H NMR (CDCl ₃ , 300 MHz): δ 0.54-0.64 (4H, m); 1.3 (1 H, t); 2.48 (2H, d); 2.6 (2H, d)

The present invention relates to 1- (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl), which is a precursor of intermediate 1- (mercaptomethyl) cyclopropaneacetic acid, which is important in the synthesis of pharmaceuticals, in particular the asthma drug' Montelukast ' It can be usefully used to prepare cyclopropane acetic acid and its derivatives.

Claims (5)

1. 1- of Structural Formula (1) characterized by reacting a cyclopropaneacetic acid derivative of Structural Formula (8) with disodium disulfide (Na ₂ S ₂ ) to prepare a disulfide compound of Structural Formula (9) and alkali hydrolysis thereof (1 '-(carboxymethyl) cyclopropanemethyldisulfanylmethyl) cyclopropaneacetic acid

   

   Wherein X is a halogen atom or a sulfonate group, and Y is an organic acid derivative.
2.        The method according to claim 1, wherein Y is an inorganic base such as caustic soda, sodium carbonate, potassium hydroxide or potassium carbonate, and is an alkyl ester or an aryl ester which is easily hydrolyzed.
3.        The solvent used in the substitution reaction of disodium disulfide is a polar organic solvent such as dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, alcohols such as methanol and ethanol, nitrile such as acetonitrile. And a ketone such as acetone, a mixed solvent of these organic solvents, or a mixed solvent with water.
4.       The method according to claim 2, wherein the alkyl ester is an alkyl ester having 1 to 6 carbon atoms, and the aryl ester is phenyl or substituted phenyl ester.
5.        The method according to claim 1, wherein the alkali used for alkali hydrolysis is an inorganic base selected from the group consisting of caustic soda, sodium carbonate, potassium hydroxide, potassium carbonate, lithium hydroxide and lithium carbonate.