JP2003306483A - Method for producing 4-oxypyrimidine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an industrially suitable method for producing a 4- oxypyrimidine derivative in a good yield from a readily available carboxylic ester and 3-aminoacrylonitrile by a simple method. <P>SOLUTION: The method for producing the 4-oxypyrimidine derivative represented by general formula (1) (wherein R<SP>1</SP>, R<SP>2</SP>and R<SP>3</SP>are each a group which may have a substituent group and do not participates in the reaction comprises reacting the carboxylic ester with 3-aminoacrylonitrile in the presence of a metal alkoxide. <P>COPYRIGHT: (C)2004,JPO

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 4-oxypyrimidine derivative from a carboxylic acid ester and a 3-aminoacrylonitrile. A 4-oxypyrimidine derivative is a compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and the like. 2. Description of the Related Art Conventionally, as a method for producing a 4-oxypyrimidine derivative, a chlorinating agent is allowed to act on a pyrimidine-4-one to form a 4-chloropyrimidine, which is then reacted with an alcohol. (Eg, DJ Brown, "HETEROCYCLICCOMPOUNDS; THE PYRIMI
DINES SUPPLEMENT I, Chapter VII ", JOHN WILEY & SON
S (1970)). However, this method is not satisfactory as an industrial production method, for example, the post-treatment is complicated because a highly toxic chlorinating agent is used. [0003] The object of the present invention is to provide a method for producing a carboxylic acid ester and 3-aminoacrylonitrile, which are easily available, by a simple method in good yield.
An object of the present invention is to provide an industrially suitable method for producing a pyrimidine derivative for producing a 4-oxypyrimidine derivative. Means for Solving the Problems The general formula (1) (Wherein M represents a metal atom, and R ¹ represents
It represents a hydrocarbon group which may have a substituent. ) In the presence of a metal alkoxide of the general formula (2) (In the formula, R ² represents a group which may have a substituent and does not participate in the reaction, and R ³ represents a hydrocarbon group which may have a substituent.) And a carboxylic acid ester represented by the general formula (3): (Wherein R ⁴ represents a group which may have a substituent and does not participate in the reaction), characterized by reacting with a 3-aminoacrylonitrile represented by the formula:
General formula (4) (Wherein, R ² and R ⁴ have the same meanings as described above, and R ⁵ has the same meaning as any ^one of the above R ^{1 and} R ³ ). Manufacturing method. BEST MODE FOR CARRYING OUT THE INVENTION The metal alkoxide used in the reaction of the present invention is represented by the above general formula (1). In the general formula (1), M is a metal atom. Also, R
¹ is a hydrocarbon group which may have a substituent, and specifically, for example, may have a substituent,
It is an alkyl group, a cycloalkyl group, an aralkyl group or an aryl group. Examples of the metal atom include a Group 1A metal atom such as a lithium atom, a sodium atom, a potassium atom and a cesium atom; a Group 2A atom such as a magnesium atom and a calcium atom; and a Group 3A atom such as an aluminum atom. Is preferably a sodium atom, a potassium atom, and more preferably a sodium atom. Examples of the alkyl group include a methyl group, an ethyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group. These groups include various isomers. As the cycloalkyl group, for example,
Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. These groups include various isomers. Examples of the aralkyl group include a benzyl group, a phenethyl group and a phenylpropyl group. These groups include various isomers. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group and an anthryl group. These groups include various isomers. The above-mentioned hydrocarbon group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom. Examples of the substituent formed through the carbon atom include alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group and hexyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl. Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group and cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl A heterocyclic group such as a group; an aryl group such as a phenyl group, a tolyl group, a fluorophenyl group, a xylyl group, a biphenyl group, a naphthyl group, an anthryl group, a phenanthryl group; a halogenated alkyl group such as a trifluoromethyl group; No. These groups include various isomers. Examples of the substituent formed through the oxygen atom include alkoxyl groups such as methoxyl, ethoxyl, propoxyl, butoxyl, pentyloxyl, hexyloxyl, heptyloxyl, and benzyloxyl; And aryloxyl groups such as a phenoxyl group, a toluyloxyl group and a naphthyloxyl group. These groups include various isomers. Examples of the substituent formed through the nitrogen atom include dimethylamino, diethylamino, dibutylamino, methylethylamino, methylbutylamino, diphenylamino, N-methyl-N-methanesulfonyl. Secondary amino groups such as amino groups; and heterocyclic amino groups such as morpholino group, piperidino group, piperazinyl group, pyrazolidinyl group, pyrrolidino group and indolyl group. These groups include various isomers. Examples of the substituent formed through the sulfur atom include an alkylthio group such as a methylthio group, an ethylthio group and a propylthio group; and an arylthio group such as a phenylthio group, a toluylthio group and a naphthylthio group. These groups include various isomers. As the halogen atom, a fluorine atom,
Examples include a chlorine atom, a bromine atom and an iodine atom. The amount of the metal alkoxide used is preferably 0.5 to 5.0 mol per 1 mol of the carboxylic acid ester.
More preferably, it is 1.0 to 2.5 mol. The carboxylic acid esters used in the reaction of the present invention are represented by the above general formula (2). In the general formula (2), R ² may have a substituent.
Although it is a group which does not participate in the reaction, specific examples thereof include a hydrogen atom, an alkyl group, a cycloalkyl group, an aralkyl group, an aryl group and a heterocyclic group which may have a substituent. Examples of the alkyl group include a methyl group, an ethyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group. These groups include various isomers. As the cycloalkyl group, for example,
Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. These groups include various isomers. Examples of the aralkyl group include a benzyl group, a phenethyl group and a phenylpropyl group. These groups include various isomers. Examples of the aryl group include a phenyl group, a tolyl group, a naphthyl group and an anthryl group. These groups include various isomers. Examples of the heterocyclic group include a furyl group, thienyl group, pyrazolyl group, pyrrolyl group, imidazolyl group, oxazolyl group, thiazolyl group, triazolyl group, thiazolyl group, tetrazolyl group, pyridyl group, pyrimidylyl group, and pyrimidinoyl group. Quinolyl group, methylenedioxyphenyl group and the like. These groups include various isomers. The group which does not participate in the above reaction may have a substituent. As the substituent are the same as those described in the description of R ^1. R ³ may have a substituent;
Is a hydrocarbon group. Specifically, the same meaning as R ¹ above. The 3-aminoacrylonitriles used in the reaction of the present invention are represented by the general formula (3). In the general formula (3), R ⁴ is a group which may have a substituent and does not participate in the reaction, and has the same meaning as R ² described above. The amount of the 3-aminoacrylonitrile used is preferably 0.1 to 1 mol of the carboxylic acid ester.
It is 5 to 5.0 mol, more preferably 1.0 to 2.5 mol. The reaction of the present invention may be carried out in the presence of a solvent other than the alcohol existing before the reaction or formed during the reaction. The solvent used is not particularly limited as long as it does not inhibit the reaction or affect the reaction product. Examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dioxane; benzene, toluene, and the like. Aromatic hydrocarbons;
Halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; sulfoxides such as dimethyl sulfoxide; amides such as N, N-dimethylformamide; and ureas such as N, N'-dimethylimidazolidinone. Preferably, ethers, sulfoxides and ureas are used. These solvents may be used alone or in combination of two or more. The amount of the solvent to be used is appropriately adjusted depending on the uniformity of the reaction solution, the stirring property and the like.
For 1 g, preferably 0.5 to 20 g, more preferably 0.75
~ 10g. The reaction of the present invention is carried out, for example, by a method in which a metal alkoxide, a carboxylic acid ester and 3-aminoacrylonitrile are mixed in an inert gas atmosphere and reacted with stirring. The reaction temperature at that time is preferably 40 to 110 ° C, more preferably 50 to 100 ° C.
And the reaction pressure is not particularly limited. After completion of the reaction, the final product, 4-oxypyrimidine derivative, is extracted, concentrated, distilled,
It is isolated and purified by a general method such as crystallization, recrystallization, and column chromatography. The 4-oxypyrimidine derivative is represented by the general formula (4). In the general formula (4),
R ⁵ is the same as any ^one of R ^{1 and} R ³ described above. EXAMPLES Next, the present invention will be described specifically with reference to examples, but the scope of the present invention is not limited to these examples. Example 1 (2-cyclopropyl-4-methoxy-
Synthesis of 6-methylpyrimidine) 100ml inner volume equipped with stirrer, thermometer and reflux condenser
Under a nitrogen atmosphere, under nitrogen atmosphere, 3.59 g (18.6 mmol) of 28% by mass sodium methoxide, 1.86 g (18.6 mmol) of methyl cyclopropanecarboxylate and 1.53 g (18.6 mmol) of 3-aminoacrylonitrile were added, and the mixture was refluxed. (67 ° C.) for 10 hours. After the reaction is completed, cool to room temperature and add toluene 50
After adding ml, 20 ml of water was slowly added while maintaining the liquid temperature at 30 ° C or lower. Next, the organic layer and the aqueous layer are separated,
The aqueous layer was extracted twice with 20 ml of toluene. The extract (toluene layer) and the organic layer were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (filler: Wakogel C-200).
(Wako Pure Chemical Industries, Ltd.), developing solvent; n-hexane / ethyl acetate = 9: 1 (volume ratio)), and 2.10 g of 2-cyclopropyl-4-methoxy-6-methylpyrimidine as a colorless transparent liquid. Was obtained (isolation yield: 69%). 2-cyclopropyl-4-methoxy-6-
Physical properties of methylpyrimidine were as follows. EI-MS (m / e); 163 (M-1), CI-MS (m / e); 165
(M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 0.94 to 1.00 (2H, m), 1.03 to 1.1
3 (2H, m), 2.07 ~ 2.16 (1H, m), 2.36 (3H, d, J = 0.5Hz), 3.8
8 (2H, s), 6.30 (1H, d, J = 0.5 Hz) IR (liquid film method, cm ^-1 ); 3100 to 2870, 1590 to 1570, 1470 to 136
0, 1296, 1196, 1162, 1103 Example 2 (2-isopropyl-4-methoxy-6-
Synthesis of methylpyrimidine) 100ml inner volume equipped with stirrer, thermometer and reflux condenser
Under a nitrogen atmosphere, under nitrogen atmosphere, 3.86 g (20.0 mmol) of 28% by mass sodium methoxide, 2.04 g of methyl isobutyrate
(20.0 mmol) and 1.64 g of 3-aminoacrylonitrile (20.0 mm
ol) and reacted under reflux (67 ° C.) for 10 hours. After the completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added, and 20 ml of water was slowly added while keeping the liquid temperature at 30 ° C. or lower. Next, the organic layer and the aqueous layer were separated, and the aqueous layer was dissolved in toluene 20
Extracted twice with ml. The extract (toluene layer) and the organic layer were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 9: 1 (volume ratio))
To give 2.29 g of 2-isopropyl-4-methoxy-6-methylpyrimidine as a colorless transparent liquid (isolation yield: 69)
%). Physical properties of 2-isopropyl-4-methoxy-6-methylpyrimidine were as follows. EI-MS (m / e); 151 (M-CH ₃ ), CI-MS (m / e);
7 (M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.30 (6H, d, J = 7.2 Hz), 2.38 (3
H, s), 3.05 (1H, sept, J = 7.2Hz), 3.94 (3H, s), 6.35 (1H,
d, s) Example 3 (Synthesis of 2-t-butyl-4-methoxy-6-methylpyrimidine) 100 ml of internal volume equipped with a stirrer, thermometer and reflux condenser
Under a nitrogen atmosphere, 3.86 g (20.0 mmol) of 28% by weight sodium methoxide,
2 g (20.0 mmol) and 1.64 g of 3-aminoacrylonitrile (20.0
mmol) and reacted at reflux (67 ° C.) for 10 hours. After completion of the reaction, the mixture was cooled to room temperature, and 50 ml of toluene was added.
While maintaining the liquid temperature at 30 ° C. or lower, 20 ml of water was slowly added. Next, the organic layer and the aqueous layer were separated, and the aqueous layer was dissolved in toluene 20
Extracted twice with ml. The extract (toluene layer) and the organic layer were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 9: 1 (volume ratio))
2-t-butyl-4-methoxy- as a colorless transparent liquid
2.45 g of 6-methylpyrimidine was obtained (isolation yield: 68%). 2-t
The physical properties of -butyl-4-methoxy-6-methylpyrimidine were as follows. ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.36 (9H, s), 2.4
0 (3H, s), 3.93 (3H, s), 6.32 (1H, s) Example 4 (Synthesis of 2-ethyl-4-methoxy-6-methylpyrimidine) Stirrer, thermometer and reflux cooling 100ml with container
3.86 g (20.0 mmol) of 28% by mass sodium methoxide in a nitrogen flask under a nitrogen atmosphere, and methyl propionate
1.76 g (20.0 mmol) and 1.64 g of 3-aminoacrylonitrile (2
0.0mmol), and reacted at reflux (67 ° C) for 10 hours. After the completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added, and 20 ml of water was slowly added while keeping the liquid temperature at 30 ° C. or lower. Next, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with 20 ml of toluene. The extract (toluene layer) and the organic layer were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 9: 1 (volume ratio)) To give 1.98 g of 2-ethyl-4-methoxy-6-methylpyrimidine as a colorless transparent liquid (isolation yield: 65%).
Physical properties of 2-ethyl-4-methoxy-6-methylpyrimidine were as follows. EI-MS (m / e); 151 (M-1), CI-MS (m / e); 153
(M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 1.32 (3H, t, J = 7.6 Hz), 2.40 (3
H, s), 2.83 (2H, q, J = 7.6 Hz), 3.94 (3H, s), 6.37 (1H, s) Example 5 (2-benzyl-4-methoxy-6-methylpyrimidine Synthesis) Internal volume 100ml equipped with stirrer, thermometer and reflux condenser
Under a nitrogen atmosphere, 3.86 g (20.0 mmol) of 28% by mass sodium methoxide, methyl phenylacetate
3.00 g (20.0 mmol) and 1.64 g of 3-aminoacrylonitrile (2
0.0mmol), and reacted at reflux (67 ° C) for 10 hours. After the completion of the reaction, the mixture was cooled to room temperature, 50 ml of toluene was added, and 20 ml of water was slowly added while keeping the liquid temperature at 30 ° C. or lower. Next, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with 20 ml of toluene. The extract (toluene layer) and the organic layer were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (filler: Wakogel C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: n-hexane / ethyl acetate = 9: 1 (volume ratio)) To give 3.08 g of 2-benzyl-4-methoxy-6-methylpyrimidine as a colorless transparent liquid (isolation yield: 72
%). Physical properties of 2-benzyl-4-methoxy-6-methylpyrimidine were as follows. EI-MS (m / e); 213 (M-1), CI-MS (M + 1); 215
(M + 1) ¹ H-NMR (CDCl ₃ , δ (ppm)); 2.40 (3H, s), 3.90 (3H, s), 4.1
2 (2H, s), 6.37 (1H, s), 7.17 to 7.41 (5H, m) According to the present invention, carboxylic acid esters which are easily available and 3- An industrially suitable method for producing a 4-oxypyrimidine derivative, which is capable of producing a 4-oxypyrimidine derivative in good yield from aminoacrylonitriles, can be provided.

   ────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventor Takashi Harada             5 Ube, 1978 Kogushi, Ube City, Yamaguchi Prefecture             Kosan Co., Ltd.

Claims (1)

[Claim 1] The general formula (1) (Wherein M represents a metal atom, and R ¹ represents a hydrocarbon group which may have a substituent.) In the presence of a metal alkoxide represented by the general formula (2): ] (Wherein, R ² represents a group which may have a substituent and does not participate in the reaction, and R ³ represents a hydrocarbon group which may have a substituent). Carboxylic esters and general formula (3) (Wherein, R ⁴ represents a group which may have a substituent and does not participate in the reaction), characterized by reacting with a 3-aminoacrylonitrile represented by the general formula (4): Embedded image (Wherein, R ² and R ⁴ are as defined above, and R ⁵ is
It is the same as any ^one of R ^{1 and} R ³ described above. A method for producing a 4-oxypyrimidine derivative represented by the formula: