KR102287585B1 - Methods for manufacturing n-(4-acetyl-2,6-difluorophenyl)methanesulfonamide - Google Patents

Abstract

The present specification is a method for preparing N- (4-acetyl-2,6-difluorophenyl) methanesulfonamide, the step of reacting 3,4,5-trifluoroacetophenone and methanesulfonamide in a nitrile solvent method to include. According to the manufacturing method of the present specification, INT-1 can be easily manufactured in a high yield, and in particular, INT-1 can be manufactured without including a metal catalyst and without generating impurities. Therefore, since it does not contain a metal catalyst, it is economical compared to other methods, and it can be used effectively in the field of manufacturing INT-1 because INT-1 can be obtained in high yield.

Description

Method for producing N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide

The present specification relates to a method for preparing N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide.

The general method used for the preparation of N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide is the Heck reaction and methanesulfonation reaction described in Scheme 1.

In general, in the case of a reaction in which methanesulfone is introduced into an amine group, a methanesulfone group can be easily introduced using methanesulfonyl chloride, and in the case of a Heck reaction, an acetyl group can be easily introduced into a compound having an aryl halide structure. -(4-acetyl-2,6-difluorophenyl)methanesulfonamide is the most used method because it has the advantage of relatively easy introduction of an acetyl group.

However, since methanesulfonyl chloride, known as a genotoxic chemical in this method, is classified as a substance causing genotoxicity, a compound made of methanesulfonyl chloride needs data to prove its safety in terms of safety. It is desirable to manufacture from this high material.

In the case of the hexide reaction, acetyl can be efficiently introduced in the preparation of N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide, but it is not economical because an expensive noble metal catalyst, a palladium metal catalyst, must be used. It is not easy to use commercially. In addition, the method of introducing acetyl into the aryl halide is limited in utilizing similar organometallic reactions because most of the methods use noble metal catalysts.

[Scheme 1]

WO 2007/129188 WO 2007/133637 WO 2010/010934 WO 2008/013414

Dr. Sarah M. Crawford et al, BippyPhos: A Single Ligand With Unprecedented Scope in the Buchwald-Hartwig Amination of (Hetero)aryl Chlorides, Chemistry - A European Journal, 19(49), 16760-16771; December 2, 2013.

Therefore, in order to solve the above problems, the present specification provides N-(4-acetyl-2, 6-difluorophenyl)methanesulfonamide (INT-1) in a short time without using genotoxic substances and expensive organometallic catalysts. ) for the purpose of providing a method for manufacturing

In order to achieve the above object, the present invention in one aspect, as a method for preparing N- (4-acetyl-2,6-difluorophenyl) methanesulfonamide 3,4,5-trifluoroacetope Provided is a method comprising reacting rice paddy with methanesulfonamide in a polar aprotic solvent.

According to the manufacturing method according to an aspect of the present invention, INT-1 can be easily manufactured in a high yield, and in particular, INT-1 can be manufactured without including a metal catalyst and without generating impurities.

In one aspect, the present invention provides N-(4-acetyl-2,6) comprising reacting 3,4,5-trifluoroacetophenone and methanesulfonamide in polar aprotic solvents. -Difluorophenyl) methanesulfonamide (INT-1) may be related to a manufacturing method.

In one aspect of the present invention, the polar aprotic solvent may be at least one selected from the group consisting of a nitrile solvent, dimethyl sulfoxide, acetone, ethyl acetate, tetrahydrofuran, and dimethylformamide.

In one aspect of the present invention, the nitrile solvent may be at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, benzonitrile, hexanenitrile, and acrylonitrile. Specifically, in one aspect of the present invention, the nitrile solvent may be acetonitrile.

The polar aprotic solvent may be a nitrile solvent or dimethylsulfoxide.

In one aspect of the present invention, the polar aprotic solvent may be acetonitrile or dimethylsulfoxide.

In one aspect of the present invention, methanesulfonamide may be used in an amount of 0.1 to 2 equivalents based on 1 equivalent of 3,4,5-trifluoroacetophenone. Specifically, in one aspect of the present invention, methanesulfonamide is 0.1 equivalent or more, 0.2 equivalent or more, 0.3 equivalent or more, 0.4 equivalent or more, 0.5 equivalent or more, 0.6 equivalent to 1 equivalent of 3,4,5-trifluoroacetophenone At least 0.7 equivalents, at least 0.8 equivalents, at least 0.9 equivalents, at least 1.0 equivalents, at least 1.1 equivalents, at least 1.2 equivalents, at least 1.3 equivalents, at least 1.4 equivalents, at least 1.5 equivalents, at least 1.6 equivalents, at least 1.7 equivalents, at least 1.8 equivalents , 1.9 equivalents or more, 2.0 equivalents or more, 2.5 equivalents or more, or 3.0 equivalents or more, 3.0 equivalents or less, 2.5 equivalents or less, 2.0 equivalents or less, 1.9 equivalents or less, 1.8 equivalents or less, 1.7 equivalents or less, 1.6 equivalents or less, 1.5 equivalents or less, 1.4 equivalents or less, 1.3 equivalents or less, 1.2 equivalents or less, 1.1 equivalents or less, 1.0 equivalents or less, 0.9 equivalents or less, 0.8 equivalents or less, 0.7 equivalents or less, 0.6 equivalents or less, 0.5 equivalents or less, 0.4 equivalents or less, 0.3 equivalents or less, 0.2 equivalents or less, or 0.1 equivalent or less.

In one aspect of the present invention, the step may be to react by further adding potassium carbonate.

In one aspect of the present invention, the method may be characterized in that the reaction without a metal catalyst. Specifically, in one aspect of the present invention, the metal catalyst may be palladium (Pd), rhodium (Rh) or platinum (Pt).

In one aspect of the present invention, the solvent may be 2 to 10 times (v/w) relative to the total weight of 3,4,5-trifluoroacetophenone and methanesulfonamide.

In one aspect of the present invention, the solvent is 2 or more, 3 or more, 4 or more, 5 or more, 6 or more relative to the total weight of 3,4,5-trifluoroacetophenone and methanesulfonamide Multiple or more, 7 or more, 8 or more, 9 or more, 10 or more, or 15 or more, and 15 or less, 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, It may be 5 times or less, 4 times or less, 3 times or less, or 2 times or less.

In one aspect of the present invention, the reaction may be heating and refluxing for 6 to 12 hours.

In one aspect of the present invention, the reaction may be carried out at a temperature of 80 ℃ to 130 ℃. Specifically, the reaction temperature may be 80 °C or higher, 90 °C or higher, 100 °C or higher, 110 °C or higher, 120 °C or higher, 130 °C or higher, 140 °C or higher, or 150 °C or higher, and 150 °C or lower, 140 °C or lower, 130 °C or higher. ℃ or less, 120 ℃ or less, 110 ℃ or less, 100 ℃ or less, 90 ℃ or less, or 80 ℃ or less. Specifically, the reaction time may be 2 hours or more, 3 hours or more, 4 hours or more, 5 hours or more, 6 hours or more, or 7 hours or more, and 8 hours or less, 7 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, or 2 hours or less.

In one aspect of the present invention, N-(4-acetyl-2,6-difluorophenyl)methanesulfonamide is one which may be described interchangeably with INT-1, Cas number 956901-21-6 and , may mean a compound having a molecular weight of 249.23 Da.

In one aspect of the present invention, 3,4,5-trifluoroacetophenone (3,4,5-trifluoroacetophenone) is a compound of Cas number 220141-73-1, which may refer to a compound having a molecular weight of 174.12 Da. there is.

In one aspect of the present invention, methanesulfonamide (methanesulfonamide) is a compound having Cas number 3144-09-0, and may refer to a compound having a molecular weight of 95.12 Da.

In one aspect of the present invention, the manufacturing method may be performed in the following steps:

(1) dissolving 3,4,5-trifluoroacetophenone in a nitrile solvent, adding methanesulfonamide and potassium carbonate, and heating to reflux to react;

(2) cooling to room temperature after completion of the reaction in step (1);

(3) adding ethyl acetate and hydrochloric acid to the cooled reaction solution to separate the organic layer and the water layer;

(3-1) adding ethyl acetate to the separated water layer to separate the organic layer again;

(4) mixing the organic layers separated in (3) and (3-1), washing with water and brine, adding magnesium sulfate and stirring;

(5) filtering and concentrating the stirred organic layer under reduced pressure;

(6) dissolving the concentrated solid in ethyl acetate, adding hexane, and stirring to precipitate;

(7) filtration of the precipitated solid to obtain an INT-1 compound.

