Method for producing 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives, 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives and 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-triones and methods for producing them

Abstract

To provide 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione.SOLUTION: A ketomalonic acid ester derivative is used as raw material; (perfluoroalkyl)trimethylsilane is used for perfluoroalkylation; and a 2-hydroxy-2-(perfluoroalkyl) malonic acid ester derivative is produced (the reaction formula below). Furthermore, the 2-hydroxy-2-(perfluoroalkyl) malonic acid ester derivative is reacted with urea in the presence of a base in an organic solvent, followed by treatment with hydrochloric acid, thereby producing 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a simple method for producing a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative. The 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative is a useful compound as a synthetic intermediate in the fields of medicine, agrochemicals, and electronic materials, for example, as a synthetic intermediate for 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives and 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione. [Background technology]

[0002] Conventionally, only one example of a method for producing a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative is known, which involves starting with malonic acid ethyl ester shown in the following formula, for a compound in which the perfluoroalkyl group is a trifluoromethyl group, obtaining ethoxycarbonyl(trifluoromethyl)ketene in several steps, reacting it with ethyl nitrite to obtain 2-nitroso-2-(trifluoromethyl)malonic acid ethyl ester, and then reacting it with hydrogen peroxide (e.g., Non-Patent Document 1). However, the method described in Non-Patent Document 1 has the problem that it requires a long reaction step and uses ethyl nitrite, which has safety issues. Although it can be applied to small-scale synthesis, it is a production method that cannot be implemented on a large industrial scale.

[0003] [ka]

[0004] On the other hand, the perfluoroalkylation reaction of ketomalonic acid ester derivatives using (perfluoroalkyl)trimethylsilanes has not been known so far. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] LN Kryukov et al., Zhur. Vses. Khim. Obshsh. Im. Mendeleeva 1977, 22, 355. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a method for simply producing a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative using a ketomalonic acid ester derivative as a raw material. A further object of the present invention is to provide 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives and 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-triones using 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives, and methods for producing them. [Means for solving the problem]

[0007] The present inventors have intensively investigated methods for producing 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives, and as a result have found that perfluoroalkylation is possible using (perfluoroalkyl)trimethylsilane from ketomalonic acid ester derivatives as raw materials, and further that 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives can be used to produce 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives and 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione, thereby completing the present invention.

[0008] That is, the present invention relates to a compound represented by the following general formula (1): [ka] (In formula (1), R 1 and R 2each independently represents a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a benzyl group. In an organic solvent, in the presence of a base and / or a fluoride ion generator, a ketomalonic acid ester derivative represented by the following general formula (2) is reacted with a ketomalonic acid ester derivative represented by the following general formula (2): R f Sim 3 (2) (In formula (2), R f represents a trifluoromethyl group or a pentafluoroethyl group. and then treating with an aqueous hydrochloric acid solution. [ka] (In formula (3), R 1 and R 2 each independently represents a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a benzyl group; R f represents a trifluoromethyl group or a pentafluoroethyl group. The present invention provides a method for producing a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the following formula:

[0009] Furthermore, the present invention relates to a method for producing a 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the following general formula (4) and a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the above general formula (3) by reacting with chlorotrimethylsilane to produce a compound represented by the following general formula (4): [ka] (In formula (4), R 1 and R 2 each independently represents a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a benzyl group; R frepresents a trifluoromethyl group or a pentafluoroethyl group. The present invention provides a method for producing a 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the following formula:

[0010] In addition, the present invention relates to a compound represented by the following general formula (5), which is characterized by reacting 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the following general formula (5) and the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative obtained by the above with urea in an organic solvent in the presence of a base, and then treating with hydrochloric acid. [ka] (In formula (5), R f represents a trifluoromethyl group or a pentafluoroethyl group. The present invention provides a method for producing 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the following formula: Effect of the Invention

[0011] INDUSTRIAL APPLICABILITY The present invention provides a method for easily producing a 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative, which is useful as an industrial production method. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The present invention will be described in detail below. Specific examples of the ketomalonic acid ester derivative represented by the general formula (1) of the present invention include dimethyl ketomalonic acid, 1-ethyl 3-methyl ester ketomalonic acid, 1-n-propyl 3-methyl ester ketomalonic acid, 1-isopropyl 3-methyl ester ketomalonic acid, 1-n-butyl 3-methyl ester ketomalonic acid, 1-isobutyl 3-methyl ester ketomalonic acid, 1-sec-butyl 3-methyl ester ketomalonic acid, 1-tert-butyl 3-methyl ester ketomalonic acid, 1-benzyl 3-methyl ester ketomalonic acid, diethyl ester ketomalonic acid, 1-n-propyl 3-ethyl ester ketomalonic acid, 1-isopropyl 3-ethyl ester ketomalonic acid, 1-n-butyl 3-ethyl ester ketomalonic acid, 1-isobutyl 3-ethyl ester ketomalonic acid, 1-sec-butyl 3-ethyl ester, 1-tert-butyl 3-ethyl ester of ketomalonic acid, 1-benzyl 3-ethyl ester of ketomalonic acid, di-n-propyl ethyl ester of ketomalonic acid, 1-isopropyl 3-n-propyl ester of ketomalonic acid, 1-n-butyl 3-n-propyl ester of ketomalonic acid, 1-isobutyl 3-n-propyl ester of ketomalonic acid, 1-sec-butyl 3-n-propyl ester of ketomalonic acid, 1-tert-butyl 3-n-propyl ester of ketomalonic acid, 1-benzyl 3-n-propyl ester of ketomalonic acid, diisopropyl ester of ketomalonic acid, 1-n-butyl 3-isopropyl ester of ketomalonic acid, 1-isobutyl 3-isopropyl ester of ketomalonic acid, 1-sec-butyl 3-isopropyl ester of ketomalonic acid, ketomalonic acid 1-tert-Butyl 3-isopropyl ester, 1-benzyl 3-isopropyl ester of ketomalonic acid, di-n-butyl ester of ketomalonic acid, 1-isobutyl 3-n-butyl ester of ketomalonic acid, 1-sec-butyl 3-n-butyl ester of ketomalonic acid, 1-tert-butyl 3-n-butyl ester of ketomalonic acid, 1-benzyl 3-n-butyl ester of ketomalonic acid, diisobutyl ester of ketomalonic acid, 1-sec-butyl3-isobutyl ester, 1-tert-butyl ketomalonic acid 3-isobutyl ester, 1-benzyl ketomalonic acid 3-isobutyl ester, di-sec-butyl ketomalonic acid, 1-tert-butyl ketomalonic acid 3-sec-butyl ester, 1-benzyl ketomalonic acid 3-sec-butyl ester, di-tert-butyl ketomalonic acid, 1-benzyl 3-tert-butyl ester, and dibenzyl ketomalonic acid.

[0013] Specific examples of the (perfluoroalkyl)trimethylsilane represented by the general formula (2) of the present invention include (trifluoromethyl)trimethylsilane, (pentafluoroethyl)trimethylsilane, and the like.

[0014] Specific examples of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives of the present invention represented by the general formula (3) in which the perfluoroalkyl group is a trifluoromethyl group include 2-hydroxy-2-(trifluoromethyl)malonic acid dimethyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-ethyl 3-methyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-n-propyl 3-methyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-isopropyl 3-methyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-n-butyl 3-methyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-isobutyl 3-methyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-methyl ester, and 2-hydroxy-2-(trifluoromethyl)malonic acid 1-tert-butyl. 3-Methyl ester, 1-benzyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-methyl ester, diethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-n-propyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-isopropyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-n-butyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-isobutyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-sec-butyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-tert-butyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 1-benzyl 3-ethyl ester of 2-hydroxy-2-(trifluoromethyl)malonic acid, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-Isopropyl 3-n-propyl ester, 2-Hydroxy-2-(trifluoromethyl)malonic acid di-n-propylethyl ester, 2-Hydroxy-2-(trifluoromethyl)malonic acid 1-n-butyl 3-n-propyl ester, 2-Hydroxy-2-(trifluoromethyl)malonic acid 1-isobutyl3-n-propyl ester, 1-sec-butyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-n-propyl ester, 1-tert-butyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-n-propyl ester, 1-benzyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-n-propyl ester, diisopropyl 2-hydroxy-2-(trifluoromethyl)malonic acid 1-n-butyl 3-isopropyl ester, 1-isobutyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-isopropyl ester, 1-sec-butyl 3-isopropyl ester, 1-tert-butyl 3-isopropyl ester, 1-benzyl 2-hydroxy-2-(trifluoromethyl)malonic acid 3-isopropyl ester, di-n-butyl 2-hydroxy-2-(trifluoromethyl)malonate, 1-isobutyl 2-hydroxy-2-(trifluoromethyl)malonate 3-n-butyl ester, 1-sec-butyl 2-hydroxy-2-(trifluoromethyl)malonate 3-n-butyl ester, 1-tert-butyl 2-hydroxy-2-(trifluoromethyl)malonate 3-n-butyl ester, 1-benzyl 2-hydroxy-2-(trifluoromethyl)malonate 3-n-butyl ester, diisobutyl 2-hydroxy-2-(trifluoromethyl)malonate, 1-sec-butyl 2-hydroxy-2-(trifluoromethyl)malonate 3-isobutyl ester, 1-tert-butyl 2-hydroxy-2-(trifluoromethyl)malonate 3-isobutyl ester, 1-benzyl 2-hydroxy-2-(trifluoromethyl)malonate 3-isobutyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid di-sec-butyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-sec-butyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-benzyl2-hydroxy-2-(trifluoromethyl)malonic acid 3-sec-butyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid di-tert-butyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-benzyl 3-tert-butyl ester, 2-hydroxy-2-(trifluoromethyl)malonic acid dibenzyl ester, and the like.

[0015] Specific examples of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivatives represented by the general formula (3) of the present invention in which the perfluoroalkyl group is a pentafluoroethyl group include dimethyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-ethyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-n-propyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-isopropyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-n-butyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-isobutyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-sec-butyl 3-methyl 2-hydroxy-2-(pentafluoroethyl)malonic acid, and 1-tert-butyl 2-hydroxy-2-(pentafluoroethyl)malonic acid. 3-Methyl ester, 1-benzyl 2-hydroxy-2-(pentafluoroethyl)malonic acid 3-methyl ester, diethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-n-propyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-isopropyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-n-butyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-isobutyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-sec-butyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-tert-butyl 3-ethyl ester of 2-hydroxy-2-(pentafluoroethyl)malonic acid, 1-benzyl 2-hydroxy-2-(pentafluoroethyl)malonic acid 3-Ethyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid di-n-propyl ethyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-isopropyl 3-n-propyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-n-butyl3-n-propyl ester, 1-isobutyl 2-hydroxy-2-(pentafluoroethyl)malonic acid 3-n-propyl ester, 1-sec-butyl 2-hydroxy-2-(pentafluoroethyl)malonic acid 3-n-propyl ester, 1-tert-butyl 2-hydroxy-2-(pentafluoroethyl)malonic acid 3-n-propyl ester, 1-benzyl 3-n-propyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid diisopropyl ester, 1-n-butyl 3-isopropyl ester, 1-isobutyl 3-isopropyl ester, 1-sec-butyl 3-isopropyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-isopropyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-benzyl 3-isopropyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid di-n-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-isobutyl 3-n-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-n-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-n-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-benzyl 3-n-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid diisobutyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-isobutyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-tert-Butyl 3-isobutyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-benzyl 3-isobutyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid di-sec-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-tert-butyl2-hydroxy-2-(pentafluoroethyl)malonic acid 3-sec-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-benzyl 3-sec-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid di-tert-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid 1-benzyl 3-tert-butyl ester, 2-hydroxy-2-(pentafluoroethyl)malonic acid dibenzyl ester, and the like.

[0016] Specific examples of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives represented by the general formula (4) of the present invention in which the perfluoroalkyl group is a trifluoromethyl group include 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid dimethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-ethyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-n-propyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isopropyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-n-butyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isobutyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-methyl ester, 1-tert-butyl 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 3-methyl ester, 1-benzyl 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 3-methyl ester, diethyl 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid, 1-n-propyl 3-ethyl ester, 1-isopropyl 3-ethyl ester of 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid, 1-n-butyl 3-ethyl ester of 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid, 1-isobutyl 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 3-Ethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-Ethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-Ethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl3-ethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isopropyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid di-n-propylethyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-n-butyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isobutyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid diisopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-n-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isobutyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid di-n-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-isobutyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl3-n-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid diisobutyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-sec-butyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid di-sec-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-tert-butyl 3-sec-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 3-sec-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid di-tert-butyl ester, 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid 1-benzyl 3-tert-butyl ester, and 2-(trimethylsilyloxy)-2-(trifluoromethyl)malonic acid dibenzyl ester.

[0017] Specific examples of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivatives represented by the general formula (4) of the present invention in which the perfluoroalkyl group is a pentafluoroethyl group include 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid dimethyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-ethyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-n-propyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-isopropyl 3-methyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-n-butyl 3-methyl ester, and 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-isobutyl 3-methyl ester. 3-Methyl ester, 1-sec-butyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Methyl ester, 1-tert-butyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Methyl ester, 1-benzyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Methyl ester, diethyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Ethyl ester, 1-isopropyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Ethyl ester, 1-n-butyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-Ethyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-isobutyl 3-ethyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-ethyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-ethyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl3-ethyl ester, di-n-propyl ethyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-isopropyl 3-n-propyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-n-butyl 3-n-propyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-isobutyl 3-n-propyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-sec-butyl 3-n-propyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-tert-butyl 3-n-propyl ester of 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid, 1-benzyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-n-propyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid diisopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-n-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-isobutyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl 3-isopropyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid Di-n-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-isobutyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-n-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl3-n-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid diisobutyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-sec-butyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl 3-isobutyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid di-sec-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-tert-butyl 3-sec-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 3-sec-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid di-tert-butyl ester, 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid 1-benzyl 3-tert-butyl ester, and 2-(trimethylsilyloxy)-2-(pentafluoroethyl)malonic acid dibenzyl ester.

[0018] Specific examples of the 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the general formula (5) of the present invention include 5-hydroxy-5-(trifluoromethyl)pyrimidine-2,4,6(1H,3H,5H)-trione, 5-hydroxy-5-(pentafluoroethyl)pyrimidine-2,4,6(1H,3H,5H)-trione, and the like.

[0019] Specific examples of bases applicable to the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium acetate, sodium acetate, potassium acetate, etc., and they can be used in the range of 0.01 mol to 0.50 mol per 1 mol of the ketomalonic acid ester derivative represented by the general formula (1) used in the reaction.

[0020] Examples of fluoride ion generators applicable to the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention include sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, and tetra-n-butylammonium fluoride, and can be used in the range of 0.01 mol to 0.50 mol per 1 mol of the ketomalonic acid ester derivative represented by the general formula (1) used in the reaction.

[0021] The (perfluoroalkyl)trimethylsilane applicable to the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention can be used in the range of 1.1 mol to 3.0 mol per 1 mol of the ketomalonic acid ester derivative represented by the general formula (1) used in the reaction.

[0022] As the organic solvent applicable to the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention, any solvent can be used as long as it is inert to the reaction. From the viewpoints of reactivity and solubility of the substrate and reagent, however, preferred are aprotic polar solvents such as ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, etc., and these can be used in an amount of 5 to 1,000 times by weight relative to the ketomalonic acid ester derivative represented by the general formula (1) used in the reaction.

[0023] The temperature and time applicable to the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention are in the range of 0° C. to 50° C. and 5 hours to 20 hours.

[0024] As a post-treatment after the production of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) of the present invention, a known method can be used. For example, a saturated aqueous ammonium chloride solution is added, followed by extraction with diethyl ether or the like, drying with sodium sulfate or the like, filtration, and concentration under reduced pressure to obtain a residue, which is then treated with a 2M hydrochloric acid / diethyl ether solution, neutralized with a saturated aqueous sodium hydrogen carbonate solution, extracted with diethyl ether or the like, dried with sodium sulfate or the like, filtration, and concentration under reduced pressure to obtain a crude target product, which can be further purified by a silica gel column chromatograph or the like, if necessary.

[0025] Specific examples of bases applicable to the production of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) of the present invention include triethylamine, N,N-diisopropylethylamine, N,N-dimethyl-4-aminopyridine (DMAP), 1,8-diazabicyclo[5.4.0]undecen-4-en (DBU), etc., and they can be used in the range of 1.1 mol to 3.0 mol per 1 mol of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) used in the reaction.

[0026] The chlorotrimethylsilane used in the production of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) of the present invention can be used in the range of 1.1 mol to 3.0 mol per 1 mol of the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) used in the reaction.

[0027] As the organic solvent applicable to the production of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) of the present invention, any solvent can be applied as long as it is inert to the reaction. From the viewpoints of reactivity and solubility of the substrate and reagent, preferred examples include ethers such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, etc., aliphatic halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, etc., and aromatic hydrocarbons such as toluene, ethylbenzene, etc., and it is possible to use the organic solvent in an amount of 5 to 100 times by weight relative to the 2-hydroxy-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (3) used in the reaction.

[0028] The temperature and time applicable to the production of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) of the present invention are in the range of 0° C. to 50° C. and 0.5 hours to 5 hours.

[0029] As a post-treatment after the production of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) of the present invention, a known method can be used. For example, after adding water, extracting with diethyl ether or the like, drying with sodium sulfate or the like, filtration, and concentrating under reduced pressure, a residue is obtained, which is then treated with a 2M hydrochloric acid / diethyl ether solution, neutralized with a saturated aqueous solution of sodium bicarbonate, extracted with diethyl ether or the like, dried with sodium sulfate or the like, filtration, and concentrating under reduced pressure to obtain a crude target product, which can be further purified by a silica gel column chromatograph or the like, if necessary.

[0030] The amount of urea used in the production of 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the general formula (5) of the present invention can be in the range of 1.1 mol to 3.0 mol per 1 mol of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) used in the reaction.

[0031] Examples of bases that can be used in the production of 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the general formula (5) of the present invention include sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium isopropoxide, and potassium tert-butoxide, and can be used in an amount of 2.0 mol to 5.0 mol per mol of the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) used in the reaction.

[0032] As the organic solvent applicable to the production of 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the general formula (5) of the present invention, any solvent can be applied so long as it is inert to the reaction. From the viewpoints of reactivity and solubility of substrates and reagents, preferred examples include alcohols such as ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol. The organic solvent can be used in an amount of 3 to 30 times by weight relative to the 2-(trimethylsilyloxy)-2-(perfluoroalkyl)malonic acid ester derivative represented by the general formula (4) used in the reaction.

[0033] The temperature and time applicable to the production of 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by general formula (5) of the present invention are in the range of 60° C. to 120° C. and in the range of 5 hours to 20 hours.

[0034] As a post-treatment after the production of 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the general formula (5) of the present invention, a known method can be used. For example, the solvent is distilled off under reduced pressure, followed by crystallization by adding 1M aqueous hydrochloric acid, filtration, washing with water, and drying to obtain a crude target product, which may be further recrystallized from a solvent such as ethanol or acetone, if necessary. EXAMPLES

[0035] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0036] The following instruments were used for the analysis: 1 H-NMR(300 MHz), 19 F-NMR (282MHz), 13 C NMR (126 MHz): Varian Mercury 300 and Bruker Avance 500 NMR. ATR-FTIR: JASCO FT / IR-4100 spectrometer. ESI-MS: Shimadzu LCMS-2020 (SHIMAZU LCMS-2020). HRMS (ESI): Waters Synapt G2 HDMS.

[0037] Example 1 Preparation of 2-hydroxy-2-(trifluoromethyl)malonic acid diethyl ester (6) [ka]

[0038] After replacing the atmosphere in a 50 mL recovery flask equipped with a magnetic stirrer with nitrogen, ketomalonic acid diethyl ester (52.2 mg, 0.3 mmol, 1.0 equiv), tetramethylammonium fluoride (TMAF, 2.8 mg, 0.03 mmol, 10 mol%), and anhydrous tetrahydrofuran (THF, 6.0 mL) were charged and stirred at room temperature. Next, (trifluoromethyl)trimethylsilane (CF 3 Sim 3 , 85.3 mg, 88.5 μL, 0.6 mmol, 2.0 equiv) was charged and reacted at room temperature for 12 hours with stirring. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with diethyl ether. The organic layer obtained was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue obtained was then dissolved in THF (3.0 mL), to which was added a 2M hydrochloric acid / diethyl ether solution (0.225 mL, 0.45 mmol, 1.5 equiv), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with diethyl ether. The organic layer obtained was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. Benzotrifluoride was used as an internal standard for the crude product obtained. 19 Quantitative analysis by F-NMR gave a yield of 73%. Furthermore, the obtained crude product was purified by flash chromatography (silica gel, n-hexane / ethyl acetate=8 / 2 vol / vol) to obtain the target compound, 2-hydroxy-2-(trifluoromethyl)malonic acid diethyl ester (6), as a colorless transparent liquid (50.5 mg, 0.207 mmol, yield 69%).

[0039] The analysis results were as follows: 1 H-NMR (300MHz, Chloroform-d) δ: 4.39 (q, J = 7.1 Hz, 4H), 1.34 (t, J = 7.1 Hz, 6H) ppm. 13 C-NMR (126MHz, Chloroform-d) δ: 164.3, 121.2 (q, J = 285.3 Hz), 77.7 (q, J = 30.9 Hz), 64.1, 13.8 ppm. 19 F-NMR (282MHz, Chloroform-d) δ: -5.7(s,3F)ppm. ATR-FTIR(neat):ν=3462,2991,1755,1379,1227,1036,858,451cm ?1 . HRMS(ESI,m / z)calcd. for C 8 H 11 F 3 NaO 5 [M+Na] +:267.0456,Found:267.0457.

[0040] Examples 2-7 Preparation of 2-hydroxy-2-(trifluoromethyl)malonic acid diethyl ester (6) [ka]

[0041] The reactions were carried out using the same reaction apparatus as in Example 1, and using the fluoride ion generator or base shown in Table 1 instead of tetramethylammonium fluoride in all cases except for Example 2, and using the solvent shown in Table 1 instead of THF in all cases except for Example 3. The results are shown in Table 1.

[0042] [Table 1]

[0043] Examples 8 to 10 Preparation of various 2-hydroxy-2-(trifluoromethyl)malonic acid ester derivatives [ka]

[0044] The same reaction apparatus as in Example 1 was used, and the same operations as in Example 1 were carried out except that the ketomalonic acid ester derivatives shown in Table 2 were used instead of ketomalonic acid diethyl ester, to obtain the target 2-hydroxy-2-(trifluoromethyl)malonic acid esters. The results are shown in Table 2.

[0045] [Table 2]

[0046] Example 11 Preparation of 2-hydroxy-2-(trifluoromethyl)malonic acid 1-benzyl 3-methyl ester (7) The same reaction apparatus as in Example 1 was used, and the same reaction operation as in Example 1 was carried out except that ketomalonic acid 1-benzyl 3-methyl ester (66.7 mg, 0.3 mmol, 1.0 equiv), lithium acetate (30.0 mg, 0.45 mmol, 0.2 equiv) and DMF (6.0 mL) were used, to obtain the target product, 2-hydroxy-2-(trifluoromethyl)malonic acid 1-benzyl 3-methyl ester (7) as a colorless transparent liquid (52.6 mg, 0.18 mmol, yield 60%).

[0047] Example 12 Preparation of 2-hydroxy-2-(pentafluoroethyl)malonic acid diethyl ester (8) [ka]

[0048] The same reaction apparatus as in Example 1 was used, and (trifluoromethyl)trimethylsilane (CF 3 Sim 3 , 85.3 mg, 88.5 μL, 0.6 mmol, 2.0 equiv) was replaced with (pentafluoroethyl)trimethylsilane (CF 3 CF 2 Sim 3 The same procedure as in Example 1 was carried out except that a 2-hydroxy-2-(pentafluoroethyl)malonic acid diethyl ester (8) was used as a colorless transparent liquid (54.7 mg, 0.186 mmol, yield 62%).

[0049] The analysis results were as follows: 1 H-NMR (300MHz, Chloroform-d) δ: 4.44-4.34 (m, 4H), 1.34 (t, J = 7.1Hz, 6H) ppm. 19 F-NMR (282MHz, Chloroform-d) δ: -79.46(s,3F), -118.91(a,2F)ppm.

[0050] Example 13 Preparation of 5-hydroxy-5-(trifluoromethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (9) [ka]

[0051] [Preparation of 2-(trifluoromethyl)-2-((trimethylsilyl)oxy)malonic acid diethyl ester (8)] Into a 25 mL eggplant-shaped flask equipped with a magnetic stirrer, 2-hydroxy-2-(trifluoromethyl)malonic acid diethyl ester (122.1 mg, 0.5 mmol, 1.0 equiv) obtained by the same method as in Example 1, dichloromethane (2.5 mL), and triethylamine (101.2 mg, 139 μL, 1.0 mmol, 2.0 equiv) were placed and stirred at room temperature for 15 minutes. Then, chlorotrimethylsilane (127 μL, 1.0 mmol, 2.0 equiv) was added thereto, and the reaction was carried out at room temperature for 1 hour.

[0052] After the reaction was completed, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9 / 1 vol / vol) to obtain the target product, 2-(trifluoromethyl)-2-((trimethylsilyl)oxy)malonic acid diethyl ester (8), as a colorless, transparent liquid (142.4 mg, 0.45 mmol, yield 90%).

[0053] The analysis results were as follows: 1 H-NMR (300MHz, Chloroform-d) δ: 4.32 (q, J = 7.0 Hz, 4H), 1.33 (t, J = 7.1 Hz, 6H), 0.21 (s, 9H) ppm. 13 C-NMR (126MHz, Chloroform-d) δ: 164.5, 121.5 (q, J = 286.9 Hz), 81.0 (q, J = 30.4 Hz), 63.0, 13.8, 1.2 ppm. 19 F-NMR (282 MHz, Chloroform-d) δ: -75.8(s,3F)ppm. ATR-FTIR(neat):ν=2983,2908,1763,1379,1201,1041,903,852,758cm ?1 . HRMS(ESI,m / z)calcd. for C 11 H 19 F 3 NaO 5 Si[M+Na] + :339.0852,Found:339.0846.

[0054] [Preparation of 5-hydroxy-5-(trifluoromethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (9)] Urea (36.0 mg, 0.6 mmol, 2.0 equiv), sodium methoxide (21 wt% ethanol solution, 0.6 mL, 0.3 mmol, 3.0 equiv) and absolute ethanol (0.3 mL) were added to a 10 mL test tube equipped with a magnetic stirrer and heated to 80°C. Then, a solution of 2-(trifluoromethyl)-2-((trimethylsilyl)oxy)malonic acid diethyl ester (8) (94.9 mg, 0.3 mmol, 1.0 equiv) in ethanol (0.2 mL) was added thereto and the reaction was carried out at the same temperature for 11 hours. After completion of the reaction, the reaction product was concentrated under reduced pressure, and then 1M hydrochloric acid was added to precipitate a solid. The solid was then filtered, washed with cold water (0.5 mL), and dried under reduced pressure to obtain the target compound, 5-hydroxy-5-(trifluoromethyl)pyrimidine-2,4,6(1H,3H,5H)-trione (9), as a white solid (40.7 mg, 0.192 mmol, yield 64%).

[0055] The analysis results were as follows: 1 H-NMR (300MHz, DMSO-d 6 )δ:11.94(s,2H),7.59(s,1H)ppm. 13 C-NMR (126MHz, DMSO-d6 )δ:164.3,149.6,121.5(q,J=290.5Hz),74.7(q,J=27.8Hz)ppm. 19 F-NMR (282MHz, DMSO-d 6 ) δ: -75.7(s,3F)ppm. ATR-FTIR(NaBr):ν=3560,3305,2449,1739,1211,870,769,696,424cm ?1 . mp:205-206℃. HRMS(ESI,m / z)calcd. for C 5 H 2 F 3 N 2 O 4 [MH] - :210.9967,Found:210.9965. [Industrial Applicability]

[0056] The 2-hydroxy-2-(trifluoromethyl)malonic acid ester derivatives obtained by the method of the present invention are useful as starting materials for the synthesis of trifluoromethyl group-containing heterocycles used in the fields of medicines, agrochemicals, and electronic materials.

Claims

[Claim 1] The following general formula (5) 【Chemistry 11】 (In formula (5), R ｆ represents a trifluoromethyl group or a pentafluoroethyl group. The present invention relates to a 5-hydroxy-5-(perfluoroalkyl)pyrimidine-2,4,6(1H,3H,5H)-trione represented by the formula:

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