JPWO2004067517A1 - Process for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol - Google Patents

Abstract

While the conventionally known methods for producing 2-alkoxy-6-trifluoro-pyrimidin-4-ol have problems such as generation of pollution and low yield, in the present invention, in the presence of sulfuric acid. To produce an O-alkylisourea by reacting cyanamide with a C1-C8 alcohol, and then reacting it in the presence of ethyl trifluoroacetoacetate and an alkali metal hydroxide. The target product can be obtained in good yield by the production method.

Description

  The present invention relates to a process for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol from alkoxyisourea hydrogensulfate or alkoxyisourea sulfate, in particular 2-isopropoxy-6-trifluoromethyl- The present invention relates to a method for producing pyrimidin-4-ol.

As a method for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol, particularly 2-isopropoxy-6-trifluoromethyl-pyrimidin-4-ol, which is an important intermediate for the production of insecticides, The reaction of O-isopropylisourea hydrochloride with ethyl trifluoroacetoacetate,
(1) A method carried out in methanol in the presence of sodium methoxide (for example, see JP-T-10-508860),
(2) a method carried out in an alcohol solvent in the presence of at least one base selected from alkali metal carbonates and bicarbonates (see, for example, JP-A-2001-322985) and (3) alkali metal hydroxide A method of performing in water in the presence of an object (for example, see JP-A-10-29983) is known.

（式中、ＲはＣ_１〜Ｃ_８の直鎖又は分岐のアルキル基を示す）
で示される。However, the method described in (1) has a problem that the separation apparatus that can be used is limited because the target product is separated from petroleum ether after the reaction. In the method (2), a centrifuge cannot be used to isolate the target product by recrystallization from a mixed organic solvent such as ethyl acetate / hexane. In the production facility in which the reactor and various separators are combined, there is a problem that the operating rate is lowered. Furthermore, in the method (3) and the method (2), O-isopropylisourea hydrochloride is obtained by reacting cyanamide and isopropanol at 70 ° C. to reflux temperature in the presence of hydrogen chloride. ing.
However, this formulation is not suitable for the production of the object on an industrial scale. This is because, in this method, when hydrogen chloride is used in an equimolar amount or less with respect to cyanamide, it takes a long time to complete the reaction. This is because hydrogen and isopropanol react to produce isopropyl chloride, which is harmful to the environment.
As is known, isopropyl chloride is mutagenic. The reaction mixture also contains free hydrogen chloride, which is highly corrosive, and the volatile isopropyl chloride and hydrogen chloride must not be released into the environment, so the separation and removal are costly. There was a problem of being expensive and expensive.
These problems make the conventional method unattractive both environmentally and economically as a method for industrial production.
The present invention has been made in view of the above points, and reduces the load on facilities necessary to prevent the release of harmful gases into the environment, thereby reducing the cost of 2-alkoxy-6-trifluoromethyl-pyrimidine. It aims at providing the method of manufacturing -4-ol.
As a result of intensive studies to solve the above problems, the present inventors reacted alkoxyisourea hydrogen sulfate or sulfate with trifluoroacetoacetic acid alkyl ester or sodium salt thereof, and crystallized in water. It was found that 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol could be easily obtained, and the present invention was completed.
The compound produced by the method of the present invention is represented by the formula (I):

(Wherein, R represents a linear or branched alkyl group of _C 1 -C ₈₎
Indicated by

Hereinafter, detailed embodiments of the present invention will be described.
In the present invention, a hydrogen sulfate or sulfate of alkoxyisourea derived from cyanamide is reacted with a trifluoroacetoacetic acid alkyl ester or a sodium salt thereof in the presence of a strong base alkali metal hydroxide. It is carried out through the following three steps.
That is, a first step in which an alcohol is added to cyanamide in the presence of sulfuric acid to produce an alkoxyisourea hydrogen sulfate or sulfate, and an alkyl trifluoroacetoacetate is obtained by alkaline condensation of an alkyl trifluoroacetate and an alkyl acetate. Second step of producing ester sodium enolate or alkyl trifluoroacetoacetate, hydrogen sulfate or sulfate of alkoxyisourea, trifluoroacetoacetic acid alkyl ester or sodium salt thereof in the presence of alkali metal hydroxide This is the third step of converting to the target compound using a salt.
According to the present invention, in the first step, cyanamide is reacted in the presence of alcohol and sulfuric acid to produce alkoxyisourea hydrogen sulfate. Can be used, C ₁ -C ₈ alcohol, C ₁ -C ₄ alcohol is preferable, and specific examples thereof, such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butanol, be mentioned isobutanol Can do.
As for the usage-amount of alcohol, it is preferable to use about 2-15 molar equivalent with respect to cyanamide. An excessive amount of alcohol also serves as a solvent, and an excessive amount of alcohol can be recovered and reused.
It is also possible to control the reaction well by suppressing the amount of alcohol used to reduce the load on the recovery operation, and adding an inert solvent such as toluene that forms two layers with the reaction solution instead. it can.
By using an inert solvent, the inert solvent layer can be recovered simply by separating the two layers, and the recovered inert solvent can be recycled for the formation of additional alkoxyisourea hydrogen sulfate described below. It is.
As the sulfuric acid used in the first step, concentrated sulfuric acid is preferable, and sulfuric acid having a concentration of 95% or more is more preferable in terms of obtaining a good yield. The amount of sulfuric acid is preferably 0.9 to 1.2 mol, more preferably 1.0 mol, relative to 1 mol of cyanamide.
The reaction temperature is preferably −10 to 90 ° C., more preferably 0 to 35 ° C. The reaction time is preferably 1 to 20 hours, more preferably 3 to 15 hours.
The produced hydrogen sulfate of alkoxyisourea can be obtained by ordinary purification and isolation procedures. This alkoxyisourea hydrogen sulfate can be appropriately salt-exchanged to an alkoxyisourea sulfate.
For example, half of the obtained alkoxyisourea hydrogensulfate is neutralized in anhydrous alcohol with a metal alcoholate or alkali metal hydroxide, and the precipitated inorganic salt is removed by filtration, and then remains in this solution. Can be obtained by adding a half amount of alkoxyisourea hydrogensulfate.
In addition, for example, a metal alcoholate or alkali metal hydroxide equivalent to ½ molar equivalent of sulfuric acid is added to a reaction solution of alkoxyisourea hydrogensulfate, and a normal isolation operation is performed to obtain alkoxyisourea sulfate. Can also be obtained.
Both the obtained crystalline alkoxyisourea hydrogen sulfate and alkoxyisourea sulfate can be used in the third step of the present invention. It is preferable to use in the third step as it is without isolation from the reaction solution.
According to the present invention, in the second step, the condensation of the trifluoroacetic acid alkyl ester and the acetic acid alkyl ester is carried out in the presence of a sodium-containing strong base condensing agent, whereby the trifluoroacetoacetic acid alkyl ester Sodium enolate is formed. The produced trifluoroacetoacetic acid alkyl ester / sodium enolate can be appropriately converted into a free trifluoroacetoacetic acid alkyl ester using an acid described later.
