KR101881918B1 - New process for the synthesis of acylsulfonamides derivatives - Google Patents

Abstract

The present invention relates to a process for synthesizing acylsulfonamides which are useful as intermediates for synthesizing drugs necessary for the treatment of diseases such as Alzheimer's or are useful as special intermediates which can selectively participate in the N-acylation reaction, Methods are a harsh reaction condition in which a carboxyl group is activated to activate a carboxyl group and then heated to a high temperature and reacted with sulfonamide for a long time to synthesize an acylsulfonamide, or an organic acid is transformed into an anhydrous form The organic acid is reacted with sulfonamide in the presence of an organic base and triphosgene at a mild reaction condition of 5 ° C to 25 ° C to obtain acyl sulfonamide in a high reaction rate within a short reaction time of about 1 hour, Can be manufactured with high purity This will contribute greatly to the development of medicines, medicinal intermediates and related fine chemicals that require them.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel process for preparing acylsulfonamide derivatives,

The present invention provides a novel method for synthesizing acylsulfonamides which are useful as intermediates for synthesizing drugs necessary for the treatment of diseases such as Alzheimer's or as special intermediates which can selectively participate in N-acylation reactions.

The usefulness of acylsulfonamides has long been recognized and efforts have been made to find a suitable synthesis method in many parts of the world. Graham Johnson et al., 1988, in a paper published in Tetrahedron Letters, vol. 29, p. 1653, , The carboxylic acid group of the amino acid was activated by using carbodiimidazole and heated with toluene sulfonamide for a long time to obtain acylated sulfonamide. Although this method has suggested a direct reaction with carboxylic acid from the sulfonamide, it is necessary to use an activator to activate the carboxylic acid, and the reaction temperature must be heated. In the presence of functional groups with poor thermal stability, Deformation can occur and reaction time is relatively long, which is not suitable for industrial manufacturing methods.

 In Marvin J. Miller et al., 1994, Tetrahedron 50, No. 28, No. 8292, a compound having a carboxylic acid in the side chain of beta- lactam was used as an excess amount of N, N-dimethylaminopyridine, The water-soluble carbodiimide was used as a carboxylic acid activating agent and the mixture was stirred at room temperature for 48 hours in toluene sulfonamide and methylene chloride solvent to obtain an acylsulfonamide. This method has progressed to the extent that it reacts at room temperature without heating compared to the method proposed by Graham Johnson, et al., But it also lacks the industrial usefulness of using an activator and requiring a reaction time of 48 hours or more.

 Shriniwas D. Samant et al., In a paper published in Tetrahedron Letters, vol. 45, pp. 4805, 2004, using a specific catalyst, iron-exchanged montmorillonite K10, to convert organic compounds and sulfonamide derivatives in the acid anhydride form to acetonitrile Was reacted at 60 deg. C using a solvent to obtain acylsulfonamide. This method has the advantage of not using an activating agent separately, but it is pointed out that it is a fatal disadvantage that the organic acid can not be used directly but the organic acid can be transformed in an anhydrous form.

 Chada R. Reddy et al. In 2007 published Tetrahedron Letters, Vol. 48, p. 7528, found that acyl sulfonamides were obtained by reacting sulfonamide derivatives with organic compounds in acid anhydride form using Lewis acids such as zinc chloride or titanium chloride . Although this method has the advantage of using industrialized industrial catalysts, it also has a fatal problem in that it can not be used directly but transformed into an anhydrous form.

As described above, the conventional methods for preparing acylsulfonamide derivatives, when using an organic acid, require not only an activating agent for activating the carboxylic acid group but also a compound having a carboxylic acid and a sulfonamide In the method in which acylsulfonamide is obtained by reacting an acid anhydride with an acid anhydride in a severe manner such as boiling for a long time, although the reaction can proceed at relatively mild conditions near room temperature, a long reaction time of 48 hours or more is required , It is pointed out that it is a fatal problem that the organic acid can not be directly used but must be transformed into an acid anhydride form.

The inventors of the present invention, which have been aware of various problems of the conventional methods for producing acylsulfonamides, have proposed a method for synthesizing acylsulfonamide derivatives by directly reacting an organic acid having an acyl group to be acylated with sulfonamide under special conditions, As a result, the present inventors have completed the present invention by devising a method capable of producing acylsulfonamide at a mild reaction temperature near room temperature and a short reaction time within 1 hour.

The present invention relates to an acylsulfone of the formula (IV), which is characterized in that an organic acid represented by the formula (I) is reacted with a sulfonamide of the formula (III) in the presence of an organic base with a triphosgene of the formula Amide derivative.

 In the above formula

R ₁ represents a remaining portion including a protected amine group excluding a carboxyl group in an amino acid, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, and an aralkyl group,

R ₂ represents an alkyl group having 1 to 10 carbon atoms or an aryl group or an aralkyl group having 6 to 15 carbon atoms.

 The present invention can complete the reaction within a short reaction time of 1 hour or less in a mild reaction temperature range of 5 to 25 ° C, and obtain acyl sulfonamide with high yield and high purity.

As described above, the novel process for preparing an acyl sulfonamide derivative of the present invention as described above has the following drawbacks of conventional methods: activation of a carboxyl group using a carboxyl group activating agent, heating to a high temperature and reaction with a long- The present inventors have dramatically improved the harsh reaction conditions for synthesizing sulfonamides and completely solved the fatal problem of the conventional method in which the organic acid was not directly used but reacted with the sulfonamide after being transformed into the anhydrous form and the mild reaction It is believed that the present invention provides a method for producing acylsulfonamide at a high yield and a high purity within a short time of 1 hour under the conditions, thereby contributing greatly to the development of pharmaceuticals, medicinal intermediates and related fine chemicals.

The present invention relates to an acylsulfone of the formula (IV), which is characterized in that an organic acid represented by the formula (I) is reacted with a sulfonamide of the formula (III) in the presence of an organic base with a triphosgene of the formula Amide derivative.

 In the above formula

R ₁ represents a remaining portion including a protected amine group excluding a carboxyl group in an amino acid, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 15 carbon atoms, and an aralkyl group,

R ₂ represents an alkyl group having 1 to 10 carbon atoms or an aryl group or an aralkyl group having 6 to 15 carbon atoms.

Examples of amino acids containing protected amines among the kinds of organic acids of formula (I) include the following compounds.

The triphosgene of formula (II) can be used as a cyclic carbonate synthesis reagent from 1,3-cyclic diol as disclosed by Burk et al. In Tetrahedron Letters, vol. 34, p. 395, 1993, or runqiu et al., 2000, J. Organometallic Chem. 604, page 287. As reported by Alkhathlan in Tetrahedron, vol. 59, p. 8163, in 2003, when a benzoxazinone derivative was synthesized from 2-hydroxyacetophenone hydrazone, dehydration reaction and ring The conditions under which acylsulfonamide derivatives can be prepared with reagents mainly used in the reaction are first identified and developed by the present inventors.

The triphosgene of the formula (II) can be reacted using 0.33 to 1.0 molar times of the organic acid used in formula (I), preferably 0.4 to 0.6 molar equivalents.

In addition to triphosgene, it is necessary to use organic bases to obtain acylsulfonamides. As organic bases usable herein, tertiary amines such as triethylamine and tributylamine can be used. In addition, pyridine, N, N-dimethylaniline And the like can also be used. At this time, the amount of the organic base to be used is 2 to 9 molar times, preferably 3 to 6 molar times, based on the organic acid of the formula (I).

As the reaction solvent, most organic solvents such as chloroform, dichloromethane, ethylene dichloride, ethyl acetate, toluene, benzene, tetrahydrofuran and the like can be used. During the reaction for obtaining the aimed compound, neutralization reaction of organic base and hydrochloric acid Dichloromethane which is convenient for removing the resulting salt by filtration is preferred as a reaction solvent.

The reaction temperature is in the range of 0 ° C. to 30 ° C., preferably 5 ° C. to 25 ° C. The reaction is carried out in a simple manner. The organic acid of formula (I) is dissolved in a reaction solvent, (III) and then the ice bath is removed. The temperature is raised to room temperature, and the mixture is stirred for about 1 hour. Then, the mixture is cooled to room temperature and then the triphosgene of formula (II) , It can be confirmed that the acyl sulfonamide formation reaction of the target compound (IV) is completed.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the Examples.

Example 1

Add 2.092 g (10.0 mmole) of glycine protected with an amine in a benzyloxycarbonyl group to a 100 mL three-necked flask and add 20 mL of dichloromethane. The mixture is stirred for about 5 minutes at room temperature. Thereafter, the internal temperature was adjusted to about 5 ° C by cooling in the outside using an ice water bath, and then 1.484 g (5.0 mmole) of triphosgene and 3.036 g (30 mmole) of triethylamine were added in turn, Stir at that temperature.

0.9512 g (10.0 mmole) of methanesulfonamide was added thereto, and the mixture was stirred for about 5 minutes. Then, the ice water bath was removed, and the mixture was stirred at room temperature for about 1 hour to confirm that the reaction was completed by thin film chromatography (TLC) .

After confirming the completion of the reaction, the solid salt formed by the neutralization reaction of triethylamine and hydrochloric acid produced as a byproduct is removed by filtration, and the resulting solution is subjected to vacuum distillation to remove the solvent, whereby acyl sulfoneamide (Yield: 94.0%).

The obtained acylsulfonamide can be used as an intermediate for the next reaction. However, purification by column chromatography yields a pure solid which dissolves at around 155 ° C.

Example 2

Add 1.22 g (10.0 mmole) of benzoic acid and 12 mL of chloroform to a 50 mL three-necked flask and stir at room temperature for about 5 minutes. Thereafter, the internal temperature was adjusted to about 5 ° C by cooling in the outside using an ice water bath, and then 1.484 g (5.0 mmole) of triphosgene and 3.036 g (30 mmole) of triethylamine were added in turn, Stir at that temperature.

0.9512 g (10.0 mmole) of methanesulfonamide was added thereto, and the mixture was stirred for about 5 minutes. Then, the ice water bath was removed, and the mixture was stirred at room temperature for about 1 hour to confirm that the reaction was completed by thin film chromatography (TLC) .

After confirming the completion of the reaction, the reaction solvent was distilled off under reduced pressure, and 15 mL of water was added to the resulting solid to dissolve the solid salt formed by the neutralization reaction of triethylamine and hydrochloric acid produced as a by-product, and the desired compound, acylsulfonamide Dispersed in a solid form and stirred. After filtration, the filtrate was removed, washed with water, and the obtained solid was dried to obtain 1.89 g (yield: 94.9%) of the target compound, acylsulfonamide, as a solid.

Acylsulfonamide thus obtained can be used in the next reaction as an intermediate, but when purified by column chromatography, a pure solid which dissolves at around 149 ° C is obtained.

Example 3

Add 2.092 g (10.0 mmole) of glycine protected with an amine in a benzyloxycarbonyl group to a 100 mL three-necked flask and add 30 mL of dichloromethane, and stir for 5 minutes at room temperature. Thereafter, the internal temperature was adjusted to about 5 ° C by cooling in the outside using an ice water bath, and then 1.484 g (5.0 mmole) of triphosgene and 3.036 g (30 mmole) of triethylamine were added in turn, Stir at that temperature.

1.712 g (10.0 mmole) of paratoluenesulfonamide was added thereto, and the mixture was stirred for about 5 minutes. After removing the ice water bath, the mixture was heated to room temperature and stirred for about 1 hour. It was confirmed by thin film chromatography (TLC) have.

After confirming the completion of the reaction, the solid salt formed by the neutralization reaction of triethylamine and hydrochloric acid produced as a byproduct is removed by filtration, and the resulting solution is subjected to vacuum distillation to remove the solvent, whereby acyl sulfoneamide 3.28 g (yield: 90.5%) was obtained.

The obtained acylsulfonamide can be used as an intermediate for the next reaction. However, purification by column chromatography yields a pure solid which melts at around 157 ° C.

Example 4

Add 1.22 g (10.0 mmole) of benzoic acid and 15 mL of chloroform to a 50 mL three-necked flask and stir at room temperature for about 5 minutes. Thereafter, the internal temperature was adjusted to about 5 ° C by cooling in the outside using an ice water bath, and then 1.484 g (5.0 mmole) of triphosgene and 3.036 g (30 mmole) of triethylamine were added in turn, Stir at that temperature.

1.712 g (10.0 mmole) of paratoluenesulfonamide was added thereto, and the mixture was stirred for about 5 minutes. After removing the ice water bath, the mixture was heated to room temperature and stirred for about 1 hour. It was confirmed by thin film chromatography (TLC) have.

After confirming the completion of the reaction, the reaction solvent was distilled off under reduced pressure, and 15 mL of water was added to the resulting solid to dissolve the solid salt formed by the neutralization reaction of triethylamine and hydrochloric acid produced as a by-product, and the desired compound, acylsulfonamide Dispersed in a solid form and stirred. After filtration, the filtrate was removed, washed with water, and the obtained solid was dried to obtain 2.65 g (yield: 96.2%) of acyl sulfoneamide as a target compound.

The obtained acylsulfonamide can be used as an intermediate for the next reaction. However, purification by column chromatography yields a pure solid which melts at around 147 ° C.

Claims (1)

A process for preparing an acyl sulfonamide derivative of formula (IV), wherein an organic acid of formula (I) is reacted with a sulfonamide of formula (III) in the presence of an organic base with a triphosgene of formula (II) Way.

In the above formula
The above formula (I) is a glycine protected with an amine by a benzyloxycarbonyl group of the following compound 1,
R ₁ is the remainder comprising a protected amine group benzyloxycarbonyl, except for the carboxyl group in compound 1,
R ₂ represents an alkyl group having 1 to 10 carbon atoms or an aryl group or an aralkyl group having 6 to 15 carbon atoms.