JPH1067754A - Trifluoromethylpyrimidine derivatives having hypoglycemic action and method for producing the same - Google Patents

Abstract

(57) [Problem] To provide a novel trifluoromethylpyrimidine derivative having a hypoglycemic action and a method for producing the same. SOLUTION: General formula (1) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ² and R ³ may be the same or different and each represents hydrogen, a lower alkyl group or unsubstituted, A represents a lower alkoxy group or ＯO, B represents hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group; Group, = S or = O
One of the bonds between 1-2 and 2-B represents a single bond and the other represents a double bond, and the bonds between 3-4 and 4-A represent one single bond and the other a double bond. A trifluoromethylpyrimidine derivative represented by the formula:

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel trifluoromethylpyrimidine derivative which has a hypoglycemic action and is useful as a therapeutic agent for diabetes and its complications.

[0002]

2. Description of the Related Art Biguanides and sulfonylurea compounds have been conventionally used as therapeutic drugs for oral diabetes. However, biguanide compounds cause lactic acidosis or hypoglycemia, and sulfonylureas cause severe and prolonged hypoglycemia, and their side effects have become a problem. ing. It is known that trifluoromethylpyrimidine derivatives have antiviral, bactericidal and antiulcer activities, and that the following compound (A) has thymidine phosphorylase and uridine phosphorylase inhibitory activities (Bioorganicheskaya Khimiya,
Volume 13. P.38 (1987), Journal. Of Medicinal Chemis
try, Volume 19 P.71 (1976), Journal of Pharmaceutica
l Science, Vol. P.1081 (1967) etc.). However, it is not known that these derivatives having a trifluoromethylpyrimidine ring as a mother nucleus have a hypoglycemic effect, and compounds having a substituent on the benzene ring are novel.

[0003]

Means for Solving the Problems The present inventors have conducted intensive studies on highly safe drugs having a strong hypoglycemic action in order to solve the above-mentioned problems of the prior art.
The present inventors have found that a novel trifluoromethylpyrimidine derivative represented by the following general formula (1) has an excellent hypoglycemic effect, and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1): [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ² and R ³ may be the same or different and each represents hydrogen, a lower alkyl group or unsubstituted, A represents a lower alkoxy group or ＯO, B represents hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group; Group, = S or = O
One of the bonds between 1-2 and 2-B represents a single bond and the other represents a double bond, and the bonds between 3-4 and 4-A represent one single bond and the other a double bond. A trifluoromethylpyrimidine derivative compound represented by the formula:

In the present invention, the salts are conventional ones, such as metal salts, such as alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), aluminum salts, etc. And pharmacologically acceptable salts.

In the present invention, "a phenyl group having 1 to 3 substituents" means a methoxy group, a hydroxy group, a t-
Butyl group, (4-trifluoromethylphenylmethyl)
Aminocarbonyl group, 2-methoxyethoxymethoxy group, 2- (5-ethylpyridin-2-yl) ethoxy group, ethoxycarbonylmethoxy group, 4-trifluoromethylphenylmethoxy group, 4-bromophenylmethoxy group, 4-bromo Benzoylmethoxy group, 4-methoxyphenylmethoxy group, methylthio group, N- [4- (2,
4-dioxothiazolidine-5-yl) methylphenyl] carbamoylmethyloxy group, N- (2-thiazolyl) carbamoylmethyloxy group, N- (2-pyridyl) carbamoylmethyloxy group, 4-[(1,2,2
3,4-tetrahydro-2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] phenylmethyl group, methylenedioxy group, (3,5-dimethylisoxazol-4-yl) methoxy group and the like And a phenyl group having 1 to 3 groups.

The term "5- or 6-membered heteromonocyclic or condensed heterocyclic ring" means that O, S and N are 1 to 3 as hetero atoms.
Means a heteroaromatic monocyclic ring or a heterocyclic saturated monocyclic ring, and a benzene fused ring thereof, for example, pyridine, quinoline,
Tetrahydroquinoline, benzimidazole, 1,4-
Examples of the substituent which the heterocyclic ring may have include a lower alkyl group, a hydroxyl group, a lower alkoxy group, an aralkyloxy group and the like.

[0008] The term "lower alkyl group" means a linear or branched C1-C4 group such as a methyl, ethyl or propyl group.
And three. Unsubstituted in R ² and R ³ means that the nitrogen atom at the substitution position has no substituent.

The "lower alkoxy group" includes straight or branched ones having 1 to 3 carbon atoms, such as methoxy, ethoxy or propoxy groups.

The "lower alkylthio group" includes straight-chain or branched ones having 1 to 3 carbon atoms, such as a methylthio, ethylthio or propylthio group.

The "halogen atom" includes fluorine, chlorine, bromine and iodine atoms.

For the following pyrimidine rings,
Each tautomer can exist. [In the above figure, B ¹ represents an oxygen atom and a sulfur atom, B ² represents a hydrogen, a lower alkyl group, a lower alkoxy group and a lower alkylthio group, and A ¹ represents a lower alkoxy group.] It contains all of the body and may be a mixture thereof.

The compound represented by the general formula (1) can be synthesized by the following route.

The β-ketoester derivative (2) is reacted with an amidine or an alkylisothiourea (3) in water or an organic solvent such as methanol or ethanol at room temperature-reflux temperature of the solvent to give 6-trifluoromethyl-4 (3H )
A thiouracil derivative (4-b) can be synthesized by reacting the pyrimidinone derivative (4-a) with thiourea.

[0015] [In the above figure, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ⁴ represents a lower alkyl group, R ⁵ represents hydrogen, a lower alkylthio group or a lower alkyl group.]

In the above reaction formula, R ⁵ is S
A compound (1) wherein R ¹³ (R ¹³ represents a lower alkyl group);
2) is an intermediate for the synthesis of other 6-trifluoromethylpyrimidine derivatives. That is, (12) is acid-hydrolyzed or, preferably, oxidized with an oxidizing agent such as peracid, perborate, persulfate or ruthenium salt, and then water and an organic solvent such as methanol, ethanol or the like. In a mixed solvent,
Hydrolysis with an alkali, for example, sodium hydroxide, potassium hydroxide, or the like, at 0 ° C. and under reflux, can be derived to the 6-trifluoromethyluracil derivative (11-a). (11-a) is prepared in an organic solvent inert to the reaction, for example, in N, N-dimethylformamide or the like, in the presence of a base, for example, potassium carbonate or sodium carbonate.
The N-substituted compound (9-a) can be derived by reaction with an alkyl halide at 0 ° C.-reflux under heating, preferably at room temperature. The 2,4-dialkoxy-6-trifluoromethylpyrimidine derivative (6-a) is (11-
a) an organic solvent such as chloroform, methylene chloride,
In benzene or the like, a halogenating agent such as phosphorus oxychloride,
Thionyl chloride or thionyl bromide can be converted to a base, such as
In the presence of triethylamine, tripropylamine and the like, the reaction temperature is room temperature to reflux, preferably (Journal of Med.
icinal Chemistry, vol. p.1243 (1987)), that is, phosphorus oxychloride is reacted under heating and reflux in the presence of tripropylamine to halogenate,
It can be obtained by a substitution reaction with sodium alkoxide at room temperature and under reflux with heating.

[0017] [In the above figure, R ¹ is as described above, R ¹¹ is a lower alkyl group, R ¹³ is a lower alkyl group, R ¹⁴ is a lower alkyl group, and X is a halogen atom.]

In the method (12), after an oxidizing agent such as a peracid, a perborate, a persulfate or a ruthenium salt is allowed to act, the temperature is reduced to 0 °
A 2-alkoxy-6-trifluoromethyl-4 by a substitution reaction with a sodium alkoxide under heating and refluxing;
(3H) -pyrimidinone derivative (13-a). Further, (13-a) is an organic solvent, for example,
In an inert solvent such as N, N-dimethylformamide, in the presence of a base such as potassium carbonate or sodium carbonate,
The N-substituted product (9-substituted) is reacted with an alkyl halide at 0 ° C. and under reflux, preferably at room temperature.
b).

[0019]

Further, (12) is obtained by converting (11-a) to (6-
The 2-alkylthio-4-alkoxy-6-trifluoromethylpyrimidine derivative (6-b) can be derived under the same conditions as in the method for deriving a). In addition, (6
-B) is 4-alkoxy-6-trifluoromethyl- under the same conditions as in the method for deriving (12) to (11-a).
It can be derived to a 2 (1H) -pyrimidinone derivative (11-b).

[0021]

(12) is a method for preparing an organic solvent such as N,
0 ° C. in an inert solvent such as N-dimethylformamide in the presence of a base such as potassium carbonate or sodium carbonate;
The N-substituted compound (9-c) can be derived by reaction with an alkyl halide (8) at reflux, preferably at room temperature. Furthermore, (9-c) is converted from (12) to (11-
3-alkyl-6 under the same conditions as in the process leading to a)
-Trifluoromethylpyrimidine-2,4 (1H, 3
H) -dione derivative (11-c).

[0023]

The compound (16-a) can be prepared, for example, by subjecting a derivative (14-a) having a hydroxyl group protected by a 4-methoxyphenylmethyl group or a 2-methoxyethoxymethyl group to acidic conditions, for example, tosylic acid or trifluoroacetic acid. In the presence of an acid such as, in an organic solvent such as methanol, anisole and the like,
After deprotection at 0 ° C.-reflux under heating, in an organic solvent such as an inert solvent such as N, N-dimethylformamide, in the presence of a base such as potassium carbonate or sodium carbonate,
It can be synthesized by reaction with an alkyl halide at 0 ° C.-reflux with heating, preferably at room temperature. In addition, these derivatives (16-a) are prepared under the same conditions as in the above-mentioned method for deriving (12) to (11-a), using 3-alkyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H). )-
It can lead to a dione derivative (11-a).

[0025] [In the above figure, R ¹¹ , R ¹³ and X are as described above, R ¹⁵ is a 4-methoxyphenylmethyl group and a methoxyethoxymethyl group, R ¹⁶ is a benzyl group which may have a substituent,
(3,5-dimethylisoxazol-4-yl) methyl group, 4-bromobenzoylmethyl group or lower alkoxycarbonylmethyl group is shown.]

The derivative (17-a) having a lower alkoxycarbonylmethyloxy group can be prepared by converting its ester group to an acid or alkali condition, for example, sodium hydroxide or the like under water or a mixed solvent of water and an alcohol such as water and ethanol. After being hydrolyzed by acting under a temperature of ℃ ° C.-heating under reflux, the amide derivative (19-a) can be derived with an amine (18) and a common condensing agent such as diethyl cyanophosphate. In addition, the derivative (19-b) is converted from (12) to (11-b).
Under the same conditions as in the method leading to a), 3-alkyl-6-trifluoromethylpyrimidine-2,4 (1H,
3H) -dione derivative (11-e).

[0027] [In the figure, R ¹¹ and R ¹³ are the same as described above, and R ¹⁷ represents pyridine, thiazole, or a phenyl group having a (2,4-dioxothiazolidine-5-yl) methyl group]

(22-a) is obtained by subjecting (20-a) to acid hydrolysis (detailed in the description of the derivation of (6-a) to (11-a) below), followed by (17-a). It can be obtained under the same condensation conditions as those leading to (19-a) from a).

[0029] [In the formula, R ¹⁸ represents a lower alkyl group, and R ¹⁹ represents a phenyl group which may have a lower alkyl group or a trifluoromethyl group. ]

The 2,4-dialkoxypyrimidine derivative (26) having a substituent at the 5-position is treated with an organometallic reagent after halogenating the dialkoxypyrimidine derivative (23) to give an aldehyde (24) or an alkyl halide ( twenty five)
Can be synthesized by reacting

[0031] [In the above formula, R ¹ , R ¹⁴ and X are as described above, and Y represents hydrogen or a hydroxyl group.]

In the halogenation of compound (23), the reaction is carried out in an organic solvent such as chloroform, methylene chloride, benzene or the like, preferably in acetic acid, and a halogenating agent such as N-chlorosuccinimide, N-bromosuccinimide or the like. Can be performed. The reaction can be carried out at a temperature from ice cooling to the reflux temperature of the solvent. The next reaction is carried out in an inert organic solvent, for example, tetrahydrofuran or the like.
After metal-halogen exchange with an organometallic reagent such as butyllithium, the reaction can be carried out by reacting the compound of the general formula (24) or (25). The reaction temperature is-
It can be performed at 78 ° C to room temperature.

The alcohol derivative (26-a) can be converted to a compound (6-a) by reduction. [Wherein R ¹ , R ¹⁴ , X and Y are as described above]

The reaction is carried out in an organic solvent such as ethanol, ethyl acetate, N, N-dimethylformamide and the like at room temperature to room temperature.
Normal pressure to 4 in the presence of a catalyst such as palladium-activated carbon
It can be carried out by adding hydrogen to kg / cm ² under hydrogen pressure. If necessary, an acid such as hydrochloric acid may be added.

Alternatively, the compound (26-a) can be also produced by halogenating the compound (26-a) with a halogenating agent such as thionyl chloride or thionyl bromide in an organic solvent such as methylene chloride or without solvent, and then reducing the compound. The reduction is carried out by hydrogenation in an organic solvent such as ethanol, ethyl acetate, N, N-dimethylformamide or the like under room temperature to heating under normal pressure to 4 kg / cm ² of hydrogen in the presence of a catalyst such as palladium-activated carbon. It can be done by doing. If necessary, organic hydrochloric acid such as triethylamine may be added.

The compound (6-a) can be converted to a uracil derivative (11-a) by acid hydrolysis. [Wherein R ¹ and R ¹⁴ are as described above]

The reaction can be carried out in a mineral acid such as hydrochloric acid or sulfuric acid, or a mixed solvent of these mineral acids and an organic solvent such as acetic acid at room temperature to a solvent reflux temperature, preferably at a solvent reflux temperature. Compound (11-a) can also be synthesized by treating compound (6-a) with an iodide such as sodium iodide. The reaction can be carried out in an organic solvent such as acetic acid at room temperature to a solvent reflux temperature, preferably at a solvent reflux temperature.

[0038]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
The abbreviations used in the examples have the following meanings. ¹ H NMR proton nuclear magnetic resonance spectrum MS electron impact ionization mass spectrometry MS (FAB) Fast atom bombardment mass spectrometry HRMS High resolution electron impact ionization mass spectrometry GC-MS Gas chromatography / electron impact ionization mass spectrometry CDCl ₃ fold Hydrogenated chloroform d6-DMSO deuterated dimethyl sulfoxide Bn benzyl group PMB 4-methoxyphenylmethyl group

Reference Example 1 2-[(3,4-dimethoxyphenyl) methyl] -3-
Synthesis of ethyl oxo-4,4,4-trifluorobutyrate

Ethyl trifluoroacetoacetate (11.2 g) was added to a suspension of 60% sodium hydride oil (2.45 g) in 1,2-dimethoxyethane (50 ml) under ice-cooling, and the reaction solution was heated to reflux for 2 minutes. Thereafter, a solution of 3,4-dimethoxybenzyl chloride (10.9 g) in 1,2-dimethoxyethane (30 ml) and sodium iodide (8.70 g) were added.
The mixture was refluxed for 8 hours. The reaction solution was poured into ice water, made weakly acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer is water and
Wash with saturated saline, dry with anhydrous sodium sulfate,
It was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 4:
Purification in 1) gave the title compound as a pale yellow oil. Yield 16.6 g, 85% MS (m / z): 334 (M ⁺ )

Reference Examples 2 to 8 The compounds shown in Table 1 were obtained in the same manner as in Reference Example 1.

[0042]

[Table 1]

Example 1 5-[(1,3-benzodioxol-5-yl) methyl] -2-methylthio-6-trifluoromethyl-4
(3H) -pyrimidinone

A solution of potassium hydroxide (680 mg) in a methanol-water mixture (5 ml-5 ml) was added to a methanol suspension of methyl isothiourea sulfate (2.89 g), and the mixture was stirred at room temperature for 10 minutes. , 3-Benzodioxol-5-yl) methyl] -3-oxo-4,4,4-trifluorobutyrate (3.00 g) in methanol (10 ml) was added and stirred at room temperature for 3 hours. Further, after heating under reflux for 4.5 hours, the mixture was left at room temperature overnight. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was saturated with sodium chloride, made weakly acidic with dilute hydrochloric acid, and further extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-hexane to give the title compound as colorless needles. 1.31 g, yield 40%, melting point 201.0-205.0 ℃

Elemental analysis: (%) C ₁₄ H ₁₁ F ₃ N ₂ O ₃
Calculated value for S: C: 48.84, H: 3.22, N: 8.14 Actual value: C: 49.05, H: 3.24, N: 8.33

Examples 2 to 8 In the same manner as in Example 1, the compounds shown in Table 2 were obtained.

[0047]

[Table 2]

Example 9 5-[(1,3-benzodioxol-5-yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1
H, 3H) -dione

5-[(1,3-benzodioxol-5)
3-yl) methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (916 mg) in a mixed solution of methylene chloride (10 ml) and tetrahydrofuran (5 ml) under ice-cooling. After adding an acid (690 mg) and stirring at room temperature for 1 hour, 3-chloroperbenzoic acid (100 mg) was added under ice cooling, and the mixture was further stirred at room temperature for 40 minutes. Ethyl acetate was added to the reaction solution, washed with a saturated aqueous solution of sodium hydrogen sulfite and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. An aqueous solution of sodium hydroxide (400 mg of NaOH, 15 ml of water) was added to the obtained residue, and the mixture was added
Heat for another minute and add sodium hydroxide (1.30 g)
After heating and stirring at 100 ° C. for 30 minutes, the mixture was left at room temperature overnight. Water was added to the reaction solution, washed with methylene chloride, acidified with 10% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether and recrystallized from ethyl acetate to give the title compound as colorless needles. Yield: 784 mg, 89% Melting point: 213.0-214.0 ° C

Elemental analysis value (%): C ₁₃ H ₉ F ₃ N ₂ O ₄
Calculated value C: 49.69, H: 2.89, N: 8.92 Actual value C: 49.43, H: 2.81, N: 8.87

Examples 10 to 14 In the same manner as in Example 9, the compounds shown in Table 3 were obtained.

[0052]

[Table 3]

Example 15 5-[(1,3-benzodioxol-5-yl) methyl] -1,3-dimethyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

5-[(1,3-benzodioxol-5)
-Yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione (416mg) and potassium hydroxide (190mg), water (10ml), methanol (3ml)
After the mixture was concentrated under reduced pressure, N, N-dimethylformamide (8 ml) was added to the residue obtained by azeotropic dehydration with toluene, and methyl iodide (0.25 ml) was added dropwise under ice cooling, and the mixture was added at room temperature for 30 minutes.
Stirred for minutes. The reaction solution was left at room temperature overnight, added with water, made weakly acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 4:
After purification in 1), preparative thin-layer chromatography (developing solvent: hexane: methylene chloride: methanol = 2:
1: 0.1) to give the title compound as a colorless oil. Yield 145mg, 32% yield

Elemental analysis value (%): C ₁₅ H ₁₃ F ₃ N ₂ O ₄
Calculated value C: 52.64, H: 3.83, N: 8.18 Actual value C: 52.65, H: 3.74, N: 8.12

Example 16 5-[(1,3-benzodioxol-5-yl) methyl] -2-methoxy-6-trifluoromethyl-4 (3
H) -Pyrimidinone

5-[(1,3-benzodioxol-5)
-Yl) methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (2.00 g) in a mixed solution of methylene chloride (20 ml) and tetrahydrofuran (50 ml) under ice-cooling. Benzoic acid (1.43 g) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous solution of sodium hydrogen sulfite, an aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was diluted with a small amount of ethyl acetate, and the insoluble crystals were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was treated with methanol (5 ml).
This was added to a methanol solution of sodium methoxide prepared from sodium metal (140 mg) -methanol (10 ml), and heated under reflux for 8 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with diluted hydrochloric acid, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate) and recrystallized from methanol to give the title compound as colorless needles. Yield 260mg, 14% melting point 183.0-184.0 ℃

Elemental analysis value (%): C ₁₄ H ₁₁ F ₃ N ₂ O ₄
Calculated value C: 51.23, H: 3.38, N: 8.53 Observed value C: 50.99, H: 3.24, N: 8.49

Example 17 5-[(1,3-benzodioxol-5-yl) methyl] -2-methyl-6-trifluoromethyl-4 (3
H) -Pyrimidinone

2-[(1,3-benzodioxol-5)
-Yl) methyl] -3-oxo-4,4,4-trifluorobutyrate (690 mg) in a solution of ethanol (5 ml) under ice cooling with acetamidine hydrochloride (225 mg) and sodium hydroxide (95.0 mg). Add a mixed aqueous solution (3 ml), and add
For 21 hours. The reaction solution was poured into water, made weakly acidic with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1 to 1: 1).
1: 1) After purification, recrystallization with ethyl acetate-hexane,
The title compound was obtained as colorless needles. Yield: 187 mg, 28% melting point: 205.0-206.0 ° C

HRMS (m / z): C ₁₄ H ₁₁ F ₃ N ₂ O
Calculated value as ₃ : 312.0722 Actual value: 312.0699

Example 18 5-[(1,3-benzodioxol-5-yl) methyl] -6-trifluoromethyl-4 (3H) -pyrimidinone

2-[(1,3-benzodioxol-5)
-Yl) methyl] -3-oxo-4,4,4-trifluorobutyrate and formamidine acetate
In the same manner as in 17, the title compound was obtained as colorless prisms. Yield 13% Melting point 200.0-201.0 ° C (ethyl acetate recrystallization)

Elemental analysis value (%): C ₁₃ H ₉ F ₃ N ₂ O ₃
Calculated value C: 52.36, H: 3.04, N: 9.39 Actual value C: 52.55, H: 2.97, N: 9.43

Example 19 5-[(1,3-benzodioxol-5-yl) methyl] -6-trifluoromethylpyrimidine-4 (3H)
-On-2 (1H) -thione

T-Butyl alcohol (30
60% oily sodium hydride (500mg) in
After stirring at room temperature for 5 minutes, thiourea (1.00 g) was added, and the mixture was further stirred at room temperature for 5 minutes. The reaction mixture was charged with 2-[(1,3-benzodioxol-5-yl) methyl] -3-oxo-4,4,4.
A solution of ethyl 4-trifluorobutyrate (4.00 g) in t-butyl alcohol (10 ml) was added, and the mixture was stirred with heating for 8 hours. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was washed with diisopropyl ether and subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 1: 1).
2) After purification, recrystallization from methanol-water gave the title compound as yellow prism crystals. Yield: 137 mg, 3% melting point: 223.0-224.5 ° C

Elemental analysis value (%): C ₁₃ H ₉ F ₃ N ₂ O ₃
Calculated value for S: C: 47.27, H: 2.75, N: 8.48 Measured value: C: 47.40, H: 2.58, N: 8.24

Example 20 5-[(1,3-benzodioxol-5-yl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine 5-[(1,3-benzodioxol-5-yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1
H, 3H) -dione (805 mg), phosphorus oxychloride (9.00)
A mixture of g) and tripropylamine (1.00 ml) was heated at reflux for 3 hours. After the temperature was brought to room temperature, the reaction solution was poured into ice water,
Stir for 10 minutes and extract with ether. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate,
It was concentrated under reduced pressure. A solution obtained by adding methanol (10 ml) to the obtained residue was added to a methanol solution of sodium methoxide prepared with 60% oily sodium hydride (500 mg) -methanol (5 ml), and the mixture was heated under reflux for 5 hours. The reaction solution was poured into ice water, made weakly acidic with diluted hydrochloric acid, and extracted with ether. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: hexane: methylene chloride = 3: 1 to 1: 1) to give the title compound as a colorless oil. Yield 465mg, 53% yield

Elemental analysis value (%): C ₁₅ H ₁₃ F ₃ N ₂ O ₄
Calculated value C: 52.64, H: 3.83, N: 8.18 Actual value C: 52.70, H: 3.68, N: 8.16

Example 21 5-[(1,3-benzodioxol-5-yl) methyl] -4-methoxy-2-methylthio-6-trifluoromethylpyrimidine

5-[(1,3-benzodioxol-5)
-Yl) methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (2.00 g), phosphorus oxychloride (20.0 g) and tripropylamine (1.11 ml)
Was heated to reflux for 1 hour. Bring the reaction to room temperature,
The mixture was poured into ice water, stirred for 30 minutes, and extracted with ether. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was diluted with methanol (10 ml), and this solution was added to a methanol solution of sodium methoxide prepared with 60% oily sodium hydride (350 mg) -methanol (10 ml), and the mixture was heated under reflux for 1 hour. The reaction solution was poured into ice water, neutralized with dilute hydrochloric acid, and extracted with ether. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (eluent: hexane: methylene chloride = 3: 1 to 1:
Purification in 1) gave the title compound as a colorless oil. yield
1.56 g, 75% yield

Elemental analysis value (%): C ₁₅ H ₁₃ F ₃ N ₂ O ₃
Calculated as S C: 50.28, H: 3.66, N: 7.82 Actual value C: 50.32, H: 3.40, N: 7.86

Example 22 5-[(1,3-benzodioxol-5-yl) methyl] -4-methoxy-6-trifluoromethyl-2 (1
H) -Pyrimidinone

5-[(1,3-benzodioxol-5)
-Yl) methyl] -4-methoxy-2-methylthio-6
To a solution of -trifluoromethylpyrimidine (1.23 g) in methylene chloride (20 ml) was added 3-chloroperbenzoic acid (850 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours.
The extract was washed with a saturated aqueous solution of sodium hydrogen sulfite and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
1N aqueous sodium hydroxide solution (15 ml) was added to the obtained residue.
After heating at 80 ° C for 1 hour, pour into ice water and add 10
The mixture was made weakly acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was washed with ether, recrystallized from methanol, and purified by silica gel column chromatography (developing solvent: methylene chloride: methanol = 30: 1). Further recrystallization from methanol-water gave the title compound as colorless needles. Yield 263 mg, 23% melting point 185.0-186.0 ℃

Elemental analysis value (%): C ₁₄ H ₁₁ F ₃ N ₂ O ₄
Calculated value: C: 51.23, H: 3.38, N: 8.53 Actual value: C: 51.16, H: 3.25, N: 8.50

Example 23 5-[(1,3-benzodioxol-5-yl) methyl] -2-methoxy-3-methyl-6-trifluoromethyl-4 (3H) -pyrimidinone

5-[(1,3-benzodioxol-5)
-Yl) methyl] -2-methoxy-6-trifluoromethyl-4 (3H) -pyrimidinone (440 mg) in N, N-dimethylformamide solution (2 ml) was mixed with potassium carbonate (66 ml).
0 mg), and methyl iodide (0.40 ml) was added dropwise with stirring under ice-cooling. The temperature was gradually raised to room temperature, and after stirring overnight, the mixture was further stirred for 8 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 5: 1), and further purified by preparative thin-layer chromatography (developing solvent: hexane: methylene chloride = 2: 3). The title compound was obtained as a colorless oil. 250 mg, 23% yield

Elemental analysis value (%): C ₁₅ H ₁₃ F ₃ N ₂ O ₄
Calculated value C: 52.64, H: 3.83, N: 8.18 Actual value C: 52.67, H: 3.79, N: 8.13

Example 24 5-[(1,3-benzodioxol-5-yl) methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone 5-[(1,3-benzodioxol-5-yl) methyl] -2-methylthio-6-trifluoromethyl-4
Potassium carbonate (1.00 g) was added to a solution of (3H) -pyrimidinone (1.35 g) in N, N-dimethylformamide (10 ml).
Then, methyl iodide (0.30 ml) was added under ice-cooling and stirring, and the mixture was allowed to stand at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue is flash silica gel column chromatography (developing solvent: hexane: ethyl acetate = 10: 1).
Purification provided the title compound. Yield: 926 mg, 66%. The product was recrystallized from hexane-ethyl acetate.
The title compound was obtained as colorless prism crystals. 133.0-134.5 ° C MS (m / z): 358 (M ⁺ )

Example 25 5-[(1,3-benzodioxol-5-yl) methyl] -3-methyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

5-[(1,3-benzodioxol-5)
-Yl) methyl] -3-methyl-2-methylthio-6-
Trifluoromethyl-4 (3H) -pyrimidinone (810m
g), Magnesium monoperoxyphthalate hexahydrate (80%; 768 mg) in ethanol (20 ml) -water (10 ml)
The mixed solution was heated at a bath temperature of 50 ° C., N, N-dimethylformamide (10 ml) and methylene chloride (10 ml) were added, and the mixture was heated and stirred for 5 hours. After methylene chloride and ethanol in the reaction solution were distilled off under reduced pressure, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from diisopropyl ether-ethyl acetate and then recrystallized from methanol to obtain the title compound as colorless granular crystals. Yield 275 mg, 37% melting point 192.0-193.0 ℃

Elemental analysis value (%): C ₁₄ H ₁₁ F ₃ N ₂ O ₄
Calculated value C: 51.23, H: 3.38, N: 8.53 Actual value C: 50.99, H: 3.35, N: 8.52

Example 26 5-[(1,3-benzodioxol-5-yl) methyl] -3-ethyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone

5-[(1,3-benzodioxol-5)
-Yl) methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (1.00 g) N, N
After potassium carbonate (600 mg) was added to a dimethylformamide solution (10 ml), ethyl iodide (0.26 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, made weakly acidic with 1N hydrochloric acid, and extracted with a mixed solution of ethyl acetate-hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1) to give the title compound as colorless prisms. Yield 402m
g, yield 37%, melting point 108.0-109.5 ° C MS (m / z): 372 (M ⁺ )

Further, 5-[(1,3-benzodioxol-5-yl) methyl] -2-methylthio-4-ethoxy-6-trifluoromethylpyrimidine was obtained. Colorless oil, yield 360mg, yield 33%

Example 27 5-[(1,3-benzodioxol-5-yl) methyl] -3-ethyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

5-[(1,3-benzodioxol-5)
-Yl) methyl] -3-ethyl-2-methylthio-6-
Trifluoromethyl-4 (3H) -pyrimidinone (375m
g) in methylene chloride (10 ml) under ice-cooling and stirring.
After adding chloroperbenzoic acid (250 mg), the mixture was left at room temperature overnight. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen sulfite, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A 1N aqueous sodium hydroxide solution (5 ml) and tetrahydrofuran (5 ml) were added to the obtained residue and dissolved. The mixture was allowed to stand at room temperature overnight, concentrated under reduced pressure, acidified with 1N hydrochloric acid, and the precipitated crystals were collected by filtration. Washed with water. The obtained crystals were washed with diisopropyl ether and then washed with methanol-
Recrystallization from water gave the title compound as colorless needles. Yield 1
38mg, yield 40%, melting point 141.0-142.0 ℃

Elemental analysis value (%): C ₁₅ H ₁₃ F ₃ N ₂ O ₄
Calculated value C: 52.64, H: 3.83, N: 8.18 Actual value C: 52.42, H: 3.67, N: 8.19

Example 28 5-[[4-Methoxy-3- (4-methoxyphenylmethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone

N, N- of 5-[[4-methoxy-3- (4-methoxyphenylmethoxy) phenyl] methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (11.2 g) After potassium carbonate (5.00 g) was added to the dimethylformamide solution (100 ml), methyl iodide (1.60 ml) was added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into water, neutralized by adding diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 7: 2 followed by hexane: ethyl acetate: methylene chloride = 1: 1: 3) to give the title compound as a colorless powder. 8.02 g, 70% yield Melting point 110.0-112.0 ° C MS (m / z): 480 (M ⁺ )

Example 29 5-[[4-Methoxy-3- (4-methoxyphenylmethoxy) phenyl] methyl] -3-methyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

In the same manner as in Example 27, 5-[[4-methoxy-3- (4-methoxyphenylmethoxy) phenyl]
Methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone gave the title compound as colorless needles. Melting point 162.0-164.0 ℃

Elemental analysis value (%): C ₂₂ H ₂₁ F ₃ N ₂ O ₅
Calculated value C: 58.67, H: 4.70, N: 6.22 Actual value C: 58.66, H: 4.92, N: 6.22

Example 30 5-[(4-methoxy-3-hydroxyphenyl) methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone

5-[[4-methoxy-3- (4-methoxyphenylmethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3
H) -pyrimidinone (7.00 g) and a catalytic amount of tosylic acid.
The monohydrate was mixed in methanol (200 ml) -tetrahydrofuran (50 ml) and heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with an aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Hexane was added to the obtained residue, and the crystals were collected by filtration and dried to obtain the title compound as pale yellow prism crystals. 5.18 g, 99% yield Melting point 178.0-180.0 ° C MS (m / z): 360 (M ⁺ )

Example 31 5-[[4-methoxy-3-[(3,5-dimethylisoxazol-4-yl) methoxy] phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl -4 (3H) -pyrimidinone

5-[(4-methoxy-3-hydroxyphenyl) methyl] -3-methyl-2-methylthio-6
Trifluoromethyl-4 (3H) -pyrimidinone (500m
g) in N, N-dimethylformamide solution (3 ml) in potassium carbonate (300 mg) and 4-chloromethyl-3,5.
-Dimethylisoxazole (218 mg) was added at room temperature, and the mixture was stirred for 3 hours. The reaction solution was poured into water, made weakly acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 5: 2).
And the title compound was obtained as a colorless powder. Yield 582 mg,
Yield 89% Melting point 95.0-97.0 ° C MS (m / z): 469 (M ⁺ )

Example 32 5-[[4-Methoxy-3-[(3,5-dimethylisoxazol-4-yl) methoxy] phenyl] methyl] -3-methyl-6-trifluoromethylpyrimidine-2, 4 (1H, 3H) -dione

5-[[4-methoxy-3-[(3,5-
Dimethylisoxazol-4-yl) methoxy] phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (560 mg
) In ethyl acetate (10 ml) -acetonitrile (5 ml) was added an aqueous solution of ruthenium trichloride n-hydrate (5 mg) and sodium metaperiodate (254 mg) in water (5 ml), and the mixture was added at room temperature. After stirring for 3 hours, an aqueous solution of sodium metaperiodate (300 mg) dissolved in water (5 ml) was further added, and the mixture was stirred for 1 hour. Ethyl acetate and water were added to the reaction solution for extraction. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Tetrahydrofuran (30 ml) and a 1 N aqueous solution of sodium hydroxide (3.00 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour.
Left overnight. Dilute hydrochloric acid was added to the reaction solution to make it weakly acidic and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride: ethyl acetate = 5: 1), and recrystallized from methanol-water to give the title compound as colorless needles. Yield 247mg, 47% melting point 169.0-170.0 ℃

Elemental analysis value (%): C ₂₀ H ₂₀ F ₃ N ₃ O ₅
Calculated value C: 54.67, H: 4.59, N: 9.56 Actual value C: 54.97, H: 4.46, N: 9.50

Example 33 5-[[3-Methoxy-4- (2-methoxyethoxymethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone

Example 28 using 5-[[3-methoxy-4- (2-methoxyethoxymethoxy) phenyl] methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (6.31 g) In the same manner as in the above, the title compound was obtained as colorless plate crystals. 5.77 g, 89% yield Melting point 82.0-84.0 ° C MS (m / z): 448 (M ⁺ )

Example 34 5-[(4-Hydroxy-3-methoxyphenyl) methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone

5-[[3-methoxy-4- (2-methoxyethoxymethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3
A catalytic amount of tosylic acid monohydrate was added to a solution of H) -pyrimidinone (4.92 g) in methanol (50 ml), and the mixture was heated under reflux for 2 hours. After the reaction solution was concentrated under reduced pressure, methylene chloride was added, and the mixture was washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from methylene chloride-hexane to give the title compound as colorless prisms. Yield 3.69 g, 93% melting point 136.0-138.0 ° C MS (m / z): 360 (M ⁺ )

Example 35 5-[(4-hydroxy-3-methoxyphenyl) methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone 5-[[3-methoxy- 4- (4-methoxyphenylmethoxy) phenyl] methyl] -2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone was used as a starting material to obtain the title compound by the same procedure as in Examples 33 to 34.

Example 36 5-[[3-methoxy-4- (4-trifluoromethylphenylmethoxy) phenyl] methyl] -3-methyl-
2-methylthio-6-trifluoromethyl-4 (3H)
-Pyrimidinone

5-[(4-hydroxy-3-methoxyphenyl) methyl] -3-methyl-2-methylthio-6-
Trifluoromethyl-4 (3H) -pyrimidinone (640m
To a solution of g) in N, N-dimethylformamide (20 ml) were added potassium carbonate (400 mg) and 4-trifluoromethylbenzylbromide (446 mg) at room temperature, and the mixture was stirred for 1 hour. After standing overnight, the mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Water was added to the obtained residue, and the precipitated crystals were collected by filtration, washed with water, and dried to give the title compound as colorless prisms. Yield: 890 mg, 97% melting point: 129.0-130.0 ° C MS (m / z): 518 (M ⁺ )

Examples 37 to 39 In the same manner as in Example 36, the compounds shown in Table 4 were obtained.

[0109]

[Table 4]

Examples 40 to 44 Using the compounds obtained in Examples 33 and 36 to 39, the method of Table 5 was carried out in the same manner as in Example 27 (Method A) or in the same manner as in Example 32 (Method B). The compound was obtained.

[0111]

[Table 5]

Example 45 5-[[3-methoxy-4- (carboxymethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-
Trifluoromethyl-4 (3H) -pyrimidinone

5-[[3-methoxy-4- (ethoxycarbonylmethoxy) phenyl] methyl] -3-methyl-
2-methylthio-6-trifluoromethyl-4 (3H)
-Pyrimidinone (3.14 g) in tetrahydrofuran (20 m
l) A 1N aqueous solution of sodium hydroxide (5.0 ml) was added to a solution of -ethanol (20 ml) under ice cooling, and then water (20 ml) and 1N sodium hydroxide (2.7 ml) were added, followed by stirring at room temperature for 2 hours. did. After standing overnight, the reaction solution was poured into water, adjusted to pH 4 with dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and ethanol, and dried to obtain the title compound as a colorless powder. Yield 2.77 g, 94% melting point 155.5-167.0 ° C MS (m / z): 418 (M ⁺ )

Example 46 5-[[3-Methoxy-4- [N- (2-pyridyl) carbamoylmethoxy] phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3
H) -Pyrimidinone

5-[[3-methoxy-4- (carboxymethoxy) phenyl] methyl] -3-methyl-2-methylthio-6-trifluoromethyl-4 (3H) -pyrimidinone (1.00 g) and 2-amino In a N, N-dimethylformamide solution (5.0 ml) of pyridine (225 mg), diethyl cyanophosphate (410 mg) under an argon atmosphere and ice cooling.
And triethylamine (0.350 ml) were added, and the mixture was stirred at room temperature for 2 hours. After standing overnight, the reaction solution was poured into water, made weakly acidic with dilute hydrochloric acid, and extracted with a mixed solution of ethyl acetate-hexane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) to give the title compound as colorless needles. Yield 300 mg, Yield 25% Melting point 161.0-163.0 ° C MS (m / z): 494 (M ⁺ )

Examples 47 and 48 The compounds shown in Table 6 were obtained in the same manner as in Example 46.

[0117]

[Table 6]

Examples 49 to 51 Using the compounds obtained in Examples 46 to 48, the compounds of Table 7 were obtained in the same manner as in Example 27 (Method A) and in the same manner as in Example 32 (Method B). Obtained.

[0119]

[Table 7]

Reference Example 9 3-oxo-2- (2-naphthyl) methyl-4,4,4
-Ethyl trifluorobutyrate

Ethyl trifluoroacetoacetate (19.3 g)
Anhydrous 1,2-dimethoxyethane (200 ml) was added to a 60% sodium hydride oily solution (4.40 g) under argon atmosphere and ice-cooled stirring.
g) was added little by little, and the mixture was stirred as it was for 1 hour. This reaction solution was heated under reflux with 2-bromomethylnaphthalene (22.1
g) Anhydrous 1,2-dimethoxyethane (100 ml) solution was slowly added dropwise, and the mixture was refluxed for 22 hours. After cooling, the reaction solution was poured into ice water (500 ml), acidified with 1N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate.
After concentration, the residue was subjected to silica gel column chromatography, eluting with hexane: ethyl acetate = 20: 1 to recover 2-bromomethylnaphthalene (5.17 g), and then eluted with hexane: ethyl acetate = 5: 1 to obtain a brown oil. The title compound was obtained. Yield 19.1 g, 59%

¹ H NMR (CDCl ₃ ), δ: 1.19
(3H, t, J = 7.0 Hz), 3.43 (2H, d, J =
7.5Hz), 4.17 (2H, q, J = 7.0Hz), 4.26
(1H, t, J = 7.5Hz), 7.30-7.83 (7H, m)

Example 52 2-Methylthio-5- (2-naphthyl) methyl-6-trifluoromethyl-4 (3H) -pyrimidinone

Methyl isothiourea sulfate (2.78 g) was added to a solution of sodium hydroxide (825 mg) in methanol (20 ml) with stirring at room temperature. The mixture was stirred for 30 minutes, and the resulting solution was added to 3-oxo-2- (2-naphthyl). ) Methyl-4,4,4
-Ethyl trifluorobutyrate (3.24 g) in methanol (20
The resulting mixture was stirred under ice-cooling and then refluxed for 5 hours. After cooling, the mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with 0.5N hydrochloric acid and water, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 5: 1) to give the title compound as a colorless powder.
886mg yield, 25% yield

¹ H NMR (d ₆ -DMSO), δ: 2.5
4 (3H, s), 4.05 (2H, s), 7.36 (1H, d
d, J = 8.8, 2.0 Hz), 7.42-7.48 (2H, m),
7.56 (1H, s), 7.81-7.86 (3H, m), 13.45
(1H, brs)

Example 53 5- (2-Naphthyl) methyl-6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

A solution of 2-methylthio-5- (2-naphthyl) methyl-6-trifluoromethyl-4 (3H) -pyrimidinone (800 mg) in acetic acid-conc.
Heated to reflux for an hour. After cooling, the mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with water and dried over anhydrous sodium sulfate. Concentration gave the title compound as a colorless powder. The yield was 721 mg, and the yield was 99%. The title compound was further recrystallized from methanol and purified as colorless prism crystals. Melting point 184.0-185.5 ° C

Elemental analysis value (%): C ₁₆ H ₁₁ F ₃ N ₂ O ₂
Calculated value C: 60.00, H: 3.46, N: 8.75 Actual value C: 60.15, H: 3.37, N: 8.72

Example 54 5-Bromo-2,4-dimethoxy-6-trifluoromethylpyrimidine

A solution of 2,4-dimethoxy-6- (trifluoromethyl) pyrimidine (45.0 g) in acetic acid (450 ml) was added with N.
-Bromosuccinimide (46.2 g) was added, and the mixture was heated to 110 ° C and stirred for 8 hours. After standing at room temperature overnight, N-bromosuccinimide (46.2 g) was added and heated to 110 ° C.
Stirred for hours. After cooling, concentrate and add ether to the residue, water,
The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: methylene chloride = 2: 1) to give the title compound as a colorless powder.
Yield 45.9g, 74% melting point 46.0-46.5 ℃

GC-MS (m / z): 286, 288
(M ⁺ ) ¹ H NMR (CDCl ₃ ), δ: 4.04 (3H, s),
4.11 (3H, s)

Example 55 5-[(1,4-benzodioxan-6-yl) hydroxymethyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

5-bromo-2,4-dimethoxy-6
To a solution of (trifluoromethyl) pyrimidine (1.50 g) in anhydrous tetrahydrofuran (50 ml) was added a 1.6 M n-butyllithium hexane solution (3.60 ml) under an argon atmosphere and dry ice-acetone cooling and stirring so that the internal temperature was maintained at -70 ° C. Was slowly dropped. After stirring for 40 minutes,
-Benzodioxane-6-carboxaldehyde (985m
g) in anhydrous tetrahydrofuran (5 ml) was added at an internal temperature of -70.
The solution was slowly dropped so as to maintain the temperature. After stirring for 1 hour as it was, a saturated aqueous ammonium chloride solution (25 ml) was added, and the temperature was gradually returned to room temperature. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate =
4: 1) to give the title compound as a yellow oil. 1.38 g yield, 71% yield

¹ H NMR (CDCl ₃ ), δ: 3.30
(1H, d, J = 11.0 Hz), 3.96 (3H, s), 4.06
(3H, s), 4.24 (4H, s), 6.01 (1H, d, J
= 11.0Hz), 6.56-6.84 (3H, m)

Examples 56 to 60 In the same manner as in Example 55, the compounds shown in Table 8 were obtained.

[0136]

[Table 8]

Example 61 Methyl 5-[(2,4-dimethoxy-6-trifluoromethylpyrimidin-5-yl) hydroxymethyl] -2-methoxybenzoate

To a solution of 5-bromo-2,4-dimethoxy-6-trifluoromethylpyrimidine (1.44 g) in anhydrous tetrahydrofuran (30 ml) was added a 1.6 M n-butyllithium hexane solution under an argon atmosphere under dry ice-acetone cooling and stirring ( 3.45 ml) was slowly added dropwise to keep the internal temperature at -70 ° C, and the mixture was stirred for 40 minutes. This reaction solution is
-Aryl atmosphere in a solution of methyl formyl-2-methoxybenzoate (1.07 g) in anhydrous tetrahydrofuran (30 ml),
The mixture was added dropwise over 40 minutes with stirring under ice-cooling, and then stirred for 30 minutes. After adding a saturated ammonium chloride aqueous solution (20 ml) and stirring for 30 minutes, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: hexane: ethyl acetate = 2:
Purification in 1) gave the title compound as a colorless oil. Yield 1.
78g, 88% yield

¹ H NMR (CDCl ₃ ), δ: 3.29
(1H, d, J = 11.0 Hz), 3.87 (3H, s), 3.89
(3H, s), 3.93 (3H, s), 4.07 (3H, s),
6.10 (1H, d, J = 11.0 Hz), 6.90 (1H, d, J
= 8.8Hz), 7.16-7.36 (1H, m), 7.64-7.72
(1H, m)

Example 62 5-[(1,4-benzodioxan-6-yl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

5-[(1,4-benzodioxane-6
Yl) hydroxymethyl] -2,4-dimethoxy-6-
A solution of trifluoromethylpyrimidine (716 mg) in ethanol (30 ml) -concentrated hydrochloric acid (0.3 ml) was hydrogenated with 10% palladium-activated carbon (300 mg) at room temperature at 4.0 kg / cm ² under hydrogen pressure. The reaction solution was filtered and concentrated to give the title compound as a colorless oil. Yield 683mg, 100% yield

¹ H NMR (CDCl ₃ ), δ: 3.92
(2H, s), 3.99 (3H, s), 4.02 (3H, s),
4.22 (4H, s), 6.58-6.63 (2H, m), 6.75 (1
H, d, J = 8.3 Hz)

Examples 63 and 64 The compounds were treated in the same manner as in Example 62 to obtain the compounds shown in Table 9.

[0144]

[Table 9]

Example 65 2,4-Dimethoxy-5-[(1,2,3,4-tetrahydroquinolin-6-yl) methyl] -6-trifluoromethylpyrimidine

2,4-dimethoxy-5-[(quinoline-
6-yl) hydroxymethyl] -6-trifluoromethylpyrimidine (79.0 mg) in ethanol (40 ml) -concentrated hydrochloric acid
(0.2 ml) solution was hydrogenated with 10% palladium-activated carbon (300 mg) at room temperature and 4.0 kg / cm ² under hydrogen pressure. Filter the reaction solution,
Concentration gave the title compound as a yellow oil. Yield 76.3 mg,
100% yield

¹ H NMR (CDCl ₃ ), δ: 1.91
(2H, m), 2.69 (1H, t, J = 6.4 Hz), 3.26
(1H, t, J = 5.4 Hz), 3.87 (2H, s), 3.98
(3H, s), 4.02 (3H, s), 6.37 (1H, d, J
= 7.8Hz), 6.70-6.73 (2H, m)

Example 66 2,4-Dimethoxy-5-[(quinolin-6-yl) methyl] -6-trifluoromethylpyrimidine

2,4-dimethoxy-5-[(quinoline-
To a solution of 6-yl) hydroxymethyl] -6-trifluoromethylpyrimidine (183 mg) in ethanol (5 ml) was slowly added a 1N hydrochloric acid ethanol solution (1.0 ml) with stirring at room temperature, and the mixture was stirred for 10 minutes. After concentration, thionyl chloride (0.3 ml) was added to the residue, and the mixture was heated under reflux for 2 hours. After cooling, benzene (10 ml) was added and the mixture was concentrated. Water (10m
l), ethyl acetate (10 ml) was added, the pH was adjusted to about 9 with a 0.1N aqueous sodium hydroxide solution under ice-cooling and stirring, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in ethanol (20 ml) and triethylamine (52.0 mg)
And 10% palladium-activated carbon (5
0.0mg). The reaction solution was filtered and concentrated, ethyl acetate was added to the residue, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give the title compound as a colorless powder. 76.5 mg, 44% yield, melting point 135.0-137.0 ° C MS (m / z): 349 (M ⁺ )

Example 67 5-[(4-aminophenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

A mixture of 2,4-dimethoxy-5-[(4-nitrophenyl) hydroxymethyl] -6-trifluoromethylpyrimidine (1.30 g) and thionyl chloride (2.78 ml) was heated under reflux for 3 hours. After cooling, the mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried over anhydrous sodium sulfate and concentrated. The residue was suspended in ethanol (150 ml) -triethylamine (5 ml), and 10% palladium-activated carbon (1.
30 g). The reaction solution was filtered and concentrated, ethyl acetate was added to the residue, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride) to give the title compound as a yellow powder. Yield 410 mg, 36% melting point 84.5-85.5 ° C MS (m / z): 313 (M ⁺ )

Example 68 5-[(3-amino-4-hydroxyphenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

5-[(4-benzyloxy-3-nitrophenyl) hydroxymethyl] -2,4-dimethoxy-
A mixture of 6-trifluoromethylpyrimidine (1.63 g) and thionyl chloride (2.70 ml) was heated under reflux for 3 hours. After cooling, the mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated. The residue was suspended in ethanol (200 ml) -triethylamine (5 ml) and hydrogenated with 10% palladium-activated carbon (500 mg) at room temperature under a hydrogen atmosphere. The reaction solution was filtered and concentrated, ethyl acetate was added to the residue, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 2) to give the title compound as a brown powder. Yield 390mg, Yield 34%

¹ H NMR (d ₆ -DMSO), δ:
3.77 (2H, s), 3.94 (3H, s), 3.95 (3H, s)
s), 4.42 (2H, s), 6.09 (1H, dd, J = 7).
8, 2.0 Hz), 6.27 (1H, d, J = 2.0 Hz), 6.5
0 (1H, d, J = 7.8 Hz), 8.79 (1H, s)

Example 69 2,4-Dimethoxy-5-[(6-hydroxy-2,
5,7,8-Tetramethylchroman-2-yl) methyl] -6-trifluoromethylpyrimidine

5-[(6-benzyloxy-2,5,
7,8-Tetramethylchroman-2-yl) hydroxymethyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (1.46 g) and thionyl chloride (1.00 ml) were stirred at room temperature for 5 hours. After concentration, ether was added to the residue, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: hexane: ethyl acetate = 10: 1) to give 5-
[(6-Benzyloxy-2,5,7,8-tetramethylchroman-2-yl) chloromethyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine was obtained as a colorless oil. Yield: 1.25 g, 83% MS (m / z): 550, 552 (M ⁺ )

Next, 5-[(6-benzyloxy-2,
5,7,8-Tetramethylchroman-2-yl) chloromethyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine in ethyl acetate (30 ml) -triethylamine (2 ml) was added at room temperature under a hydrogen atmosphere. % Palladium on activated carbon (1.00 g). The reaction solution was filtered, and the filtrate was washed with 2N hydrochloric acid and water in that order, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 8: 1) to give the title compound as a yellow powder. Yield 792 mg, yield 82
% Melting point 136.0-138.0 ° C MS (m / z): 426 (M ⁺ )

Example 70 5-[(4-benzyloxyphenyl) methyl] -2,
4-dimethoxy-6-trifluoromethylpyrimidine

A 1.6 M n-butyllithium hexane solution (5-bromo-2,4-dimethoxy-6-trifluoromethylpyrimidine (3.40 g) in anhydrous tetrahydrofuran (30 ml) was stirred under an argon atmosphere under dry ice-acetone cooling and stirring. 8.12 ml) was slowly added dropwise to keep the internal temperature at -70 ° C. After stirring for 30 minutes as it was, a solution of (4-benzyloxyphenyl) methyl bromide (3.60 g) in anhydrous tetrahydrofuran (30 ml) was slowly added dropwise while maintaining the internal temperature at -70 ° C. After stirring for 30 minutes as it was, the mixture was stirred for 3 hours under ice cooling. Saturated aqueous ammonium chloride solution (30ml)
After stirring for 30 minutes, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: methylene chloride = 2: 1) to give the title compound as colorless prisms. Yield 4.31 g, yield 90% Melting point 75.5-76.5 ° C MS (m / z): 404 (M ⁺ )

Example 71 5-[(3,5-Di-tert-butyl-4-methoxyphenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

The same procedure as in Example 70 was carried out to obtain the title compound as a colorless oil. MS (m / z): 440 (M ⁺ )

Example 72 4,4'-Bis [(2,4-dimethoxy-6-trifluoromethylpyrimidin-5-yl) methyl] diphenylmethane

To a solution of 5-bromo-2,4-dimethoxy-6-trifluoromethylpyrimidine (472 mg) in anhydrous tetrahydrofuran (7 ml) was added a 1.6 M n-butyllithium hexane solution (1.03 ml) was slowly added dropwise to keep the internal temperature at -70 ° C. After stirring for 40 minutes as it was, a solution of 4,4'-bis (bromomethyl) diphenylmethane (320 mg) in anhydrous tetrahydrofuran (10 ml) was slowly added dropwise while maintaining the internal temperature at -70 ° C. After stirring for 30 minutes as it was, the mixture was stirred for 5 hours under ice cooling. Saturated aqueous ammonium chloride solution (20m
After l) was added and stirred for 10 minutes, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1) to give the title compound as a colorless powder. Yield 222 mg, Yield 40% Melting point 114.0-115.5 ° C MS (m / z): 608 (M ⁺ )

Example 73 2,4-Dimethoxy-5-[(1-methyl-1,2,2,
3,4-tetrahydroquinolin-6-yl) methyl]-
6-trifluoromethylpyrimidine

2,4-dimethoxy-5-[(1,2,2
3,4-tetrahydroquinolin-6-yl) methyl]-
N, N of 6-trifluoromethylpyrimidine (398 mg)
-Argon atmosphere in dimethylformamide (5 ml) solution,
Under ice-cooling and stirring, 60% sodium hydride oily solution (54.0 mg) was added, and the mixture was stirred for 30 minutes and then at room temperature for 1 hour.
Methyl iodide (162 mg) was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 6 hours. The reaction solution was poured into ice water, extracted with ether, washed with water,
After drying over anhydrous sodium sulfate, the mixture was concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 6: 1) to give the title compound as a colorless oil. 208 mg, 50% yield

¹ H NMR (CDCl ₃ ), δ: 1.95
(2H, quint, J = 6.4 Hz), 2.70 (2H, t, J
= 6.4 Hz), 2.84 (3H, s), 3.17 (2H, t, J)
= 5.9Hz), 3.88 (2H, s), 3.99 (3H, s),
4.02 (3H, s), 6.48 (1H, d, J = 8.3Hz),
6.72 (1H, s), 6.82 (1H, d, J = 8.3Hz)

Example 74 2,4-Dimethoxy-5-[(4-hydroxyphenyl) methyl] -6-trifluoromethylpyrimidine

A solution of 5-[(4-benzyloxyphenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (3.50 g) in acetic acid (60 ml) was added at room temperature under a hydrogen atmosphere to 10% palladium-activated carbon ( 350 mg). The reaction solution was filtered and concentrated to obtain the title compound as a colorless powder. 2.58 g, 95% yield Melting point: 124.0-126.0 ° C MS (m / z): 314 (M ⁺ )

Example 75 5-[[4- [2- (5-ethylpyridin-2-yl)]
[Ethoxy] phenyl] methyl] -2,4-dimethoxy-
6-trifluoromethylpyrimidine

2,4-Dimethoxy-5-[(4-hydroxyphenyl) methyl] -6-trifluoromethylpyrimidine (1.08 g), 2- (5-ethylpyridin-2-yl) ethanol (530 mg), To a solution of phenylphosphine (1.12 g) in anhydrous tetrahydrofuran (30 ml) was added a diethyl azodicarboxylate (0.
65 ml) was slowly added dropwise and stirred for 30 minutes. After further stirring at room temperature for 7 hours, the mixture was left at room temperature for 8 days. After concentration, the residue was purified by alumina column chromatography (developing solvent: hexane: ethyl acetate = 6: 1) to obtain the title compound as a colorless powder. Yield 808 g, Yield 53% Melting point 58.5-60.0 ° C MS (m / z): 447 (M ⁺ )

Example 76 5-[(4-acetamido-3-nitrophenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine

5-[(4-aminophenyl) methyl]-
A solution of 2,4-dimethoxy-6-trifluoromethylpyrimidine (400 mg) in methylene chloride (30 ml) was stirred under ice cooling with stirring.
Triethylamine (144 mg) and acetyl chloride (103 mg) were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methylene chloride (20 ml), concentrated nitric acid (1 ml)-fuming nitric acid (1 ml)
-It was added dropwise to a mixed solution of methylene chloride (10 ml) over 30 minutes while stirring on ice. After stirring for 2 hours, the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into ice water, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give the title compound as a yellow powder. Yield: 383 mg, yield: 75% Melting point: 146.0-147.0 ° C MS (m / z): 400 (M ⁺ )

Example 77 2,4-Dimethoxy-5-[(2-methylbenzimidazol-5-yl) methyl] -6-trifluoromethylpyrimidine

A solution of 5-[(4-acetamido-3-nitrophenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (485 mg) in acetic acid (10 ml) was added at room temperature to a 10% palladium-hydrogen atmosphere. Hydrogenated with activated carbon (100 mg). The reaction solution was filtered and concentrated. Water and ethyl acetate were added to the residue, and the mixture was adjusted to pH about 8 with a saturated aqueous solution of sodium hydrogen carbonate under stirring at room temperature. The organic layer was separated, and the water bath was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride: methanol = 50: 1) to obtain the title compound as a pale brown powder.
Yield 105 mg, 25% melting point 189.0-191.0 ° C MS (m / z): 352 (M ⁺ )

Example 78 5-[(4-amino-3-nitrophenyl) methyl]-
2,4-dimethoxy-6-trifluoromethylpyrimidine

5-[(4-acetamido-3-nitrophenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (380 mg) in methanol (20 ml)
2N aqueous sodium hydroxide solution (40 ml) was added to the solution, and
Stirred for 24 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated to obtain the title compound as a yellow powder. Yield 333 mg, 98% melting point 134.5-135.5 ° C MS (m / z): 358 (M ⁺ )

Example 79 5-[(benzimidazol-5-yl) methyl]-
2,4-dimethoxy-6-trifluoromethylpyrimidine

A suspension of 5-[(4-amino-3-nitrophenyl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (330 mg) in ethanol (50 ml) was added at room temperature to a 10% hydrogen atmosphere. Palladium-activated carbon (30.4m
Hydrogenated in g). After the reaction solution was filtered and concentrated, the residue was dissolved in formic acid (3.0 ml) and heated under reflux for 3 hours. After cooling, the mixture was concentrated, and water was added to the residue.
The mixture was adjusted to about H8, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride: methanol = 25: 1) to obtain the title compound as a pale brown powder.
Yield: 257 mg, 82% melting point: 184.0-185.0 ° C MS (m / z): 338 (M ⁺ )

Example 80 2,4-Dimethoxy-5-[(4-hydroxy-3-nitrophenyl) methyl] -6-trifluoromethylpyrimidine

A solution of 2,4-dimethoxy-5-[(4-hydroxyphenyl) methyl] -6-trifluoromethylpyrimidine (1.50 g) in methylene chloride (20 ml) was treated with concentrated nitric acid (3 ml) and fuming nitric acid (3 ml). -To the mixture of methylene chloride (60 ml) was slowly added dropwise with stirring under ice-cooling, followed by stirring for 3 hours. The reaction solution was poured into ice water, the organic layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give the title compound as a yellow powder. Yield 1.56 g, 91% melting point 79.5-80.0 ° C MS (m / z): 359 (M ⁺ )

Example 81 5-[(1,4-benzodioxan-6-yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1
H, 3H) -dione

5-[(1,4-benzodioxane-6
Yl) methyl] -2,4-dimethoxy-6-trifluoromethylpyrimidine (466 mg) in acetic acid-concentrated hydrochloric acid (1: 1,
The solution was heated to reflux for 8 hours. After cooling and concentration, the resulting crystals were recrystallized from methanol to give the title compound as colorless prisms. Yield 365 mg, 85% melting point 280.5-282.0 ℃

Elemental analysis value (%): C ₁₄ H ₁₁ F ₃ N ₂ O ₄
Calculated value C: 51.23, H: 3.38, N: 8.53 Actual value C: 51.06, H: 3.32, N: 8.56

Examples 82 and 83 The compounds were treated in the same manner as in Example 81 to obtain the compounds shown in Table 10.

[0186]

[Table 10]

Example 84 2-methoxy-5-[(1,2,3,4-tetrahydro-2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] benzoic acid

Methyl 5-[(2,4-dimethoxy-6-trifluoromethylpyrimidin-5-yl) methyl] -2-methoxybenzoate (1.54 g) in acetic acid-conc.
(1,40 ml) was heated to reflux for 5 hours. After cooling, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as colorless needles. Yield 1.17 g, 85% melting point 257.0-259.0 ° C MS (m / z): 344 (M ⁺ )

Example 85 4,4'-Bis [(1,2,3,4-tetrahydro-
2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] diphenylmethane

4,4'-bis [(2,4-dimethoxy-
6-trifluoromethylpyrimidin-5-yl) methyl] diphenylmethane (220 mg) in acetic acid-conc.
1,20 ml) was heated to reflux for 6 hours. After cooling, the reaction solution was poured into water, the crystals were collected by filtration, washed with water and hot methanol in that order, and dried to obtain the title compound as a colorless powder. Yield 146mg, 73% melting point 300.0 ℃ or more

Elemental analysis value (%): C ₂₅ H ₁₈ F ₆ N ₄ O ₄
Calculated value C: 54.36, H: 3.28, N: 10.14 Actual value C: 54.12, H: 3.04, N: 9.87

Example 86 5-[(quinolin-6-yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

2,4-dimethoxy-5-[(quinoline-
A suspension of 6-yl) methyl] -6-trifluoromethylpyrimidine (485 mg) in 6N hydrochloric acid (30 ml) was heated under reflux for 5 hours. After cooling, the mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the precipitated crystals were collected by filtration, washed with water and dried. The obtained crystals were washed with hot methanol to give the title compound as a colorless powder. Yield 3
7.6 mg, 84% yield, melting point 300.0 ℃ or more

Elemental analysis value (%): C ₁₅ H ₁₀ F ₃ N ₃ O ₂
Calculated value C: 56.08, H: 3.14, N: 13.08 Actual value C: 55.96, H: 3.17, N: 13.08

Examples 87 to 92 In the same manner as in Example 86, the compounds shown in Table 11 were obtained.

[0196]

[Table 11]

Example 93 5-[(3,5-Di-tert-butyl-4-methoxyphenyl) methyl] -6-trifluoromethylpyrimidine-
2,4 (1H, 3H) -dione

5-[(3,5-di-tert-butyl-4-methoxyphenyl) methyl] -2,4-dimethoxy-6
Acetic acid (15) of (trifluoromethyl) pyrimidine (500 mg)
ml) solution was added with sodium iodide (510 mg), heated to 100 ° C., and stirred for 6 hours. After cooling, the solution was concentrated and the residue was dissolved in ethyl acetate. The solution was washed with water, a saturated aqueous solution of sodium hydrogen sulfite and water in that order, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: hexane:
Purification by ethyl acetate (2: 1) gave the title compound as a colorless powder. This was recrystallized from methylene chloride to give the purified title compound as colorless needles. Melting point 255.0-257.0 ℃

Elemental analysis value (%): C ₂₁ H ₂₇ F ₃ N ₂ O ₃
Calculated value C: 61.15, H: 6.60, N: 6.79 Actual value C: 61.07, H: 6.67, N: 6.80

Example 94 5-[(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl) methyl] -6-trifluoromethylpyrimidine-2,4 (1H, 3H) -dione

2,4-Dimethoxy-5-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl) methyl] -6-trifluoromethylpyrimidine is
This was treated in the same manner as in Example 93 to obtain the title compound as a colorless powder. Melting point 193.0-195.0 ° C (recrystallization solvent methylene chloride)

Elemental analysis value (%): C ₁₉ H ₂₁ F ₃ N ₂ O ₄
・ Calculated value as 1/4 H ₂ O C: 56.64, H: 5.38, N: 6.95 Actual value C: 56.56, H: 5.67, N: 6.93

Example 95 4-t-butyl-2-methoxy-N- [4-[(1,
2,3,4-tetrahydro-2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] phenyl] benzamide

5-[(4-aminophenyl) methyl]-
A solution of 2,4-dimethoxy-6-trifluoromethylpyrimidine (357 mg) in 4N hydrochloric acid (20 ml) was heated under reflux for 6 hours. After cooling, the mixture was concentrated and the residue was dissolved in water (20 ml) and neutralized with a saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals were collected by filtration, washed with water and dried. The obtained crystals were dissolved in anhydrous N, N-dimethylformamide (3 ml), and 4-t-butyl-2-methoxybenzoic acid (221 mg) was added.
Under ice-cooling and stirring, triethylamine (108 mg) and diethyl cyanophosphate (176 mg) were added. After stirring for 1 hour,
Stirred at room temperature for 7 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water and dried to give the title compound as a colorless powder. Yield: 497 mg, yield: 92% The product was recrystallized from methanol-water to give the title compound as colorless prisms. 260.0-262.0 ° C

Elemental analysis value (%): C ₂₄ H ₂₄ F ₃ N ₃ O ₄
Calculated value C: 60.63, H: 5.09, N: 8.84 Actual value C: 60.82, H: 5.33, N: 8.78

Example 96 2-methoxy-5-[(1,2,3,4-tetrahydro-2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] -N-[(4- Trifluoromethylphenyl) methyl] benzamide

2-methoxy-5-[(1,2,3,4-
Tetrahydro-2,4-dioxo-6-trifluoromethylpyrimidin-5-yl) methyl] benzoic acid (1.15
g), 4-trifluoromethylbenzylamine (632 mg)
Triethylamine (370 mg) and diethyl cyanophosphate (620 mg) were added to an anhydrous N, N-dimethylformamide (20 ml) solution under an argon atmosphere and ice-cooled stirring, and the mixture was stirred at room temperature for 4 hours and then left at room temperature for 4 days. The reaction solution was poured into ice water, the crystals were collected by filtration, washed with water and dried. The obtained crystals were recrystallized from methanol to give the title compound as colorless needles. Yield 1.07
g, yield 64%, melting point 260.0-261.5 ° C

Elemental analysis value (%): C ₂₂ H ₁₇ F ₆ N ₃ O ₄
Calculated value C: 52.70, H: 3.42, N: 8.38 Measured value C: 52.58, H: 3.22, N: 8.38

Test Example 1 Using a genetically obese mouse (C57BL ob / ob), blood was collected from the tail vein before the test to measure the blood glucose level. Groups were divided so that there was no difference in blood glucose level, and the compound of the present invention was orally administered at a dose of 30 or 10 mg / kg for 5 days. Glucose tolerance test after fasting overnight
2 g / kg of glucose was orally administered, and the blood glucose level was measured at 0, 30, and 60 minutes. The blood sugar lowering rate was determined by the following equation. Table 12 shows the results. These results indicate that the compound of the present invention has a strong blood glucose lowering effect.

[0210]

[Table 12]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication location C07D 403/06 235 C07D 405/06 239 405/06 239 413/12 239 413/12 239 417/12 239 417/12 239 239/54 (72) Inventor Koji Murakami 386-2 Marubayashi Nogicho, Shimotsuga-gun, Tochigi 704 Pre-Scene Nogi Highlands 704 (72) Inventor Masaki Tsunoda 5932 Tomonuma, Nogicho, Shimotsuga-gun, Tochigi Prefecture

Claims (13)

[Claims] 1. General formula (1) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ² and R ³ may be the same or different and each represents hydrogen, a lower alkyl group or unsubstituted, A represents a lower alkoxy group or ＯO, B represents hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group; Group, = S or = O
One of the bonds between 1-2 and 2-B represents a single bond and the other represents a double bond, and the bonds between 3-4 and 4-A represent one single bond and the other a double bond. And a pharmaceutically acceptable salt thereof. 2. General formula (1) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ² and R ³ may be the same or different and each represents hydrogen, a lower alkyl group or unsubstituted, A represents a lower alkoxy group or ＯO, B represents hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group; Group, = S or = O
One of the bonds between 1-2 and 2-B represents a single bond and the other represents a double bond, and the bonds between 3-4 and 4-A represent one single bond and the other a double bond. A hypoglycemic agent comprising a trifluoromethylpyrimidine derivative represented by the following formula: and a pharmaceutically acceptable salt as active ingredients. 3. General formula (2) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or Wherein R ⁴ represents a lower alkyl group, and a β-keto ester derivative represented by the following general formula (3): Wherein R ⁵ represents hydrogen, a lower alkylthio group or a lower alkyl group, or a thiourea represented by the following general formula (4): Wherein R ¹ is as described above, R ⁶ is hydrogen or unsubstituted, R ⁷ is hydrogen, a lower alkylthio group, a lower alkyl group or ＳS, a bond between 1-2 and between 2-R ⁷ Represents a single bond and the other represents a double bond]. 4. General formula (5) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ⁶ is hydrogen or unsubstituted, R ⁸ is a lower alkyl group, a lower alkylthio group or ＯO,
-2 and between bond between 2-R ⁸ is one of a single bond, then the other is a compound represented by] indicates a double bond is reacted with a halogenating agent, wherein the reaction with lower alkoxide General formula (6) Wherein R ¹ is as described above, R ⁹ is a lower alkoxy group, and R ¹⁰ is a lower alkyl group, a lower alkylthio group or a lower alkoxy group. 5. General formula (7) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ⁶ is hydrogen or unsubstituted, B is hydrogen, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, ＳS or ＯO, the bond between 1-2 and 2-B is one side. Is a single bond and the other is a double bond] and a general formula (8) R ¹¹ X (8) wherein R ¹¹ is a lower alkyl group and X is a halogen atom. General formula (9) characterized by reacting a compound [Wherein R ¹ , R ¹¹ and B are as described above, and R ¹² is a lower alkyl group or unsubstituted. Between 1-2 and 2-B
One bond is a single bond and the other is a double bond. ] The manufacturing method of the trifluoromethyl pyrimidine derivative represented by these. 6. The general formula (10) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or R ³ is hydrogen, a lower alkyl group or unsubstituted, A is a lower alkoxy group or ＯO, R ¹³ is a lower alkyl group, one of the bonds between 3-4 and 4-A is A compound represented by the following general formula (1):
1) [Wherein R ¹ , R ³ and A are as described above. 3-4
One of the bonds between A and A is a single bond and the other is a double bond. ] The manufacturing method of the trifluoromethyl pyrimidine derivative represented by these. 7. General formula (12) [Wherein, R ¹ represents a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5- or 6-membered heteromonocyclic ring which may have a substituent, or complex fused ring, after oxidizing the R ¹³ of the compound represented by] a lower alkyl group, the general formula, characterized in that is reacted with a lower alkoxide (13) [In the formula, R ¹ is as defined above, R ¹⁴ represents a lower alkyl group] The method for producing a trifluoromethyl pyrimidine derivative represented by the. 8. The general formula (14) [Wherein R ¹⁰ represents a lower alkyl group, a lower alkylthio group or a lower alkoxy group, R ¹¹ represents a lower alkyl group,
¹⁵ represents a protecting group such as a 2-methoxyethoxymethyl or 4-methoxyphenylmethyl group], after removal of the protecting group from the compound represented by the general formula (15) R ¹⁶ X (15) wherein R ¹⁶ is A benzyl group which may have a substituent,
X represents a halogen atom with a (3,5-dimethylisoxazol-4-yl) methyl group, 4-bromobenzoylmethyl group or an ethoxycarbonylmethyl group]. General formula (16) [Wherein R ¹⁰ , R ¹¹ and R ¹⁶ are as defined above]. 9. Formula (17) [Wherein R ¹⁰ represents a lower alkyl group, a lower alkylthio group or a lower alkoxy group, and R ¹¹ represents a lower alkyl group]
After hydrolyzing the compound represented by the general formula (18), using a condensing agent or forming a reactive derivative, R ¹⁷ NH ₂ (18) wherein R ¹⁷ is pyridine, thiazole, or (2 ,
A phenyl group having a 4-dioxothiazolidin-5-yl) methyl group]. [Wherein R ¹⁰ , R ¹¹ and R ¹⁷ are as described above]. 10. The general formula (20) [Wherein R ² and R ³ are the same or different and are hydrogen, lower alkyl group or unsubstituted, A is lower alkoxy group or ＯO, B is hydrogen, lower alkyl group, lower alkoxy group, lower alkylthio group, ＳS or ＯO, R ¹⁸ is a lower alkyl group, one of the bonds between 1-2 and 2-B is a single bond, the other is a double bond, and between 3-4 and 4-
One of the bonds between A is a single bond and the other is a double bond], and after hydrolyzing the compound represented by the formula (21) R ¹⁹ CH ₂ NH ₂ (21) wherein R ¹⁹ represents a phenyl group which may have a lower alkyl group or a trifluoromethyl group. Wherein R ² , R ³ , R ¹⁹ , A and B are as described above. One of the bonds between 1-2 and 2-B is a single bond, and the other is a double bond. One of the bonds between 3-4 and 4-A is a single bond, and the other is a double bond. ] The manufacturing method of the trifluoromethyl pyrimidine derivative represented by these. 11. General formula (23) A compound represented by the formula [wherein R ¹⁴ represents a lower alkyl group] is halogenated with a halogenating agent and then treated with an organolithium reagent to obtain a compound represented by the general formula (24) or (25) R ¹ CHO (24), R ¹ CH ₂ X (25) wherein R ¹ is a phenyl group having 1 to 3 substituents, a naphthalene which may be substituted with a lower alkyl group, a 5-membered group which may have a substituent Or a compound represented by the general formula (26), wherein X is a halogen atom, and X is a halogen atom. [Wherein R ¹ and R ¹⁴ are as described above, and Y represents hydrogen or a hydroxyl group]. A method for producing a trifluoromethylpyrimidine derivative represented by the following formula: 12. The general formula (26-a) [Wherein R ¹ is a phenyl group having ¹ to 3 substituents, a naphthalene which may be substituted by a lower alkyl group, a 5- or 6-membered heteromonocyclic or heterocondensed which may have a substituent. the ring, if R ¹⁴ represents a lower alkyl group] with a compound hydrogenated or require represented, after halogenating the hydroxyl group, the general formula for causing hydrogenated (6-
a) [Wherein R ¹ and R ¹⁴ are as defined above]. 13. The general formula (6-a) [Wherein R ¹ is a phenyl group having ¹ to 3 substituents, a naphthalene which may be substituted by a lower alkyl group, a 5- or 6-membered heteromonocyclic or heterocondensed which may have a substituent. rings, R ¹⁴ is formula which comprises treating with an acid or iodide salt of the compound represented by] a lower alkyl group (11-a) [Wherein R ¹ is as defined above].