[1]Herein it relates to a process for preparing a (4-acetyl-2,6-difluoro-phenyl) -methanesulfonamide N-.
BACKGROUND
[2]
N- manufacturing method used in the preparation of (4-acetyl-2,6-fluorophenyl) methanesulfonamide is a general way to use a Heck reaction (Heck reaction) and methane sulfonation described in scheme 1.
[3]
For the reaction to generally introduced methanesulfonamide amine group generally it methanesulfonyl using ponnil chloride can easily introducing a methanesulfonamide, and the case of Heck reaction is a reaction that can be easily introduced into the acetyl group in the compound having an aryl halide structure N - a relatively easy method most commonly used because it is advantageous to introduce the acetyl group in the preparation (4-acetyl-2,6-difluorophenyl) methanesulfonamide.
[4]
However, because methanesulfonyl ponnil chloride known as genotoxic chemicals in the process are classified as substances that cause genotoxic compound made of methanesulfonyl ponnil chloride is possible, it requires the data to demonstrate the clear safety in the safety side safety be made of a high material is preferred.
[5]
In the case of Heck reaction, method for introducing an acetyl efficiently manufacture (4-acetyl-2,6-difluoro-phenyl) -methanesulfonamide N- but economical because they use a palladium metal catalyst, an expensive noble metal catalyst not easy to utilize commercially away. In addition, a method of introducing the acetyl aryl halide is a limit to take advantage of the organometallic reaction is similar due to the use of most of the noble metal catalyst.
[6]
[Reaction Scheme 1]
[7]
Detailed Description of the Invention
SUMMARY
[8]
Accordingly, the specification is N- (4- acetyl-2,6-difluorophenyl) methanesulfonamide (INT-1 in a short time without the use of genotoxic substances and expensive organometallic catalyst in order to solve the above problems ), and an object thereof is to provide a method for producing a.
Problem solving means
[9]
In order to achieve the above object, the invention according to one aspect, N- (4- acetyl-2,6-difluorophenyl) 3,4,5-trifluoro-methanesulfonamide as a method for producing the acetophenone paddy fields and a methanesulfonamide provides a method comprising the step of reacting the polar aprotic solvent.
[10]
[Advantageous Effects]
[11]
It can be easily produced the INT-1 at a high yield according to the production method in accordance with one aspect of the present invention and, in particular, an effect that may be produced standing INT-1 without generating impurities, not including the metal catalyst.
Best Mode for Carrying Out the Invention
[12]
In June 2015, the Korea Patent Application No. 10-2015-0093691 filed on May 30, the call is incorporated by reference herein is brilliant being of the Heavens, as all purposes. The present application claims the Korea Patent Application No. 10-2015-0093691 favors profit, incorporated by reference herein in its entirety.
[13]
The invention in one aspect, the 3,4,5-trifluoro-N- (4- acetyl-2,6, comprising the step of reacting the ketones acetophenone aprotic polar solvent, a methanesulfonamide (polar aprotic solvents) - may be prepared according to the method of-difluorophenyl) methanesulfonamide (INT-1).
[14]
In one aspect of the invention, the polar aprotic solvent may be one or more selected from a nitrile solvent, dimethyl sulfoxide, acetone, ethyl acetate, tetrahydrofuran, the group consisting of dimethylformamide.
[15]
In one aspect of the invention, the nitrile solvent may be one or more selected from the group consisting of acetonitrile, propionitrile, butyronitrile, benzonitrile, hexane nitrile, and acrylic. In one aspect of the present invention in detail, the nitrile solvent may be acetonitrile.
[16]
A polar aprotic solvent may be a nitrile solvent, or dimethyl sulfoxide.
[17]
In one aspect of the invention, the polar aprotic solvent may be acetonitrile or dimethyl sulfoxide.
[18]
In one aspect of the invention, methane sulfonamide may be 0.1 to 2 equivalents based on one equivalent of 3,4,5-trifluoro-acetophenone. In one aspect of the present invention in detail, methanesulfonamide is 3,4,5-trifluoro-acetophenone at least 0.1 equivalent based on 1 equivalent, at least 0.2 equivalents, more than 0.3 equivalent, at least 0.4 equivalents, more than 0.5 equivalent, 0.6 equivalent or more, 0.7 or more equivalents, more than 0.8 equivalent, and 0.9 equivalent or more and 1.0 equivalents or more and 1.1 equivalents or more and 1.2 equivalents or more and 1.3 equivalents or more and 1.4 equivalents or more and 1.5 equivalents or more, more than 1.6 equivalent weight, more than 1.7 eq., 1.8 eq. , 1.9 equivalents of at least 2.0 equivalent, at least 2.5 equivalents, or is more than 3.0 equivalents 3.0 equivalents or less, more than 2.5 equivalents, 2.0 equivalents or less, 1.9 equivalents or less, less than 1.8 equivalents, more than 1.7 equivalents, more than 1.6 equivalent weight, more than 1.5 equivalents, less than 1.4 equivalent weight, more than 1.3 equivalents, 1.2 equivalents or less, 1.1 equivalent or less, 1.0 equivalent or less, and 0.9 equivalents or less, and 0.8 equivalents or less, 0.7 equivalents or less, less than 0.6 equivalent, more than 0.5 eq., 0.4 eq., 0.3 eq., 0.2 eq. It may be, or up to 0.1 equivalent.
[19]
In one aspect of the invention, the step may be reacted further potassium carbonate.
[20]
In one aspect of the invention, the method may be one comprising a step of reaction without the metal catalyst. In one aspect of the present invention in detail, the metal catalyst may be palladium (Pd), rhodium (Rh) or platinum (Pt).
[21]
In one aspect of the invention, the solvent may be a 3,4,5-trifluoro-acetophenone and the second drain 10 to drain in preparation for the total combined weight of the methane sulfonamide (v / w).
[22]
In one aspect of the invention, the solvents in case the total weight 3,4,5-trifluoro-acetophenone and combined methanesulfonamide second drain, at least three drainage, 4 or more drainage, drainage more than 5, 6 be any multiple or more, 7 or more drainage, 8 or more water drain, at least 9, a multiple, at least 10 multiple, or at least 15 drainage and 15 drain or less, 10 drain or less, 9 drain or less, 8 multiple hereinafter seven drainage or less, six drain below, less than 5 or less drainage, drainage 4 or less, 3 or less drained, or may be a second drain.
[23]
In one aspect of the invention, the reaction can be allowed to warm to reflux for 6 hours to 12 hours.
[24]
In one aspect of the invention, the reaction can be carried out at a temperature of 80 ℃ to 130 ℃. Specifically, the reaction temperature may be in more than 80 ℃, more than 90 ℃, more than 100 ℃, more than 110 ℃, more than 120 ℃, more than 130 ℃, more than 140 ℃, or more than 150 ℃ and below 150 ℃, 140 ℃ or less, 130 ℃ or less, it can be not more than 120 ℃ or less, 110 ℃, less than 100 ℃, below 90 ℃, or 80 ℃. Specifically, the reaction time is 2 hours or more for 3 hours or more, 4 hours or more, 5 hours or more, 6 hours or more, or may be more than 7 hours, and 8 hours, 7 hours, 6 hours, 5 hours, 4 hours or less, it may be less than 3 hours, or 2 hours.
[25]
In one aspect of the present invention, N- (4- acetyl-2,6-difluorophenyl) methanesulfonamide, which will be described as INT-1 and interchangeably, Cas No. 956901-21-6 and , and a molecular weight of 249.23 Da can mean a compound.
[26]
In one aspect of the invention, 3,4,5-trifluoro-acetophenone (3,4,5-trifluoroacetophenone) it is to mean a compound having a phosphorus compound as a Cas No. 220141-73-1, molecular weight of 174.12 Da have.
[27]
In one aspect of the invention, methanesulfonamide (methanesulfonamide) can refer to the compound as a Cas No. 3144-09-0, molecular weight of 95.12 Da compound.
[28]
In one aspect of the invention, the production method can be carried out in steps as described below are:
[29]
(1) reacting the nitrile was dissolved in the solvent acetophenone was added methanesulfonamide and potassium carbonate and heated under reflux with 3,4,5-trifluoro;
[30]
And then (2) (1) completion of the reaction of Step is cooled to room temperature;
[31]
(3) adding ethyl acetate and hydrochloric acid to separate the organic layer and an aqueous layer in the cooled reaction mixture;
[32]
(3-1) by the addition of ethyl acetate to separate an aqueous layer comprising: the organic layer was separated again;
[33]
(4) stirring (3) and a mixture of the organic layer in (3-1), insert the (washing) after the magnesium sulfate washed with water and brine;
[34]
(5) step of filtration and concentration under reduced pressure the organic layer was stirred;
[35]
(6) by the concentrated solid after stirring the hexane was dissolved in ethyl acetate phase to precipitation;
[36]
7 by filtration to obtain the INT-1 compound and the precipitated solid.
[37]
[38]
In the following, examples and test example, the configuration and effect of the present invention will be described in detail. However, these examples and test examples are not intended to be limited by the examples to the spirit and scope of the invention as only be provided for purposes of illustration to aid understanding of the present invention.
[39]
[40]
[Example 1] Preparation of INT-1
[41]
[42]
3 liters 3,4,5-trifluoroacetate To a round bottom flask was added acetophenone (alpha-capture obtained from chemistry, alfa-chemistry) 88.8g (510mmol) was dissolved in acetonitrile (Sigma Aldrich) 450ml methanesulfonamide ( Sigma-Aldrich Co.) to 72.83g (764.99mmol, 1.5 eq.) and potassium carbonate (Sigma Aldrich) 140.94g (1019.99mmol, 2 eq). Then reflux at an external temperature of 95 ℃ heating for 5 hours, the reaction was terminated, it cooled to room temperature (25 ℃). Ethyl acetate to the cooled reaction mixture (Sigma-Aldrich, Inc.) and an aqueous layer was separated and the organic layer was added to 900ml of hydrochloric acid and 900ml of 2N and again separating the organic layer was then added 400ml of ethyl acetate again to separate an aqueous layer. So after the each of the organic layer the mixture separate the organic layer in two steps, washed with brine 400ml saturated with water 400ml (washing), into the magnesium sulfate 5g, stirring after then filtered through a Buchner funnel under reduced pressure at 40 ℃ and 10 Torr and concentrated. Dissolve the concentrated solids in ethyl acetate 450ml was precipitated by stirring into 1440ml of hexane. The precipitated solid was filtered off to give a yellow solid compound 103.95g (81%).
[43]
Thus a yellow solid compound obtained using a Bruker 400 MHz NMR spectrometer was measured NMR data, the NMR data are as follows.
[44]
1H NMR(400MHz, CDCl3): δ7.58 (d, 2H, J = 11.6Hz), 3.13 (s, 3H), 2.29 (s, 3H).
[45]
[46]
[Examples 2 to 12]
[47]
[48]
In the production method of Example 1, to the solvent instead of acetonitrile (ACN) with that described in Table 1 was obtained in a yield of a yellow solid compound Table 1, respectively.
[49]
To organize the each example the solvent used, the reaction conditions, yield and impurity if shown in Table 1 below.
[50]
TABLE 1
menstruum Temperature (℃) time NH 2 MS (eq) K 2 CO 3 (equiv.) yield 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%

[51]
* DME: dimethoxyethane (dimethoxyethane)
[52]
NMP: N- methyl-2-pyrrolidone (N-methyl-2-pyrrolidone)
[53]
Reflux: heated under reflux
[54]
THF: Ted la tetrahydrofuran (tetrahydrofuran)
[55]
DMF: dimethylformamide (dimethylformamide)
[56]
[57]
[Examples 13 to 19]
[58]
[59]
In the production of the first embodiment, while the solvent using acetonitrile and DMSO, while controlling the equivalent of methane sulfonamide to the acetophenone 3,4,5-trifluoro-1 equivalent of the experiment was performed, as a result to give a yellow solid compound, respectively. Performed to organize the Examples 13 to 19 using a solvent, the reaction conditions, yield and impurity if the are shown in Table 2 below.
[60]
TABLE 2
menstruum Temperature (℃) time NH 2 MS (eq) K 2 CO 3 (equiv.) yield 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%

[61]
According to Table 1, Examples 6 to 8, but in the case of organic chemical reactions typically proceed with the experiment on the organic solvent which may be used, and it was confirmed that all low yield. This is according to an aryl halide amination reaction (aryl halide amination) For the method according to the invention, since a halogen adjacent to the reactant is nitrogen, have a metal catalyst such as Bondi palladium since the reaction yield increased, without such a metal catalysis as shown in examples 6 to 8 shows a case proceed with the result that the INT-1 to give a low yield.
[62]
Further, if the polarity biyang as solvent using magnetic THF, acetone, DMF, ethyl acetate, and although the yield is high but to obtain a 3,4,5-trifluoro-1 to INT reacting acetophenone paddy methanesulfonamide It was able to determine that. For each yield showed the highest result in the case of DMF. Therefore, when a polar aprotic solvent can be confirmed that it is possible to synthesize the INT-1 purpose to be achieved in the present invention.
[63]
According to the results of Example 5 When using the solvent DMSO could give the INT-1 at a high yield compared to other solvents. However, in the case of using the DMSO has been 3,5-difluoro generation of impurities such as 4-hydroxy-acetophenone (3,5-difluoro-4-hydroxyacetophenone) it was difficult to obtain a completely pure INT-1.
[64]
On the other hand, if as in Example 1 according to the nitrile solvent with acetonitrile, the obtained yields of the INT-1 was significantly higher with 81% 3,5-di-fluoro -4-hydroxy-acetophenone ketones such impurities do not occur fully it confirmed that it is possible to obtain a pure INT-1.
[65]
According to Table 2 it confirmed the generation amount of acetonitrile and the product yield and impurity of INT-1, while varying the equivalent of methanesulfonamide each other in the use of the solvent DMSO. When more specifically, increase in the equivalent of methanesulfonamide (Examples 13 to 15) when using acetonitrile as a solvent tended to yield increase compared to the results in Table 1 when the methanesulfonamide of 1.5 equivalent of the it can be confirmed that the yield is maximized.
[66]
Further, when the solvent is DMSO (Examples 16 to 19), more 3,4,5-trifluoro increase the equivalent of methane sulfonamide to the acetophenone was confirmed that the yield of the reduction of INT-1. In particular, in contrast, the equivalent weight of the methanesulfonamide of 1.0 and 1.2, the impurity of the formula shown in Table 1 does not almost occur as more than 0.5%, in the 5% and 7% impurity or more the equivalent of methanesulfonamide 2.0 It was found to increase. The content of these impurities can be about 10 times as I difference, to achieve these results the yield of DMSO In low impurity content and high INT-1 when the equivalent weight of the methanesulfonamide of less than 2.0 to the use of the solvent according to the.
[67]
Therefore, in the case of the manufacturing method according to an aspect of the invention, even without generating impurities do not use a metal catalyst can be obtained pure INT-1 at a high yield.

Claims

[Claim 1]3,4,5-trifluoro-N-, comprising the step of reacting the polar aprotic solvent the ketones acetophenone methanesulfonamide (4-acetyl-2,6-difluorophenyl) methanesulfonamide (INT-1 method for manufacturing a).
[Claim 2]
The method of claim 1 wherein the polar aprotic solvent is a nitrile solvent, wherein at least one selected from dimethyl sulfoxide, acetone, ethyl acetate, tetrahydrofuran, the group consisting of dimethylformamide.
[Claim 3]
The method of claim 2 wherein the nitrile solvent is at least one selected from the group consisting of acetonitrile, propionitrile, butyronitrile, benzonitrile, hexane nitrile, and acrylic.
[Claim 4]
The method of claim 2 wherein the polar aprotic solvent is a nitrile solvent, or a method of dimethylsulfoxide.
[Claim 5]
The method of claim 4 wherein the polar aprotic solvent is acetonitrile or dimethyl sulfoxide.
[Claim 6]
The method of claim 1 wherein the 3,4,5-trifluoro-methanesulfonamide method of 0.1 to 2 equivalents based on 1 equivalent of acetophenone.
[Claim 7]
7. The method of claim 6, methanesulfonamide was 3,4,5-trifluoro method of 0.5 to 1.5 equivalents based on 1 equivalent of acetophenone.
[Claim 8]
The method of claim 1, wherein the step is reacted with further potassium carbonate.
[Claim 9]
The method of claim 1, said method comprising a step of reaction without the metal catalyst.
[Claim 10]
The method of claim 5, wherein the metal catalyst is a palladium (Pd), rhodium (Rh) or platinum (Pt).
[Claim 11]
The method of claim 1 wherein the solvent is a method in 3,4,5-trifluoro-acetophenone and a 2 to 10 multiple drain in preparation for the total combined weight of the methane sulfonamide (v / w).
[Claim 12]
The method of claim 1, wherein the reaction is warmed to reflux for 6 hours to 12 hours.
[Claim 13]
The method of claim 1 wherein the reaction is carried out at a temperature of 80 ℃ to 130 ℃.