Hereinafter, the configuration and effect of the present invention will be described in more detail with reference to Examples and Test Examples. However, these Examples and Test Examples are provided only for the purpose of illustration to help the understanding of the present invention, and the scope and scope of the present invention are not limited by the following examples.

[Example 1] Preparation of INT-1

In a 3 liter round-bottom flask, 88.8 g (510 mmol) of 3,4,5-trifluoroacetophenone (obtained from Alpha-Chemistry, alfa-chemistry) was dissolved in 450 ml of acetonitrile (Sigma-Aldrich) and methanesulfonamide ( Sigma-Aldrich Co.) 72.83 g (764.99 mmol, 1.5 eq) and potassium carbonate (Sigma-Aldrich Co.) 140.94 g (1019.99 mmol, 2 eq) were added. Then, it was heated and refluxed at an external temperature of 95 °C for 5 hours, and when the reaction was completed, it was cooled to room temperature (25 °C). After adding 900 ml of ethyl acetate (Sigma-Aldrich) and 900 ml of 2N hydrochloric acid to the cooled reaction solution, the organic layer was separated from the water layer, 400 ml of ethyl acetate was added to the separated water layer, and the organic layer was separated again. After washing the organic layer in which each organic layer separated into two steps was mixed with 400 ml of water and 400 ml of saturated brine, 5 g of magnesium sulfate was added, stirred, filtered with a Buchner funnel, and then filtered under reduced pressure at 40° C. and 10 Torr. concentrated. The concentrated solid was dissolved in 450 ml of ethyl acetate, and 1440 ml of hexane was added thereto and stirred to precipitate. The precipitated solid was filtered to obtain 103.95 g (81%) of a yellow solid compound.

The yellow solid compound thus obtained was measured for NMR data using a Bruker 400 MHz NMR spectrometer, and the NMR data are as follows.

¹ H NMR (400 MHz, CDCl ₃ ): δ7.58 (d, 2H, J = 11.6 Hz), 3.13 (s, 3H), 2.29 (s, 3H).

[Examples 2 to 12]

In the preparation method of Example 1, a yellow solid compound was obtained in the yield of Table 1 by using the solvent described in Table 1 instead of acetonitrile (ACN).

Table 1 below summarizes the solvents, reaction conditions, yields, and impurities used in each Example.

menstruum Temperature (℃) time NH ₂ MS( equivalent weight ) K2CO3( equivalent weight ) transference number impurities Example 1 ACN reflux 9 1.5 2 81% x Example 2 t-BuOH reflux 9 1.5 2 24% Example 3 DME reflux 9 1.5 2 27% Example 4 NMP 120 9 1.5 2 54% Example 5 DMSO 120 9 1.5 2 75%

Example 6 MeOH reflux 9 1.5 2 20% Example 7 EtOH reflux 9 1.5 2 25% Example 8 n-BuOH reflux 9 1.5 2 45% Example 9 THF reflux 9 1.5 2 46% Example 10 ACTONE reflux 9 1.5 2 47% Example 11 DMF 120 9 1.5 2 67% Example 12 Ethylacetate reflux 9 1.5 2 51%

* DME: dimethoxyethane

NMP: N-methyl-2-pyrrolidone (N-methyl-2-pyrrolidone)

Reflux : Warm reflux

THF: tetrahydrofuran

DMF: dimethylformamide

[Examples 13 to 19]

In the preparation of Example 1, the experiment was performed while adjusting the equivalent of methanesulfonamide to 1 equivalent of 3,4,5-trifluoroacetophenone while using acetonitrile and DMSO as solvents, and as a result A yellow solid compound was obtained, respectively. The solvents, reaction conditions, yields, and impurities used in Examples 13 to 19 are summarized in Table 2 below.

menstruum Temperature (℃) time NH ₂ MS( equivalent weight ) K2CO3( equivalent weight ) transference number impurities Example 13 ACN reflux 9 1.0 2 64 - Example 14 ACN reflux 9 1.2 2 77 - Example 15 ACN reflux 9 2.0 2 80 - Example 16 DMSO 120 9 1.0 2 81 <0.5 Example 17 DMSO 120 9 1.2 2 80 <0.5 Example 18 DMSO 120 9 2.0 2 78 5% Example 19 DMSO 120 9 3.0 2 75 7%

According to Table 1, in the case of Examples 6 to 8, experiments were conducted on organic solvents that can be generally used in organic chemical reactions, but it was confirmed that all yields were low. In the case of the method according to the present invention, in the aryl halide amination reaction, since there is no nitrogen adjacent to the halogen of the reactant, a metal catalyst such as Bondi palladium is required to increase the reaction yield, so the reaction without such a metal catalyst This shows the result of obtaining INT-1 in a low yield as in Examples 6 to 8.

In addition, when THF, acetone, DMF, and ethyl acetate are used as polar aprotic solvents, although the yield is not high, INT-1 can be obtained by reacting 3,4,5-trifluoroacetophenone with methanesulfonamide. I could confirm that I could. For each yield, the highest result was shown in the case of DMF. Therefore, it can be confirmed that INT-1, which is the object to be achieved in the present invention, can be synthesized when a polar aprotic solvent is used.

According to the results of Example 5, when DMSO solvent was used, INT-1 could be obtained in high yield compared to other solvents. However, when DMSO was used, impurities such as 3,5-difluoro-4-hydroxyacetophenone were generated, so it was difficult to obtain pure INT-1.

In contrast, when acetonitrile was used as the nitrile solvent according to Example 1, the yield of INT-1 was remarkably high as 81%, and impurities such as 3,5-difluoro-4 hydroxyacetophenone did not occur. It was confirmed that it is possible to obtain completely pure INT-1.

According to Table 2, it was possible to confirm the production yield of INT-1 and the degree of generation of impurities while using acetonitrile and DMSO solvents with different equivalents of methanesulfonamide. Specifically, when acetonitrile was used as a solvent (Examples 13 to 15), the yield showed a tendency to increase as the equivalent of methanesulfonamide increased. Compared with the results in Table 1, when methanesulfonamide was 1.5 equivalents, the It can be seen that the yield is maximized.

In addition, when the solvent was DMSO (Examples 16 to 19), it was confirmed that the yield of INT-1 decreased as the equivalent of methanesulfonamide to 3,4,5-trifluoroacetophenone increased. In particular, when the equivalent weight of methanesulfonamide is 1.0 and 1.2, the impurity of the formula shown in Table 1 is hardly generated as 0.5% or less, whereas when the equivalent weight of methanesulfonamide is 2.0 or more, the impurity is 5% and 7%. increase could be observed. The content of these impurities differs by about 10 times. According to these experimental results, when the equivalent of methanesulfonamide is less than 2.0, low impurity content and high yield of INT-1 can be achieved when the equivalent of methanesulfonamide is less than 2.0.

Therefore, in the case of the manufacturing method according to an aspect of the present invention, pure INT-1 can be obtained in high yield without generating impurities even without using a metal catalyst.

Claims (13)

Reacting 3,4,5-trifluoroacetophenone and methanesulfonamide in a polar aprotic solvent,
The polar aprotic solvent is a nitrile solvent, a method for producing N- (4-acetyl-2,6-difluorophenyl) methanesulfonamide (INT-1). delete According to claim 1,
The nitrile solvent is at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, benzonitrile, hexanenitrile, and acrylonitrile. delete According to claim 1,
wherein the polar aprotic solvent is acetonitrile. According to claim 1,
Methanesulfonamide is 0.1 to 2 equivalents based on 1 equivalent of 3,4,5-trifluoroacetophenone. 7. The method of claim 6,
Methanesulfonamide is 0.5 to 1.5 equivalents based on 1 equivalent of 3,4,5-trifluoroacetophenone. According to claim 1,
The step is a method of reacting by further adding potassium carbonate. According to claim 1,
The method is characterized in that the reaction is carried out without a metal catalyst. 10. The method of claim 9,
The metal catalyst is palladium (Pd), rhodium (Rh) or platinum (Pt). According to claim 1,
The solvent is 2 to 10 times (v/w) with respect to the total weight of 3,4,5-trifluoroacetophenone and methanesulfonamide. According to claim 1,
The reaction is a method of heating to reflux for 6 hours to 12 hours. According to claim 1,
The method wherein the reaction is carried out at a temperature of 80 ℃ to 130 ℃.