JPH1112253A - Method for producing 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially produce the subject compound useful as medicines and agrochemicals by reacting 4-amino-5-chloro-6-(1bromoethyl)pyrimidine derivative with an alkali metal fluoride compound in a specific solvent. SOLUTION: A 4-amino-5-chloro-(1-brommmoethyl)pyrimidine derivative of formula I [R is H, a 1-4C (halo)alkyl, a 1-4C (halo)alkoxy, a halogen, nitro, etc.] is reacted with an alkali metal fluoride compound of the formula M-F (M is an alkali metal, preferably potassium) by using formamide, N- methylformamide, or a mixture of formamide or N-methylformamide, with 1,3-dimethyl-2-imidazolidinone as a solvent at a temperature from a room temperature to the boiling point of the used solvent, preferably 50-100 deg.C ordinary for 1-3 hr to provide the objective compound of formula II, 4-amino-5-chloro-6-(1- fluoroethyl)pyrimidine derivative.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an industrial process for producing a 4-amino-5-chloro- (1-fluoroethyl) pyrimidine derivative which is useful as a pharmaceutical or agrochemical.

[0002]

BACKGROUND OF THE INVENTION A 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine derivative produced by the present invention is:
It is known to be useful as an insecticide, acaricide, fungicide, nematicide, and the like. (For example, see Japanese Patent Application Laid-Open No. 5-199
4417, JP-A-5-230036, JP-A-6-25187, JP-A-6-116247, JP-A-6-247939, JP-A-7-258
However, in these prior arts, the reaction steps must use complicated and expensive reagents, the reaction intermediate is unstable, and the yield is low. It is hard to say that it is an industrial production method due to bad things. That is, in these prior arts, the following production methods 1 to 3 are known, but there are various problems as described above, and it is difficult to say that these methods are industrially advantageous.

(1) Production method 1 The desired compound (3) is prepared as follows:
And compound (5).

[0004]

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(In the formula, X represents a halogen atom, and R has the same meaning as described above.) Compound (4) is disclosed in JP-A-5-1994 as shown below.
No. 417, can be synthesized.

[0006]

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It can be manufactured by the following method. However, in this step, the reaction step is complicated and expensive raw materials have to be used, and the compound (4) is unstable. Therefore, this manufacturing method is hardly an industrial manufacturing method.

(2) Production method 2 The desired compound (3) is prepared as follows:
After obtaining a compound (10) from the compound (5) and the compound (5), the compound (10) is reacted with the compound (7), then reacted with the compound (8), and further reacted with the compound (9).

[0009]

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(Wherein, R has the same meaning as described above.) However, in this production method, the reaction is complicated and an expensive fluorinating agent (compound (9)) must be used. Therefore, this manufacturing method is hardly an industrial manufacturing method.

(3) Production method 3 The target compound (3) is a compound (1) as shown below.
0) and the compound (2).

[0012]

Embedded image (In the formula, M and R have the same meanings as described above.) However, in this production method, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,3-dimethyl- 2-imidazolidone,
Although dimethyl sulfoxide, sulfolane and a mixture thereof are used, a high reaction temperature and a long reaction time are required, and the yield is poor. Therefore, this method is also not an industrial production method.

[0013]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrial method for producing a 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine derivative which is useful as a pharmaceutical or agricultural chemical. .

[0014]

The inventors of the present invention have studied to solve the above-mentioned problems, and as a result, an object of the present invention is to provide 4-amino-5-chloro-6- useful as a medicine and a pesticide.
The present inventors have found a method for industrially producing a (1-fluoroethyl) pyrimidine derivative, and have completed the present invention. That is, the present invention provides the following formula (1):

[0015]

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(Wherein R is a hydrogen atom and has 1 to 4 carbon atoms)
Alkyl groups, alkoxy groups having 1 to 4 carbon atoms,
A halogen atom, a haloalkyl group having 1 to 4 carbon atoms,
Represents a haloalkoxy group having 1 to 4 carbon atoms and a nitro group. ) And a 4-amino-5-chloro- (1-bromoethyl) pyrimidine derivative represented by the following formula (2):

[0017]

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(Wherein M represents an alkali metal) with an alkali metal fluorine compound represented by the following formula:
N-methylformamide, or formamide or N
Wherein the mixture of -methylformamide and 1,3-dimethyl-2-imidazolidinone is reacted as a solvent, the following formula (3):

[0019]

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(Wherein R is a hydrogen atom and has 1 to 4 carbon atoms)
Alkyl groups, alkoxy groups having 1 to 4 carbon atoms,
A halogen atom, a haloalkyl group having 1 to 4 carbon atoms,
Represents a haloalkoxy group having 1 to 4 carbon atoms and a nitro group. The present invention relates to a 4-amino-5-chloro- (1-fluoroethyl) pyrimidine derivative represented by the following formula:

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The target compound, 4-amino-5-chloro- (1
R, M and X represented by the (-fluoroethyl) pyrimidine derivative (3) and the raw material for producing the same (compounds (1), (2) and (11)) are as follows.

[R] R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group having 1 to 4 carbon atoms, Examples thereof include a haloalkoxy group having 1 to 4 atoms and a nitro group.

Examples of the alkyl group include linear or branched ones having 1 to 4 carbon atoms; preferably, a methyl group or an ethyl group. Examples of the alkoxy group include straight or branched ones having 1 to 4 carbon atoms; preferably, a methoxy group and an ethoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably a fluorine atom and a chlorine atom.

Examples of the haloalkyl group include those in which alkyl is a straight or branched chain having 1 to 4 carbon atoms and having a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Although it is; preferably a -CF _3. Examples of the haloalkoxy group include those in which alkoxy is a linear or branched one having 1 to 4 carbon atoms and has a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. There; preferably -OCF _3, -OCHF _2, -OCH
_{2 CF 3, -OCF 2 CHFCF 3} , -OCHFCHF
_2, it is a -OCF ₂ CHFCl and -OCBrF _2;
Even more preferably -OCF ₃ and -OCH ₂ CF _3.

[M] M is an alkali metal,
Examples include sodium, potassium, and cesium; preferably, potassium.

[X] X is a halogen atom,
Examples thereof include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; preferably a chlorine atom and a bromine atom.

The compound (1) used in the present invention can be prepared by converting the compound (11) and the compound (5) in the presence of a base without a solvent, as described in JP-A-7-258223, as shown below. It can be easily produced by reacting in a solvent.

[0028]

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(In the formula, X and R have the same meanings as described above.) As the compound (1), for example, those shown in Table 1 synthesized by the method shown in the below-mentioned reference example can be mentioned. it can. As the compound (2) used in the present invention, a commercially available product (for example, spray-dried potassium fluoride) can be used. In the present invention, the target compound (3) can be produced by reacting the compound (1) with the compound (2) in a solvent. As the type of the solvent, formamide, N-methylformamide, or formamide or N-methylformamide and 1,3-dimethyl-
Mixtures with 2-imidazolidone (DMI) can be mentioned.

The amount of the solvent used is such that the compound (1) is 5-80.
Weight percent can be used; however, 10
~ 50% by weight is preferred. The amount of the compound (2) to be used may be 1 to 10-fold the molar amount of the compound (1), but is preferably a 2- to 5-fold molar amount. The reaction temperature ranges from room temperature to a temperature not higher than the boiling point of the solvent used; The reaction time is
It varies depending on the concentration and temperature as described above; After completion of the reaction, the target compound (3) produced as described above is subjected to ordinary post-treatments such as extraction, concentration and filtration, and if necessary, by known means such as recrystallization and various types of chromatography. It can be appropriately purified.

[0031]

EXAMPLES The present invention will be specifically described below with reference examples, examples and comparative examples. Note that these examples do not limit the scope of the present invention. Reference Example [Synthesis of Compound (1)] (1) (±) 6- (1-bromoethyl) -5-chloro-4
Synthesis of-(2-phenylethylamino) pyrimidine (Compound 1-1) 2-Phenylethylamine (1.2 g) and triethylamine (1.2 g) were dissolved in toluene (30 ml), and
-Bromo-6- (1-bromoethyl) -5-chloropyrimidine (3.0 g) was added, and the mixture was stirred at about 40 ° C for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 1).
0: 1 elution) to give the desired product as colorless powdery crystals.
9 g (85.3%) were obtained.・ M. p. 103-105 ° C

(2) (±) 6- (1-bromoethyl) -5
-Chloro-4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 1-7) Synthesis 2- (4-trifluoromethoxyphenyl) ethylamine (3.0 g) and triethylamine (3.0 g) Was dissolved in toluene (50 ml), 4-bromo-6- (1-bromoethyl) -5-chloropyrimidine (4.5 g) was added, and the mixture was stirred at about 40 ° C. for 3 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography (Wakogel C-20).
0, toluene: ethyl acetate = 10: 1 elution) to obtain 5.9 g (92.7%) of the target compound as colorless powdery crystals.・ M. p. 91 to 91.5 ° C

(3) (±) 6- (1-bromoethyl) -5
-Chloro-4- [2- (4-nitrophenyl) ethylamino] pyrimidine (Compound 1-10) Synthesis 2- (4-Nitrophenyl) ethylamine hydrochloride (3.
0 g) was suspended in toluene (50 ml), and triethylamine (3.0 g) and 6- (1-bromoethyl) -4,
Add 5-dichloropyrimidine (3.8 g) and add about 50 ° C.
For 5 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene:
(Ethyl acetate = 10: 1 elution) to give 5.1 g (88.2%) of the target compound as colorless powdery crystals.・ M. p. 114-116 ° C

(4) Synthesis of Other Compound (1) in Table 1 Other compounds (1) in Table 1 were synthesized according to the methods described in (1) to (3) above. Table 1 shows the compounds synthesized as described above and their physical properties.

