JPH10114755A - Pyrimidine derivative and its production intermediate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a medicine in a good yield at a low cost by easy purification by reacting a cyclized substance prepared by using thiourea, acetylacetone and acetaldehyde as starting substances with a specific piperazine derivative. SOLUTION: The cyclizing reaction of thiourea with acetylacetone and acetaldehyde to provide a compound of formula I, which is then subjected to an alkylating reaction to afford a compound. The dehydrogenating reaction of the resultant compound is carried out to provide 5-acetyl-4,6-dimethyl-2- methylthiopyrimidine, which is then oxidized to afford 5-acetyl-4,6-dimethyl-2 methylsulfonylpyrimidine of formula II. The prepared compound is subsequently reacted with 1-(2 aminoethyl)-4(2-methoxyphenyl)piperazine of formula III to provide 5-acetyl-4,6-dimenthyl-2( 2-[4-(2-methoxyphenyl)piperazin-1yl]ethyl}amino) pyrimidine of formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel method for producing a pyrimidine derivative useful as a pharmaceutical, and an intermediate for producing the pyrimidine derivative. More specifically, the formula (I)

[0002]

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A method for producing a pyrimidine derivative represented by the formula:
And the general formula (VII)

[0004]

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(Wherein all symbols have the same meanings as described below).

[0006]

BACKGROUND OF THE INVENTION JP-A-62-151672 discloses a compound of the formula (I):

[0007]

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Since the pyrimidine derivative represented by the formula has a sustained antihypertensive action, a blood flow increasing action or a platelet aggregation inhibiting action, it can be used as a therapeutic agent for hypertension, or for blood vessels against peripheral vascular disorders, ischemic cerebral blood flow disorders and cerebral thrombosis. It is described as being useful as a cerebral circulation improving agent such as a flow improving agent. The specification also describes that the pyrimidine derivative represented by the formula (I) is produced according to the following reaction scheme 1.

[0009]

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(In the reaction scheme 1, n-BuLi represents normal butyl lithium.) Further, as an improved method for producing the compound represented by the formula (A-1), JP-A-3-7265 is disclosed. Describes a method represented by the following reaction scheme 2.

[0011]

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[0012]

[Problems of the prior art] In the reaction process formula 1, the formula (A-
The method of synthesizing the compound shown in 1) requires six steps from urea and acetylacetone, and requires the use of expensive and dangerous normal butyllithium and Grignard reagents, which is not suitable as an industrial method ( That is described in JP-A-3-7265).

Further, in the reaction step formula 2, the formula (A-1)
In order to synthesize the compound represented by the formula (A-2), the compound represented by the formula (A-2) is used as an intermediate. The compound represented by the formula (A-2) is produced by subjecting the compound represented by the formula (A-3) to a dehydrogenation reaction. When we performed the above additional test of the dehydrogenation reaction, it was thought that the reaction proceeded cleanly and the desired product was formed, but the compound represented by the formula (A-3) was very poor. Due to the high water solubility, it has been difficult to perform an extraction operation with an organic solvent, and as a result, the reaction yield has been significantly reduced. The production method of Reaction Scheme 2 having such a problem is also unsuitable for industrial production.

The present inventors have made intensive studies to solve the above problems and find a novel method for producing a pyrimidine derivative represented by the formula (I). As a result, equation (I)
Was found to be produced in good yield by the following reaction scheme 3.

[0015]

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[0016]

[Comparison with the prior art] In the reaction scheme 3, the formulas (V) and (I)
The intermediate compounds represented by V), (III) and (II) have extremely low water solubility. Therefore, the extraction operation performed with an organic solvent is easy, the isolation and purification operation of the compound is very simple, and the yield is improved. As a result, the total yield from the conventional raw material to the pyrimidine derivative represented by the formula (I) was 7.8%, whereas the total yield in the production method of the present invention was 26%. The total yield according to the prior art used herein means that the compound represented by the formula (A-1) is obtained by the reaction scheme 2, and then the compound is represented by the formula (A-1) according to the reaction scheme 1. This is the case where the pyrimidine derivative represented by the formula (I) is obtained from the compound. The route from the compound represented by the formula (A-3) to the compound represented by the formula (A-2) is actually determined by the present inventors. Calculated using the yield (24%, see Comparative Example 1 in the present specification) obtained after additional testing.

In the method of the present invention, the yield of each reaction used for calculating the total yield is calculated according to the reaction scheme 3
And in Examples 1 (1), 2, 3, 4, and 5 herein. In the prior art method, the formula (A-
The reactions for obtaining the compounds represented by 3) and the formula (A-1) are described in Examples 1 and 23 in JP-A-3-7265, respectively, and are 86% and 89%, respectively. . A reaction for obtaining a pyrimidine derivative represented by the formula (I) from a compound represented by the formula (A-1) is described in JP-A-62-5.
Example 2b) in EP 1672.
42.6%.

In summary, the present inventors have found that the formula (I)
In the step of producing a pyrimidine derivative represented by,
From the discovery of an intermediate compound that is not highly water-soluble,
It has been found that the extraction operation with an organic solvent is easy and the isolation and purification operation is very simple. Further, in the prior art, the pyrimidine derivative is obtained from the starting material in a yield of about 8%, whereas in the present invention, the yield is 26% and the yield is excellent. The present inventors have also found that it leads to cost reduction in mass production, and completed the present invention.

[0019]

DISCLOSURE OF THE INVENTION The present invention provides a compound of formula (V) by subjecting thiourea, acetylacetone and acetaldehyde to a cyclization reaction.

[0020]

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By subjecting the compound to an alkylation reaction, the compound represented by the formula (IV)

[0022]

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A compound represented by the formula (III) is obtained by subjecting the compound to a dehydrogenation reaction.

[0024]

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By subjecting the compound to the oxidation reaction, the compound represented by the formula (II)

[0026]

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The compound represented by the formula (V)
I)

[0028]

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A compound represented by the formula (I):

[0030]

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A method for producing a pyrimidine derivative represented by the formula:
And the general formula (VII)

[0032]

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(Wherein, (i) R ¹ is a hydrogen atom, and R ² is —S
CH ₃ group,

[0034]

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Represents a single bond, or (ii) R ¹ represents nothing, R ² represents a —SCH ₃ group,

[0036]

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Represents a double bond or (iii) R
¹ represents nothing, R ² represents a —SO ₂ CH ₃ group,

[0038]

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Represents a double bond. )). A method for producing the formula (V) by reacting thiourea, acetylacetone and acetaldehyde can be carried out, for example, by the following method. Thiourea, acetylacetone and acetaldehyde are converted into an inert solvent [ether-based (tetrahydrofuran, tetrahydropyran, 1,4-dioxane, dimethoxyethane, diethylether, diisopropylether, biphenylether, methylethylether, etc.),
In nitriles (acetonitrile, etc.), amides (hexamethylphosphoramide, dimethylformamide, dimethylimidazolidinone, etc.), alcohols (methanol, ethanol, isopropanol, etc.), acetic acid, or a mixed solvent of two or more thereof] By reacting with an acid catalyst (concentrated hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, potassium hydrogen sulfate, etc.), the compound of formula (V) can be produced. The reaction temperature is preferably -20 to 100 ° C, and the reaction time is preferably 1 to 24 hours. Further, paraaldehyde may be used instead of acetaldehyde used as a starting material. The alkylation reaction for producing the compound represented by the formula (IV) from the compound represented by the formula (V) can be performed, for example, by the following method. In an inert solvent [alcohol (same as above), amide (same as above), sulfoxide (dimethylsulfoxide and the like), ether (same as above), water and the like] By reacting with an alkylating agent (methyl iodide, dimethyl sulfate, etc.), the compound represented by the formula (IV) can be produced. The reaction temperature is preferably from 0 to 100 ° C, and the reaction time is preferably from 1 to 24 hours. In this reaction, a base (sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, dimethylaniline, etc.) may coexist. The dehydrogenation reaction for producing the compound represented by the formula (III) from the compound represented by the formula (IV) can be performed, for example, by the following method. The compound represented by the formula (IV) is converted into an inert solvent [nitrile (same as above), benzene (benzene, toluene, xylene, etc.), ketone (acetone, methyl ethyl ketone, phenyl methyl ketone, etc.),
Halogenated hydrocarbons (methylene chloride, chloroform,
Carbon tetrachloride, 1,1,2,2-tetrachloroethylene,
Catalysts (copper sulfate, copper (II) chloride, copper bromide (I), perchlorethylene, chlorobenzene, etc.), alcohol (same as above), water, or a mixed solvent of two or more thereof.
I), iron (III) chloride, iron (III) sulfate, ruthenium (III) chloride, ruthenium (IV) oxide, selenium dioxide, sodium tungstate dihydrate) and oxidizing agents (sodium persulfate, hydrogen peroxide) , T-butyl hydroperoxide, concentrated nitric acid, manganese dioxide, potassium permanganate, sodium periodate, 2,3-dichloro-5,6
-Dicyano-1,4-benzoquinone, sodium chlorite, oxygen and the like) to produce the compound represented by the formula (III). As the reaction temperature
The temperature is preferably from 0 to 100 ° C, and the reaction time is preferably from 1 to 24 hours. The oxidation reaction for producing the compound represented by the formula (II) from the compound represented by the formula (III) can be performed, for example, by the following method. A compound represented by the formula (III) is converted into an inert solvent [halogenated hydrocarbon (same as above),
Nitrile (same as above), alcohol (same as above), ketone (same as above), water, or a mixture thereof
Mixed solvent etc.], a catalyst (copper sulfate, copper (II) chloride,
Copper (II) bromide, iron (III) chloride, iron (III) sulfate, ruthenium (III) chloride, ruthenium (IV) oxide, selenium dioxide, sodium tungstate dihydrate, etc.) and an oxidizing agent (potadium peroxy) Monosulfate, metachloroperbenzoic acid, t-butyl hydroperoxide, potassium permanganate, sodium chlorite, sodium hypochlorite, peracetic acid, etc.)
The compound represented by I) can be produced. The reaction temperature is preferably -20 to 100 ° C, and the reaction time is 1 to 24.
Time is preferred. Formula (VI) is added to the compound represented by formula (II).
The reaction for producing the compound represented by the formula (I) by reacting the compound represented by the formula (I) can be carried out, for example, by the following method. Inert solvent [alcohol (same as above), amide (same as above), sulfoxide (same as above), ether (same as above), benzene (same as above), nitrile (same as above) ), Water, or a mixed solvent of two or more thereof], a compound represented by the formula (II) and a nucleophile (a compound represented by the formula (VI)) and a base (triethylamine, diisopropylethylamine, dimethylaniline, water Sodium oxide, potassium hydroxide,
(Potassium carbonate, sodium carbonate, etc.). The reaction temperature is preferably from 0 to 150 ° C, and the reaction time is preferably from 1 to 24 hours.

In addition to the compound represented by the formula (VI) as a nucleophile, for example, an alkylamine (methylamine,
Ethylamine, isopropylamine, etc.), allylamine (benzylamine, etc.), ethanolamine, aniline,
Ethanol, methanol, phenols and the like can also be used in the above coupling reaction.

The other starting materials and reagents in the present invention are known per se or can be produced by known methods. The product of each reaction may be isolated, washed, dried and purified at each step and used in the next reaction, or the operation may not be performed at all or may be stopped at an appropriate stage. The process may proceed.
The reaction product in each reaction may be purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate,
It can be purified by a method such as thin layer chromatography, column chromatography, washing, and recrystallization.

[0042]

EXAMPLES The present invention will be described below in detail with reference to comparative examples and examples, but the present invention is not limited to these examples.
The solvent in parentheses shown at the point of separation by chromatography indicates the elution solvent or developing solvent used,
The ratio indicates a volume ratio. Comparative Example 1 5-acetyl-4,6-dimethyl-1,2-dihydro-
Synthesis of 2-pyrimidinone

[0043]

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After cooling concentrated nitric acid (24 ml) in an ice-salt water bath, 5-acetyl-4,6-dimethyl-1,2,3,4
-Tetrahydro-2-pyrimidinone (10.1 g) at 20 ° C
It added so that it might not become above, and stirred for 30 minutes. The reaction mixture was neutralized by adding a saturated aqueous solution of sodium hydrogen carbonate, and extracted with chloroform (100 ml three times). The organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness to give the title compound (2.4 g) in a yield of 24% (this production operation was the same as in Example 10 described in JP-A-3-7265). Method). Example 1 2-thioxo-4,6-dimethyl-5-acetyl-1,
Synthesis of 2,3,4-tetrahydropyrimidine

[0045]

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Thiourea (304.5 g) was dissolved in isopropanol (800 ml) and stirred while cooling in an ice-water bath. To this, concentrated sulfuric acid (54 ml) was slowly added dropwise. To the reaction mixture, a solution of 2,4-pentadione (200 g) and 90% acetaldehyde (200 g) in isopropanol (200 ml) was added dropwise over 1 hour while maintaining the temperature at 15 ° C. or less.
Stirred on ice-water bath for minutes. After removing the ice-water bath and stirring for 40 minutes, the reaction mixture was immersed in a 60 ° C. oil bath for 1 hour 40 minutes.
Minutes. After raising the temperature of the oil bath to 80 ° C. and stirring for 50 minutes, isopropanol (200 ml) was added and the mixture was heated with stirring for 2 hours and 30 minutes. After cooling the reaction mixture, triethylamine (54 ml) was added, and the solvent was distilled off under reduced pressure. Water (1 L) and ethyl acetate (1 L) were added to the residue and stirred. Crystals precipitated. The suspension was filtered under reduced pressure. The obtained crystals were washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated. Water was added to the mixture to cause crystallization, followed by filtration. The crystals were washed with methanol and dried under reduced pressure together with the above crystals to give the title compound (140.2
g) was obtained in a yield of 38.3%. TLC: Rf 0.46 (ethyl acetate: normal hexane = 1:
1), NMR (CDCl ₃ ): δ 8.40 (1H, bs), 7.72 (1H, bs), 4.
52-4.38 (1H, m), 2.30 (3H, s), 2.27 (3H, s), 1.2
5 (3H, s), 1.23 (3H, d, J = 6.5 Hz), mp: 195.5-197 ° C (ethanol). Example 1 (1) 2-thioxo-4,6-dimethyl-5-acetyl-1,
Separate synthesis method of 2,3,4-tetrahydropyrimidine Thiourea (7.61 g), 2,4-pentadione (10.0 g)
And 90% acetaldehyde (10.0 g) were dissolved in ethanol (50 ml) and cooled in an ice-salt bath. While stirring the mixed solution, concentrated sulfuric acid (2.
A solution of 7 ml) in ethanol (3.0 ml) was added dropwise. Remove the ice-salt bath and stir at room temperature overnight. Reaction mixture solution at 40 ° C
And stirred for 2 hours. The reaction mixture was cooled in an ice-water bath. The precipitated crystals are filtered and ethanol (30 ml)
Then, the title compound (7.47 g) was obtained. Next, the crystal filtrate was concentrated, neutralized with ethanol (20 ml) and a 4N aqueous sodium hydroxide solution, and filtered. The obtained crystals were washed with water and ethanol, and then dried under reduced pressure to give the title compound (8.21 g) in a yield of 44.6% in combination with the previous crystals. Example 2 2-methylthio-4,6-dimethyl-5-acetyl-
Synthesis of 3,4-dihydropyrimidine

[0047]

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Dimethylsulfuric acid (74 ml) was added to a suspension of the compound (120.0 g) produced in Example 1 in ethanol (600 ml), refluxed for 30 minutes, cooled to room temperature and concentrated. Ethyl acetate (1 L) was added to the residue to dissolve it, and ice and a 4N aqueous sodium hydroxide solution (500 ml) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (500 ml once, 300 ml once). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give the compound of the present invention (128.0 g) having the following physical data in a yield of 99.1%. TLC: Rf 0.37 (ethyl acetate: normal hexane = 3:
2), NMR (CDCl ₃ ): δ 6.6 (1H, m), 4.75-4.50 (1H,
m), 2.45 (3H, s), 2.27 (6H, bs), 1.14 (3H, bd, J =
6.5 Hz), mp: 110.0-111.5 ° C (ethyl acetate-normal hexane). Example 3 Synthesis of 2-methylthio-4,6-dimethyl-5-acetylpyrimidine

[0049]

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The compound prepared in Example 2 (89.0 g), potassium peroxodisulfate (133.6 g) and anhydrous copper sulfate (3.6 g) were added to water (1.7 L). Reaction mixture solution at 80 ° C
For 1 hour. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (1.0 L). Ethyl acetate (0.3L)
Extracted. The organic layer was washed with water-saturated saline (1: 1) and saturated saline, dried over anhydrous sodium sulfate and concentrated to dryness. The compound of the present invention (73.0
g) was obtained with a yield of 82.9%. TLC: Rf 0.81 (ethyl acetate: normal hexane = 1:
1), NMR (CDCl ₃ ): δ 2.55 (3H, s), 2.52 (3H, s), 2.38
(6H, s), mp: 61.5-62.0 ° C (60% water-containing ethanol). Example 4 Synthesis of 2-methylsulfonyl-4,6-dimethyl-5-acetylpyrimidine

[0051]

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The compound prepared in Example 3 (73.0 g) was dissolved in acetonitrile (370 ml), and cooled in an ice-water bath.
A suspension of potadium peroxymonosulfate (343.0 g) in water (740 ml) was added in 200 ml portions at 15 minute intervals and stirred for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was cooled in an ice-water bath and cooled 4N aqueous sodium hydroxide was added to bring the pH of the solution to 5-6,
Extraction was performed with ethyl acetate (1 L). The aqueous layer was extracted with ethyl acetate (500ml, twice). The organic layers were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated to dryness. The compound of the present invention (77.6
g) was obtained in a yield of 91.4%. TLC: Rf 0.65 (ethyl acetate), NMR (CDCl ₃ ): δ 3.36 (3H, s), 2.59 (3H s), 3.56
(6H, s), mp: 106.8-107.8 ° C (isopropanol). Example 5 Synthesis of 2- (2- (4- (2-methoxyphenyl) piperazinyl) ethyl) amino-5-acetyl-4,6-dimethylpyrimidine

[0053]

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The compound prepared in Example 4 (34.44 g) and 2- (4- (2-methoxyphenyl) piperazinyl)
To a suspension of ethylamine (35.5 g) in isopropanol (150 ml) was added triethylamine (25.22 ml), and the mixture was refluxed for 2 hours. After cooling the reaction mixture to room temperature, it was further stirred and cooled in an ice-water bath. The obtained crystals were collected by filtration under reduced pressure, and washed with isopropanol (40 ml, twice) to give the title compound (45.0 g) having the following physical data in a yield of 77.7%. TLC: Rf 0.33 (ethyl acetate), NMR (CDCl ₃ ): δ 7.06-6.82 (4H, m), 5.74 (1H, b
t), 3.86 (3H, s), 3.57 (2H, q), 3.08 (4H, bt), 2.70
(4H, bt), 2.66 (2H, q), 2.47 (3H, s), 2.30 (6H,
s), mp: 104.0-105.5 ° C (ethanol).

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/505 ACB A61K 31/505 ACB

Claims (7)

[Claims] 1. A compound of the formula (V) which is obtained by subjecting thiourea, acetylacetone and acetaldehyde to a condensation reaction. By subjecting it to an alkylation reaction to give a compound of formula (IV) By subjecting it to a dehydrogenation reaction to give a compound of formula (III) By subjecting it to an oxidation reaction to give a compound of formula (II) Which is then represented by the formula (VI): Wherein the compound is reacted with a compound represented by the formula (I): A method for producing a pyrimidine derivative represented by the formula: 2. The method according to claim 1, wherein thiourea, acetylacetone and acetaldehyde are subjected to a condensation reaction. A method for producing a compound represented by the formula: 3. The method according to claim 1, wherein the compound is represented by the formula (V): Wherein the compound of formula (IV) is subjected to an alkylation reaction. A method for producing a compound represented by the formula: 4. The method according to claim 1, wherein the compound of formula (IV) is Wherein the compound of the formula (III) is subjected to a dehydrogenation reaction. A method for producing a compound represented by the formula: 5. The method according to claim 1, wherein the compound of formula (III) is Characterized by subjecting the compound represented by the oxidation reaction,
Formula (II) A method for producing a compound represented by the formula: 6. The method according to claim 1, wherein the compound has the formula (II): A compound represented by the formula (VI): A compound represented by the formula (I): A method for producing a pyrimidine derivative represented by the formula: 7. A compound of the general formula (VII) (Wherein, (i) R ¹ is a hydrogen atom, R ² is a —SCH ₃ group, Represents a single bond or (ii) R ¹ represents nothing, R ² represents a —SCH ₃ group, Represents a double bond, or (iii) R ¹ represents nothing, R ² represents a —SO ₂ CH ₃ group, Represents a double bond. ).