JP2017202992A - Method for producing (trifluoromethyl)malonic acid ester - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for efficiently producing (trifluoromethyl)malonic acid ester that is an important compound as a fluorine-containing building block of pharmaceuticals.SOLUTION: The (trifluoromethyl)malonic acid ester represented by formula (4) is produced by trifluoro-methylating 3-amino-3-alkoxy-2-propenoic acid ester or 3-amino-3-alkoxy-2-propen-imine acid ester with trifluoromethyl iodide in the presence of an iron compound, hydrogen peroxide water and sulfoxide, and then hydrolyzing in the presence of an acid. (Rand Rare each independently an alkyl group having C1 to C4 carbon atoms).SELECTED DRAWING: None

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 medical 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 is used. A 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 And then hydrolyzing with an acid (Patent Document 3, Non-Patent Document 1, and references cited therein).

  On the other hand, there has never been a production method using 3-amino-3-alkoxy-2-propenoic acid ester or 3-amino-3-alkoxy-2-propenoic acid ester as a raw material.

JP2004-115377. US 3,538,081, 1970. JP-A-58-126837.

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

  In any 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 a (trifluoromethyl) malonic acid ester using a more readily available and safe raw material.

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

(Wherein R ² and R ³ each 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 contents as described above) (trifluoromethyl) enamine represented by formula (4) is obtained, followed by hydrolysis

(Wherein R ² and R ³ have the same contents as described above); a method for producing a (trifluoromethyl) malonic ester represented by:
(Ii) The production method according to (ii), wherein the hydrolysis is performed 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) ammonium sulfate, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide, iron (II) iodide, acetic acid Any of (i) to (iii) which is iron (II), iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene, bis (η ⁵ -pentamethylcyclopentadienyl) iron or iron powder The production method of 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 is 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 any of these alkyl groups or phenyl groups, but is preferably a methyl group in terms of availability and good yield.
The alkyl group having 1 to 4 carbon atoms represented by R ² and R ³ of enamine (2) may be linear or branched, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group, an isobutyl group, a sec-butyl group, etc. can be illustrated. From the viewpoint of availability, a methyl group or an ethyl group is preferable.

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

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

The production method of the present invention comprises two steps. First, 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 contents as described above). In the presence of 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 acid triamide, N-methyl-2-pyrrolidone, ethers such as 1,4-dioxane, tetrahydrofuran and diethyl ether, methyl acetate, ethyl acetate and the like Examples include esters, acetone, ketones such as methyl (isobutyl) ketone, water, and the like, and these may be used in combination as appropriate. 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 a good yield. For example, inorganic acid salts such as iron (II) sulfate, iron (II) sulfate, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide or iron (II) iodide, Organic metal compounds such as iron acetate (II), iron oxalate (II), bisacetylacetonatoiron (II), ferrocene or bis (η ⁵ -pentamethylcyclopentadienyl) iron can be exemplified, and these May be used in appropriate combination. In addition, iron (II) salt can be generated in the system by combining iron powder, iron (0) salt or iron (I) salt and an oxidizing reagent such as peroxide. In this case, hydrogen peroxide used for 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 solids, but can also be used as solutions. When used as a solution, the solvent may be any of the above-mentioned solvents, but water, dimethyl sulfoxide or a mixed solvent of water and dimethyl sulfoxide is particularly preferable. In this case, the concentration of the iron compound solution is preferably from 0.1 to 10 mol / L, and more preferably from 0.5 to 5 mol / L in terms of good yield.

  The molar ratio of 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 used by diluting with water. 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 35% by weight of a commercially available product as it is or dilute it 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 enamine (2) to 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 carried out at a temperature appropriately selected from the range of 0 ° C to 100 ° C. From the point of good yield, 20 ° C to 70 ° C is preferable.

  When the reaction is performed in a closed system, the reaction can be performed 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. The atmosphere during the reaction may be an inert gas such as argon or nitrogen, but proceeds sufficiently even in air.

  Trifluoromethyl iodide may be used as it is, and in that case, it is diluted with a gas such as argon, nitrogen, air, helium, oxygen, etc., and mixed with a molar fraction of trifluoromethyl iodide of 1% or more. It can be used as a gas. When the reaction is carried out in a closed system, trifluoromethyl iodide or a mixed gas can be used as the reaction atmosphere. The pressure at that time 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, trifluoromethyl iodide or a mixed gas may be bubbled and introduced into the reaction solution in an open system. In this case, the introduction rate of trifluoromethyl iodide or mixed gas is in the range of 1 mL to 200 mL per minute, depending on the scale of the reaction, the amount of catalyst, the reaction temperature, and the molar fraction of trifluoromethyl iodide in the mixed gas. The speed selected from

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

  Although there is no restriction | limiting in particular in reaction time, A target object can be obtained with a sufficient yield by performing for 0.5 hour or more.

  The method for isolating the target product from the solution after the reaction is not particularly limited. The object can be obtained.

  The (trifluoromethyl) enamine (3) obtained in step 1 may be isolated, but can be subjected to 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 (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 performing Step 2 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 acid triamide, N-methyl-2-pyrrolidone, ethers such as 1,4-dioxane, tetrahydrofuran and diethyl ether, methyl acetate, ethyl acetate and the like Examples include esters, acetone, ketones such as methyl (isobutyl) ketone, and water, and these may be used in combination as appropriate. 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 in terms of yield and convenience.

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

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

  Although there is no restriction | limiting in particular in reaction time, A target object can be obtained with a sufficient yield by performing for 10 minutes or more.

  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 for pharmaceuticals.

EXAMPLES Next, although an Example and a reference example demonstrate this invention in detail, this invention is not limited to these.
Example-1

In a reaction vessel, 0.159 g (1.0 mmol) of ethyl 3-amino-3-ethoxy-2-propenoate was weighed, and the inside of the vessel was replaced with argon. Furthermore, 5 mL of a dimethyl sulfoxide solution of trifluoromethyl iodide in 0.6 mol / L (trifluoromethyl iodide 3.0 mmol), 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. To the obtained mixture, 0.2 mL of 30% aqueous hydrogen peroxide (hydrogen peroxide 2.0 mmol) was added dropwise at a rate of 0.04 mL per minute, and then 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 (deuterated dimethyl sulfoxide, 500 MHz): δ 1.16 (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 (deuterated dimethyl sulfoxide, 470 MHz): δ-49.0 (3F, s).

To the obtained reaction solution, 1.0 mL of concentrated hydrochloric acid was added, and the mixture was further stirred at room temperature for 1 hour. After the reaction, water was added and extracted three times with diethyl ether. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Thereafter, the mixture 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 (deuterated dimethyl sulfoxide, 500 MHz): δ 1.20 (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 (deuterated 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 into the reaction vessel, and the inside of the vessel was replaced with argon. Furthermore, 10 mL of trifluoromethyl iodide in a 0.6 mol / L dimethyl sulfoxide solution (6.0 mmol of trifluoromethyl iodide), 0.112 g (0.60 mmol) of ferrocene and 10 mL of dimethyl sulfoxide were added. To the obtained mixture, 0.4 mL of 30% aqueous hydrogen peroxide (4.0 mmol of hydrogen peroxide) was added dropwise at a rate of 0.04 mL per minute, and then 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, it was confirmed by ¹⁹ F-NMR that 25% of diethyl (trifluoromethyl) malonate was produced based on ethyl 3-amino-3-ethoxy-2-propenoate.

Example-3

  To the reaction vessel, 0.144 g (1.0 mmol) of ethyl 3-amino-3-ethoxy-2-propenimidate was weighed and the inside of the vessel was purged with argon. Furthermore, 5 mL of a dimethyl sulfoxide solution of trifluoromethyl iodide in 0.6 mol / L (trifluoromethyl iodide 3.0 mmol), 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. To the obtained mixture, 0.2 mL of 30% hydrogen peroxide water (2.0 mmol of hydrogen peroxide) was added dropwise at a rate of 0.04 mL per minute, and then 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, it was confirmed by ¹⁹ F-NMR that 26% of diethyl (trifluoromethyl) malonate was produced 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, it was confirmed by ¹⁹ F-NMR that 91,3% of 3,3,3-trifluoropropionic acid was produced based on diethyl (trifluoromethyl) malonate.

Claims (6)

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

(Wherein R ² and R ³ each 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 contents as described above) (trifluoromethyl) enamine represented by formula (4) is obtained, followed by hydrolysis

(Wherein R ² and R ³ have the same contents as described above.) A method for producing a (trifluoromethyl) malonic acid ester represented by:   The production method according to claim 2, wherein the hydrolysis is performed in the presence of an acid.   The production method according to claim 2, wherein the acid is a protonic acid. The iron compound is iron (II) sulfate, iron (II) sulfate, iron (II) tetrafluoroborate, iron (II) chloride, iron (II) bromide, iron (II) iodide, iron acetate (II) ), Iron (II) oxalate, iron (II) bisacetylacetonate, ferrocene, bis (η ⁵ -pentamethylcyclopentadienyl) iron or iron powder. Method.   The method according to any one of claims 1 to 3, wherein the iron compound is iron (II) sulfate. The production method according to claim 1, wherein R ¹ is a methyl group.