[0035]

[Table 1]

Example [Synthesis of Compound (3)] (1) (±) 5-chloro-6- (1-fluoroethyl)-
Synthesis of 4- (2-phenylethylamino) pyrimidine (Compound 1) 6- (1-Bromoethyl) -5-chloro-4- (2-phenylethylamino) pyrimidine (1.0 g) was added to formamide (2 ml) and 1 , 3-Dimethyl-2-imidazolidinone (DMI) (2 ml) was dissolved in a mixed solvent, spray-dried potassium fluoride (0.5 g) was added, and the mixture was stirred in an oil bath at 80 ° C. for 3 hours. After the reaction, water (10m
l) was added, extracted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 20: 1 to 5: 1).
(Elution) to give 0.56
g (68.3%).

1H-NMR (CDCl3) δ ppm 2.00 to 2.02 (q, 3H), 2.92 to 2.97
(T, 2H), 3.75-3.82 (q, 2H), 5.
38-5.45 (q, 1H), 5.55 (s, 1H),
7.22 to 7.36 (m, 5H), 8.54 (s, 1
H)

(2) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (Compound 2) 6- (1-bromoethyl) -5-chloro-4- [2-
(4-methylphenylethylamino) pyrimidine (1.
0 g) with formamide (2 ml) and 1,3-dimethyl-
Dissolve in a mixed solvent of 2-imidazolidinone (DMI) (2 ml) and spray-dry potassium fluoride (0.5
g) was added and the mixture was stirred in an oil bath at 80 ° C. for 3 hours. After completion of the reaction, water (10 ml) was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 2).
(0: 1 to 5: 1 elution) to give 0.58 g (70.0%) of the target compound as colorless powdery crystals.

(3) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-methoxyphenyl) ethylamino] pyrimidine (Compound 3) 6- (1-bromoethyl) -5-chloro-4- [2-
(4-methoxyphenylethylamino) pyrimidine (1.
0 g) with formamide (2 ml) and 1,3-dimethyl-
Dissolve in a mixed solvent of 2-imidazolidinone (DMI) (2 ml) and spray-dry potassium fluoride (0.5
g) was added and the mixture was stirred in an oil bath at 80 ° C. for 3 hours. After completion of the reaction, water (10 ml) was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate =
(20: 1 to 5: 1 elution) to give 0.60 g (72.1%) of the target compound as colorless powdery crystals.

(4) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 7) Bromoethyl) -5-chloro-4- [2-
(4-trifluoromethoxyphenylethylamino) pyrimidine (1.0 g) was added to formamide (2 ml) and 1,3
-Dimethyl-2-imidazolidinone (DMI) (2 m
The mixture was dissolved in the mixed solvent of l), spray-dried potassium fluoride (0.5 g) was added, and the mixture was stirred in an oil bath at 80 ° C for 3 hours. After completion of the reaction, water (10 ml) was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting oil was purified by column chromatography (Wakogel C-200, elution with toluene: ethyl acetate = 20: 1 to 5: 1) to give the target compound as colorless powder crystals in 0%. 0.60 g (69.8%) were obtained.

1H-NMR (CDCl3) δ ppm 2.01 to 2.03 (d, 3H), 2.93 to 2.98
(T, 2H), 3.75-3.82 (q, 2H), 5.
38 to 5.46 (q, 1H), 5.55 (s, 1H),
7.16 to 7.27 (m, 5H), 8.54 (s, 1
H)

(5) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 7) Bromoethyl) -5-chloro-4- [2-
(4-trifluoromethoxyphenylethylamino) pyrimidine (1.0 g) was added to N-methylformamide (2 m
l) and spray-dried potassium fluoride (0.1).
5g) and stirred in an oil bath at 80 ° C for 3 hours. After completion of the reaction, water (10 ml) was added, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate =
20: 1-5: 1) to give 0.58 g (67.5%) of the desired product as colorless powdery crystals.

(6) Synthesis of other compound (3) in Table 2 Other compounds (3) in Table 2 were synthesized according to the methods described in the above (1) to (5). Table 2 shows the compounds synthesized as described above and their physical properties.

[0044]

[Table 2]

Comparative Example [Synthesis of Compound (3)] Hereinafter, a comparative example corresponding to the example of the present invention (JP-A-7-2
58223). (1) (±) 5-chloro-6- (1-fluoroethyl)-
Synthesis of 4- (2-phenylethylamino) pyrimidine (Compound 1) 2-Phenylethylamine (1.2 g) and triethylamine (1.2 g) were dissolved in toluene (30 ml).
4,5-Dichloro-6- (1-fluoroethyl) pyrimidine (2.0 g) was added, and the mixture was heated under reflux for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. Wash the extract with water,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
The obtained oil is subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 10: 1 elution).
2.3 g (82.
3%). The total process yield is 19.5% considering the production yield (24%) of the starting pyrimidine.

(2) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (Compound 2) 2- (4-methylphenyl) ) Ethylamine (4.1 g)
And triethylamine (5.0 g) in toluene (100 m
l), 4,5-dichloro-6- (1-chloroethyl) pyrimidine (6.3 g) was added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate = 1).
0: 1 elution) to give 5-chloro-
8.4 g of 6- (1-chloroethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (90.
3%).

The obtained 5-chloro-6- (1-chloroethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (3.5 g) was mixed with N, N-dimethylformamide (DMF) (50 ml). ), And potassium acetate (1.4 g) and potassium carbonate (1.6 g) were added.
Heated to reflux for an hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene:
5-chloro-6- (1-acetoxyethyl) -4- [2
2.0 g (53.1%) of-(4-methylphenyl) ethylamino] pyrimidine was obtained.

The obtained 5-chloro-6- (1-acetoxyethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (2.3 g) was added to ethanol (25 m
l) and dissolved in a 1N aqueous solution of sodium hydroxide (13 m
l) was added and the mixture was heated and stirred at about 60 ° C. for 1 hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. Wash the extract with water,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,
The obtained oil was subjected to column chromatography (Wakogel C-200, eluted with toluene: ethyl acetate = 4: 1) to give 5-chloro-6- (1-hydroxyethyl) -4- [2- ( 2.0 g (quantitative) of 4-methylphenyl) ethylamino] pyrimidine were obtained.

The obtained 5-chloro-6- (1-hydroxyethyl) -4- [2- (4-methylphenyl) ethylamino] pyrimidine (1.5 g) was treated with methylene chloride (30 g).
ml), diethylaminosulfur trifluoride (DAST) (0.8 g) was added dropwise under cooling and stirring, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, under cooling and stirring
Water was slowly added, and the organic layer was separated. After the organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, elution with toluene: ethyl acetate = 10: 1) as a pale yellow oil. 1.0 g of liquid target
(66.7%). Total yield of all steps is 31.9%

(3) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-methoxyphenyl) ethylamino] pyrimidine (Compound 3) 5-chloro-6- ( 1-chloroethyl) -4- [2-
(4-Methoxyphenyl) ethylamino] pyrimidine (1.5 g) was added to N, N-dimethylformamide (DM
F) (30 ml), cesium fluoride (1.5 g) was added, and the mixture was stirred at 120 to 140 ° C. for 12 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate.
After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (Wakogel C-200, toluene: ethyl acetate =
(9: 1 elution).
5 g (35.1%) were obtained.

(4) Synthesis of (±) 5-chloro-6- (1-fluoroethyl) -4- [2- (4-trifluoromethoxyphenyl) ethylamino] pyrimidine (Compound 7) Trifluoromethoxyphenyl) ethylamine (2.05 g) and triethylamine (3.0 g) were dissolved in toluene (20 ml) to give 4,5-dichloro-6.
-(1-Fluoroethyl) pyrimidine (2.0 g) was added, and the mixture was stirred at about 60 ° C for 4 hours. After completion of the reaction, water was added, and the mixture was extracted with toluene. After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to column chromatography (Wakogel C-20).
0, toluene: ethyl acetate = 10: 1 elution) to give 2.6 g (71.5%) of the desired product as pale yellow powdery crystals. The total yield of all steps in consideration of the production yield (24%) of the starting pyrimidine is 17.2%. Table 3 shows an outline of the examples and comparative examples.

[0052]

[Table 3]

[0053]

Effects of the Invention According to the present invention, a 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine derivative useful as a medicine, a pesticide or the like can be industrially produced.

Claims (1)

[Claims] 1. The following formula (1): (Wherein, R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a halogen atom, a haloalkyl group having 1 to 4 carbon atoms, A 4-amino-5-chloro-6- (1-bromoethyl) pyrimidine derivative represented by the following formula (2): (Wherein M represents an alkali metal) with formamide, N-methylformamide, or formamide or N-methylformamide with 1,3-dimethyl-2-imidazolidinone The following formula (3) is characterized by reacting the mixture as a solvent: (Wherein, R has the same meaning as described above.) A method for producing a 4-amino-5-chloro-6- (1-fluoroethyl) pyrimidine derivative represented by the formula: