JP6723817B2 - Method for producing (trifluoromethyl)malonic acid ester - Google Patents

Description

The present invention relates to a method for producing (trifluoromethyl)malonic acid ester.

(Trifluoromethyl)malonic acid ester is a compound useful as an intermediate for medicines and agricultural chemicals (for example, Patent Document 1).

As a production method disclosed so far, 3,6-dihydro-3-methyl-4,6,6-trifluoro-5-(trifluoromethyl)-2H-1,3-oxazin-2-one was prepared. Method of obtaining dimethyl ester by reacting with sodium methoxide in methanol (Patent Document 2), reacting methyl[1,1,3,3,3-pentafluoro-2-(trifluoromethyl)propyl]ether with methanol Then, a method of hydrolyzing with an acid (Patent Document 3, Non-Patent Document 1 and references cited therein) is disclosed.

On the other hand, there has been no production method using 3-amino-3-alkoxy-2-propenoic acid ester or 3-amino-3-alkoxy-2-propenoic acid ester as a raw material.

JP 2004-115377. US 3,538,081, 1970. JP 58-126837.

Bulletin of Chemical Society of Japan, Vol. 56, p. 724, 1983. Bulletin of Chemical Society of Japan.

In each of the disclosed methods, the raw material synthesis process is complicated and it is necessary to use a highly toxic compound.

An object of the present invention is to provide a method for producing (trifluoromethyl)malonic acid ester using a raw material that is more easily available and safe.

In view of the above problems, the inventors of the present invention have conducted extensive studies, and as a result, have determined that 3-amino-3-alkoxy-2-propenoic acid ester and 3-amino-3-alkoxy-2-propenimidic acid ester are iron compounds. It was found that (trifluoromethyl)malonic acid ester can be obtained by trifluoromethylating 2-position with trifluoromethyl iodide in the presence of water, hydrogen peroxide and sulfoxide, followed by hydrolysis with acid. It was That is, the present invention is
(I) Iron compound, hydrogen peroxide solution and general formula (1) R ¹ -S(=O)-R ¹ (1) (In the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group. .) in the presence of a sulfoxide represented by the general formula (2)

(In the formula, each of R ² and R ³ independently represents an alkyl group having 1 to 4 carbon atoms. X represents an oxygen atom or an imino group.) (3)

(In the formula, R ² , R ³ and X have the same meanings as described above.) A (trifluoromethyl)enamine represented by the following formula is obtained, and the compound is then hydrolyzed.

(In the formula, R ² and R ³ have the same meanings as described above.) A method for producing a (trifluoromethyl)malonic acid ester;
(Ii) The production method according to (ii), wherein the hydrolysis is carried out in the presence of an acid;
(Iii) The production method according to (ii), wherein the acid is a protonic acid;
(Iv) The iron compound is iron(II) sulfate, iron(II) sulfate ammonium, iron(II) tetrafluoroborate, iron(II) chloride, iron(II) bromide, iron(II) iodide, acetic acid. Any of iron (II), iron (II) oxalate, bisacetylacetonato iron (II), ferrocene, bis(η ⁵ -pentamethylcyclopentadienyl) iron or iron powder (i) to (iii) The production method according to Crab;
(V) The production method according to any one of (i) to (iii), wherein the iron compound is iron (II) sulfate;
(Vi) The production method according to any one of (i) to (v), wherein R ¹ is a methyl group;
It is about.

The present invention will be described in detail below.

Specific examples of the alkyl group having 1 to 4 carbon atoms represented by R ¹ of the sulfoxide (1) include a methyl group, an ethyl group and a butyl group. R ¹ may be either an alkyl group or a phenyl group, but a methyl group is preferable because it is easily available and the yield is good.
The alkyl group having 1 to 4 carbon atoms represented by R ² and R ³ of the enamine (2) may be linear or branched, and specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, Examples thereof include a butyl group, an isobutyl group and a sec-butyl group. A methyl group or an ethyl group is preferable in terms of easy availability.

Next, the manufacturing method of the present invention will be described in detail.

The raw material enamine (2) can be obtained by the reaction of cyanoacetic acid ester or malonitrile with an alcohol described in Helvetica Chimica Acta, Vol. 74, page 1, 1991 or Tetrahedron Letters, Vol. 48, page 3273, 2007. .. The enamine (2) in which R ² and R ³ are both ethyl groups can also be obtained by neutralizing a commercially available hydrochloride.

The manufacturing method of the present invention comprises two steps. First, the step 1 will be described.
[Step 1]

(In the formula, R ² , R ³ and X have the same contents as described above.)
Step 1 is represented by an iron compound, hydrogen peroxide solution, and general formula (1) R ¹ -S(=O)-R ¹ (1) (wherein R ¹ has the same meaning as described above). In the presence of a sulfoxide, the enamine of the general formula (2) is trifluoromethylated with trifluoromethyl iodide to obtain the (trifluoromethyl)enamine of the general formula (3).

In the reaction of step 1, a solvent that does not harm the reaction can be used. Specifically, amides such as N,N-dimethylformamide, hexamethylphosphoric triamide and N-methyl-2-pyrrolidone, ethers such as 1,4-dioxane, tetrahydrofuran and diethyl ether, methyl acetate, ethyl acetate and the like. Examples thereof include esters, acetone, ketones such as methyl(isobutyl)ketone, water, and the like, and these may be used in appropriate combination. Further, sulfoxide (1) which is liquid at room temperature, such as dimethyl sulfoxide, may be used as a solvent as it is. From the viewpoint of good yield and convenience, it is preferable to use water, dimethyl sulfoxide, or a mixed solvent of water and dimethyl sulfoxide.

The iron compound that can be used in the present invention is preferably an iron (II) salt in terms of good yield. For example, inorganic acid salts such as iron (II) sulfate, iron (II) sulfate ammonium, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide or iron (II) iodide, Organic metal compounds such as iron acetate (II), iron oxalate (II), bisacetylacetonato iron (II), ferrocene or bis(η ⁵ -pentamethylcyclopentadienyl) iron can be exemplified, and May be used in combination as appropriate. Further, iron powder, iron (0) salt or iron (I) salt may be combined with an oxidizing reagent such as peroxide to generate an iron (II) salt in the system for use. At that time, hydrogen peroxide used in the reaction can be used as it is as an oxidizing reagent. It is preferable to use iron(II) sulfate or ferrocene in terms of good yield.

These iron compounds may be used as a solid, but may be used as a solution. When used as a solution, any of the above-mentioned solvents may be used, but among them, water, dimethyl sulfoxide or a mixed solvent of water and dimethyl sulfoxide is preferable. At that time, the concentration of the iron compound solution is preferably 0.1 to 10 mol/L, more preferably 0.5 to 5 mol/L from the viewpoint of good yield.

The molar ratio of the enamine (2) to the iron compound is preferably 1:0.01 to 1:10, and more preferably 1:0.1 to 1:1 in terms of good yield.

Hydrogen peroxide is preferably diluted with water and used from the viewpoint of safety. The concentration at that time may be 3 to 70% by weight, but a commercially available 35% by weight may be used as it is. From the viewpoint of good yield and safe handling, it is preferable to use commercially available 35% by weight as it is or to dilute with water to a lower limit of 10% by weight.

The molar ratio of enamine (2) to hydrogen peroxide is preferably 1:0.1 to 1:10, and more preferably 1:1.5 to 1:3 in terms of good yield.

The molar ratio of the enamine (2) to the sulfoxide (1) is preferably 1:1 to 1:200, and more preferably 1:10 to 1:100 in terms of good yield.

The molar ratio of enamine (2) to trifluoromethyl iodide is preferably 1:1 to 1:100, and more preferably 1:1.5 to 1:10 in terms of good yield.

The reaction temperature can be appropriately selected from the range of 0°C to 100°C. From the viewpoint of good yield, 20°C to 70°C is preferable.

When the reaction is carried out in a closed system, it can be carried out at a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction proceeds sufficiently even at atmospheric pressure. Further, the atmosphere during the reaction may be an inert gas such as argon or nitrogen, but it will proceed sufficiently even in air.

Trifluoromethyl iodide may be used as it is, and at that time, it is diluted with a gas such as argon, nitrogen, air, helium, oxygen, etc., and mixed with the trifluoromethyl iodide having a mole fraction of 1% or more. It can be used as a gas. When carrying out the reaction in a closed system, trifluoromethyl iodide or a mixed gas can be used as the reaction atmosphere. The pressure at that time can be a pressure appropriately selected from the range of atmospheric pressure (0.1 MPa) to 1.0 MPa, but the reaction sufficiently proceeds even at atmospheric pressure. Further, trifluoromethyl iodide or a mixed gas may be bubbled in an open system and introduced into the reaction solution. The introduction rate of trifluoromethyl iodide or a mixed gas at that time depends on the reaction scale, the amount of catalyst, the reaction temperature, and the mole fraction of trifluoromethyl iodide in the mixed gas, but is in the range of 1 mL to 200 mL per minute. The speed selected from

Further, trifluoromethyl iodide may be dissolved in the above reaction solvent and used as a solution. Dimethyl sulfoxide is preferable in terms of high solubility of trifluoromethyl iodide and convenience. The concentration at that time is preferably 0.05 to 5 mol/L, more preferably 0.1 to 2 mol/L.

The reaction time is not particularly limited, but the target product can be obtained in good yield by performing the reaction for 0.5 hours or more.

The method of isolating the desired product from the solution after the reaction is not particularly limited, but it is a general method such as solvent extraction, column chromatography, preparative thin layer chromatography, preparative liquid chromatography, recrystallization or sublimation. The target product can be obtained.

The (trifluoromethyl)enamine (3) obtained in step 1 may be isolated, but can also be used in the next step 2 without isolation.

Next, step 2 will be described.
[Step 2]

(In the formula, R ² , R ³ and X have the same contents as described above.)
Step 2 is a step of hydrolyzing the (trifluoromethyl)enamine of the general formula (3) to obtain a (trifluoromethyl)malonic acid ester.

The molar ratio of water to (trifluoromethyl)enamine (3) is preferably 1:1 to 1000:1, more preferably 5:1 to 100:1. When step 2 is carried out without isolating (trifluoromethyl)enamine (3), the molar ratio of water to enamine (2) is preferably 1:1 to 1000:1, and 5:1 to 100:1. Is more preferable.

In the reaction of step 2, a solvent that does not harm the reaction can be used. Specifically, amides such as N,N-dimethylformamide, hexamethylphosphoric triamide and N-methyl-2-pyrrolidone, ethers such as 1,4-dioxane, tetrahydrofuran and diethyl ether, methyl acetate, ethyl acetate and the like. Examples thereof include esters, acetone, ketones such as methyl (isobutyl) ketone, and water, and these may be used in appropriate combination. Further, sulfoxide (1) which is liquid at room temperature, such as dimethyl sulfoxide, may be used as a solvent as it is. Water is preferable because of its good yield and convenience.

Step 2 is preferably carried out in the presence of a protic acid in terms of good yield. Examples of the protic acid that can be used include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, hexafluorophosphoric acid or tetrafluoroboric acid, formic acid, acetic acid, propionic acid and oxalic acid. Examples thereof include acids, p-toluenesulfonic acid, trifluoromethanesulfonic acid, and organic acids such as trifluoroacetic acid. Inorganic acids are preferable, and hydrochloric acid is more preferable, from the viewpoint of good yield and easy availability.

The molar ratio of the protic acid to the (trifluoromethyl)enamine (3) is preferably 1:1 to 1000:1, more preferably 5:1 to 100:1. When step 2 is carried out without isolating the (trifluoromethyl)enamine (3), the molar ratio of the protonic acid to the enamine (2) is preferably 1:1 to 1000:1, and 5:1 to 100: 1 is more preferable.

The reaction temperature can be appropriately selected from the range of 0° C. to 80° C., but a sufficiently good yield can be obtained even at room temperature.

The reaction time is not particularly limited, but the desired product can be obtained in good yield by performing the reaction for 10 minutes or more.

INDUSTRIAL APPLICABILITY The present invention is effective as a method for efficiently producing (trifluoromethyl)malonic acid ester, which is an important compound as a fluorine-containing building block of pharmaceuticals.

Next, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.
Example-1

0.159 g (1.0 mmol) of ethyl 3-amino-3-ethoxy-2-propenoate was weighed in a reaction vessel, and the inside of the vessel was replaced with argon. Furthermore, 5 mL of a 0.6 mol/L dimethyl sulfoxide solution of trifluoromethyl iodide (3.0 mmol of trifluoromethyl iodide), 0.3 mL (0.30 mmol) of a 1.0 mol/L aqueous solution of iron sulfate, and dimethyl sulfoxide 5 0.0 mL was added. 0.2 mL of 30% aqueous hydrogen peroxide (hydrogen peroxide 2.0 mmol) was added dropwise to the obtained mixture at a rate of 0.04 mL/min, and then the mixture was stirred at room temperature for 30 minutes. The reaction solution was analyzed by ¹ H and ¹⁹ F-NMR, and it was confirmed that ethyl 3-amino-3-ethoxy-2-trifluoromethyl-2-propenoate was produced.
¹ H-NMR (heavy dimethyl sulfoxide, 500 MHz): δ1.16 (3H, t, J=7.1 Hz), 1.25 (3H, t, J=7.0 Hz), 4.06 (2H, q, J=7.1 Hz), 4.19 (2H, q, J=7.1 Hz), 8.23 (1H, brs), 9.31 (1H, brs).
¹⁹ F-NMR (heavy dimethyl sulfoxide, 470 MHz): δ-49.0 (3F, s).

1.0 mL of concentrated hydrochloric acid was added to the obtained reaction solution, and the mixture was further stirred at room temperature for 1 hour. After the reaction, water was added and the mixture was extracted 3 times with diethyl ether. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Then, it was filtered, concentrated, and purified by silica gel column chromatography to obtain diethyl (trifluoromethyl)malonate as a pale yellow oily liquid (0.114 g, 50%).
¹ H-NMR (heavy dimethyl sulfoxide, 500 MHz): δ1.20 (6H, t, J=7.1 Hz), 4.23 (4H, q, J= 7.1 Hz), 5.29 (1H, q, J=8.7 Hz).
¹⁹ F-NMR (heavy dimethyl sulfoxide, 470 MHz): δ-64.7 (3F, q, J=8.7 Hz).

Example-2
0.318 g (2.0 mmol) of ethyl 3-amino-3-ethoxy-2-propenoate was weighed in a reaction container, and the inside of the container was replaced with argon. Further, 10 mL of a 0.6 mol/L dimethyl sulfoxide solution of trifluoromethyl iodide (6.0 mmol of trifluoromethyl iodide), 0.112 g (0.60 mmol) of ferrocene, and 10 mL of dimethyl sulfoxide were added. 0.4 mL of 30% hydrogen peroxide solution (hydrogen peroxide 4.0 mmol) was added dropwise to the obtained mixture at a rate of 0.04 mL/min, and then the mixture was stirred at room temperature for 15 hours.

After the reaction, 1.0 mL of concentrated hydrochloric acid was added, and the mixture was further stirred at room temperature for 1 hour. After the reaction, ¹⁹ F-NMR confirmed that diethyl (trifluoromethyl)malonate was produced in an amount of 25% based on ethyl 3-amino-3-ethoxy-2-propenoate.

Example-3

0.144 g (1.0 mmol) of ethyl 3-amino-3-ethoxy-2-propenimidate was weighed in a reaction vessel, and the inside of the vessel was replaced with argon. Furthermore, 5 mL of a 0.6 mol/L dimethyl sulfoxide solution of trifluoromethyl iodide (3.0 mmol of trifluoromethyl iodide), 0.3 mL (0.30 mmol) of a 1.0 mol/L aqueous solution of iron sulfate, and dimethyl sulfoxide 5 0.0 mL was added. 0.2 mL of 30% hydrogen peroxide solution (hydrogen peroxide 2.0 mmol) was added dropwise to the obtained mixture at a rate of 0.04 mL/min, and then the mixture was stirred at room temperature for 15 hours.

After the reaction, 1.0 mL of concentrated hydrochloric acid was added, and the mixture was further stirred at room temperature for 1 hour. After the reaction, by ¹⁹ F-NMR, it was confirmed that diethyl (trifluoromethyl)malonate was produced in 26% based on ethyl 3-amino-3-ethoxy-2-propenimidate.

Reference example-1

0.114 g (0.5 mmol) of diethyl (trifluoromethyl)malonate was placed in a reaction vessel, 1.0 mL of acetic acid and 1.0 mL of concentrated hydrochloric acid were added, and the mixture was heated at 100° C. for 6 hours. After the reaction, ¹⁹ F-NMR confirmed that 3,3,3-trifluoropropionic acid was produced in an amount of 91% based on diethyl (trifluoromethyl)malonate.

Claims (6)

Iron compound, hydrogen peroxide solution and general formula (1) R ¹ —S(═O)—R ¹ (1) (in the formula, R ¹ represents an alkyl group having 1 to 4 carbon atoms or a phenyl group). In the presence of the represented sulfoxide, trifluoromethyl iodide was used to formula (2)

(In the formula, each of R ² and R ³ independently represents an alkyl group having 1 to 4 carbon atoms. X represents an oxygen atom or an imino group.) (3)

(Wherein R ² , R ³ and X have the same meanings as described above) to obtain a (trifluoromethyl)enamine, which is then hydrolyzed.

(In formula, R< ² > and R< ³ > shows the same content as the above.) The manufacturing method of the (trifluoromethyl) malonic acid ester represented by this. The production method according to claim 1 , wherein the hydrolysis is performed in the presence of an acid.
that's all
The production method according to claim 2, wherein the acid is a protic acid. Iron compounds include iron(II) sulfate, ammonium(II) sulfate, iron(II) tetrafluoroborate, iron(II) chloride, iron(II) bromide, iron(II) iodide, and iron(II) acetate. ), iron (II) oxalate, bisacetylacetonato iron (II), ferrocene, bis(η ⁵ -pentamethylcyclopentadienyl) iron or iron powder, according to any one of claims 1 to 3. Method. The manufacturing method according to claim 1, wherein the iron compound is iron (II) sulfate. The production method according to claim 1, wherein R ¹ is a methyl group.