In the above reaction, the strong base condensing agent containing sodium includes, for example, sodium hydride, sodium metal, sodium ethylate, sodium methylate, etc., and is equimolar equivalent to the trifluoroacetic acid alkyl ester. used.
Of the above condensing agents, powdered sodium alcoholate is easy to obtain and handle and does not generate hydrogen in the condensation reaction process.
As the trifluoroacetic acid alkyl ester, methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate and the like can be used, and ethyl trifluoroacetate is preferable.
As the alkyl acetate, methyl acetate, ethyl acetate, isopropyl acetate and the like can be used, but ethyl acetate is preferable. In the present invention, it is not always necessary to select an alkyl group according to the trifluoroacetic acid alkyl ester. The acetic acid alkyl ester is used in an amount of 1 mol or more, preferably 1.0 to 5.0 mol, per 1 mol of trifluoroacetic acid alkyl ester.
As the solvent that can be used in the above reaction, for example, an inert solvent such as cyclohexane or toluene is used, but the solvent is not necessarily used. Further, the produced trifluoroacetoacetic acid alkyl ester is not necessarily isolated.
It is not always necessary to use a solvent in the second step. Rather, too much solvent is not preferable because it makes recovery later complicated.
The reaction temperature is preferably 0 to 110 ° C., more preferably 50 to 80 ° C., and the reaction time is preferably 1 to 20 hours, more preferably 3 to 12 hours.
The acid that neutralizes the resulting trifluoroacetoacetic acid alkyl ester / sodium enolate is selected from the group consisting of organic acids, inorganic mineral acids, and iminium salts of strong inorganic acids. Preferred are those that are greater than the acidity and not too high to cause degradation of the trifluoroacetoacetic acid alkyl ester.
Examples of the acid that satisfies the above conditions include glacial acetic acid, formic acid, and an iminium salt of sulfuric acid.
The temperature during neutralization is preferably 20 to 70 ° C., more preferably 40 to 60 ° C., and the time required for neutralization is about 0.5 to 3 hours.
In the method of the present invention, any form of the trifluoroacetoacetic acid alkyl ester or trifluoroacetoacetic acid alkyl ester sodium enolate produced in the second step can be used in the third step. In addition, each can be isolated by distillation, filtration and purification, but industrially, it is preferably used as it is in the third step without being isolated, regardless of its form.
According to the method of the present invention, in the third step, the alkoxyisourea hydrogen sulfate or sulfate obtained in the first step is produced in the second step in the presence of an alkali metal hydroxide. The target compound is synthesized using fluoroacetoacetic acid alkyl ester or a sodium salt thereof.
The alkoxyisourea hydrogen sulfate or sulfate is preferably used in an amount of 1 mol or more, more preferably 1.0 to 1.2 mol, per 1 mol of the trifluoroacetoacetic acid alkyl ester.
The amount of alkali metal hydroxide used is 1.9 to 3.3 mol per 1 mol of trifluoroacetoacetic acid alkyl ester, and 0.55 per 1 mol of trifluoroacetoacetic acid alkyl ester sodium enolate. About 2.3 mol is preferable, and by carrying out the reaction in this range, the desired product can be obtained in good yield.
Examples of the alkali metal hydroxide include potassium hydroxide and sodium hydroxide, and sodium hydroxide is more preferable.
Although the reaction is carried out in an aqueous medium, the amount of water used is usually about 500 to 2000 ml per mole of trifluoroacetoacetic acid alkyl ester. In a preferred form of the reaction, the trifluoroacetoacetic acid alkyl ester or its sodium salt produced in the second step is used as it is without being isolated and dispersed in an inert solvent. The amount is about 200 ml to about 1000 ml with respect to 1 mol of trifluoroacetoacetic acid alkyl ester, and the amount of the aqueous medium is about 500 ml to 2000 ml.
In a more advantageous form of this reaction, an inert solvent that is immiscible with water is preferred, and toluene can be mentioned as an optimal example from the viewpoint of cost and physical properties. The reaction temperature is preferably 35 to 100 ° C, more preferably 75 to 95 ° C, and the reaction time is preferably about 1 to 15 hours, more preferably 2 to 10 hours.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Preparation of O-isopropylisourea salt 99.4 g of isopropyl alcohol (purity 99.5%, 1.65 mol) and 17.5 g of cyanamide (purity 99) were stirred in a 300 ml four-necked flask equipped with a thermometer and a stirrer. 0.08%, 0.413 mol) was added, and after dissolution, 41.8 g of concentrated sulfuric acid (97.5% concentration, 0.415 mol) was added over 3 hours so that the liquid temperature did not exceed 25 ° C. The liquid temperature was kept at 25 ° C. or lower and stirring was continued overnight. Thereafter, the solvent was distilled off using a rotary evaporator, and 125 ml of distilled water was added to the concentrated viscous reaction solution for dilution. Next, the resulting mixture containing O-isopropylisourea hydrogen sulfate was transferred to a 1000 ml four-necked flask, and 150.8 g (0.754 mol) of a 20% strength aqueous sodium hydroxide solution was added at room temperature. During this time, the temperature was kept below 30 ° C.
Preparation of ethyl 4,4,4-trifluoroacetoacetate In a 500 ml four-necked flask equipped with a thermometer, heat exchanger, reflux tube and stirrer, 69.2 g of toluene and 29.0 g of sodium ethoxide (purity 95.95). 0%, 0.405 mol) was added under stirring. Subsequently, 57.0 g of ethyl trifluoroacetate (purity 99.0%, 0.397 mol) was added over about 5 hours so that the liquid temperature did not exceed 25 ° C. Next, the mixture was heated to 50 ° C., 71.0 g of ethyl acetate (purity 99.5%, 0.802 mol) was added over about 4 and a half hours, and stirring was continued overnight. Subsequently, 100.0 g of toluene was added, and the mixture was heated under reduced pressure to distill 204 g of a fraction. Then, 89.0 g of toluene was introduced again, the reaction mixture was cooled to 40 ° C., and 18.4 g of formic acid ( (Concentration 99.0%, 0.396 mol) was added while maintaining the temperature at 40 ° C. over about 1 hour and 40 minutes.
Subsequently, the mixture containing 4,4,4-trifluoroacetoacetic acid ethyl ester was cooled to 15 ° C., filtered, and the residue was washed with 23.0 g of toluene. The washing liquid was mixed with the filtrate.
Next, 169.6 g of an ethyl 4,4,4-trifluoroacetoacetate mixture was added dropwise at room temperature to the mixture containing O-isopropylisourea in a 1000 ml four-necked flask. During this time, the temperature rose to 28 ° C. After completion of the dropwise addition, the mixed reaction solution was heated to the reflux temperature, and the temperature was maintained for about 3 hours and 30 minutes. Next, the organic layer was distilled off with a fractionator until the distillation temperature reached about 95 ° C., and then cooled to 40 ° C. while adding dilute hydrochloric acid of the yellow suspended reaction solution, and the pH was adjusted to 3.0. . Thereafter, a pale yellow solid was separated by filtration to obtain 62.1 g of a wet solid. This solid was dried in a vacuum drying oven overnight, and 57.7 g (yield 65.4%: based on the charged ethyl trifluoroacetate) of 2-isopropoxy-6-trifluoromethyl-pyrimidin-4-ol was added. Obtained. The purity by HPLC analysis was 100%.

Preparation of O-isopropylisourea salt In a 1000 ml four-necked flask equipped with a thermometer and a stirrer, 485 g of isopropyl alcohol (purity 99.5%, 8.03 mol) and 85.0 g of cyanamide (purity 99%, 2.00 mol) was added, and after dissolution, 201.8 g of concentrated sulfuric acid (concentration 97.5%, 2.00 mol) was added over 2 hours so that the liquid temperature did not exceed 25 ° C. The liquid temperature was kept at 25 ° C. or lower and stirring was continued overnight. After completion of the reaction, the solvent was distilled off using a rotary evaporator. The reaction mixture was then transferred to a 3000 ml four-necked flask and 640 ml of distilled water was added. Subsequently, 716.8 g (3.59 mol) of a 20% aqueous sodium hydroxide solution was added at room temperature. During this time, the temperature was kept below 30 ° C.
Preparation of ethyl 4,4,4-trifluoroacetoacetate 372.0 g of cyclohexane and 156.3 g of sodium ethoxide under stirring in a 3000 ml four-necked flask equipped with a thermometer, heat exchanger, reflux tube and stirring device (Purity 95%, 2.18 mol) was added. Subsequently, 307.3 g of ethyl trifluoroacetate (purity 99%, 2.14 mol) was added over about 4 and a half hours so that the liquid temperature did not exceed 25 ° C. Next, the mixture was heated to 50 ° C., 382.8 g of ethyl acetate (purity 99.5%, 4.32 mol) was added over about 4 hours, and stirring was continued overnight.
Next, 781.7 g of cyclohexane was added, and 1280.9 g of a fraction was distilled while heating under atmospheric pressure. Then, 355.8 g of cyclohexane was introduced again, and the reaction mixture was cooled to 40 ° C. Thereafter, a mixture of 99.3 g of formic acid (concentration 99.0%, 2.14 mol) and 234.8 g of ethyl acetate was added over about 1 hour and 50 minutes while maintaining 40 ° C. Then, after cooling to 15 ° C., the mixture was filtered, and the residue was washed with 301.9 g of cyclohexane. The washing liquid was mixed with the filtrate.
1309.7 g of the filtrate containing the obtained ethyl trifluoroacetoacetate was transferred to a distillation vessel equipped with a rectification column, a distillation column with a solenoid coil, a multi-timer, a cooling condenser and a fraction receiver. Cyclohexane and ethyl acetate were distilled under atmospheric pressure until the internal temperature reached 82 ° C. This first run contained ethyl acetate, which was recycled to the next production.
Distillation of the second fraction started at an initial pressure of 22000 Pa absolute pressure and an evaporation temperature of 48 ° C. and ended when an evaporation temperature of 62 ° C. was reached at 13000 Pa absolute pressure.
The distillation of the third fraction started at an initial pressure of 13000 Pa absolute pressure and an evaporation temperature of 62 ° C. and was terminated when the final pot temperature of 130 ° C. was reached at 9000 Pa absolute pressure.
The third fraction obtained was 312.4 g. Later, 38.0 g of a residue having a tar-like appearance remained. This third fraction contained 95.0% by weight of ethyl trifluoroacetoacetate. This corresponds to a yield of 75.3%.
Next, 312.4 g (purity 95.0%, 1.61 mol) of ethyl 4,4,4-trifluoroacetoacetate was added dropwise at room temperature to the mixture containing O-isopropylisourea in a 3000 ml four-necked flask. During this time, the temperature rose to 28 ° C. After completion of the dropwise addition, the mixed reaction solution was heated to the reflux temperature and maintained at that temperature for about 3 hours, and then the organic layer was distilled off with a fractionator until the distillation temperature reached about 95 ° C. Subsequently, it cooled to 40 degreeC, adding dilute hydrochloric acid to the pale yellow suspension, and adjusted pH to 5.0.
A pale yellow to white solid was isolated by filtration at a temperature of 40 ° C. To the obtained wet solid, 660 ml of distilled water was added and placed under reflux for 1 hour. Subsequently, the mixture was cooled to room temperature, and after filtration and drying, 275.7 g of 2-isopropoxy-6-trifluoromethylpyrimidin-4-ol was obtained. The yield based on ethyl trifluoroacetoacetate was 76.2%. This corresponds to a yield of 57.4% from ethyl trifluoroacetate. The purity determined by HPLC analysis was 98.9%.

Preparation of O-isopropylisourea salt In a 300 ml four-necked flask equipped with a thermometer and a stirrer, 113.2 g of isopropyl alcohol (purity 99.5%, 1.87 mol) and 19.9 g of cyanamide (purity 97) were stirred. (0.0%, 0.460 mol) was added, and after dissolution, 47.6 g of concentrated sulfuric acid (concentration 97.5%, 0.473 mol) was added over 3 hours so that the liquid temperature did not exceed 25 ° C. The liquid temperature was kept at 25 ° C. or lower and stirring was continued overnight. After completion of the reaction, the solvent was distilled off using a rotary evaporator to obtain 97.0 g of a mixture containing concentrated viscous O-isopropylisourea hydrogen sulfate.
Preparation of ethyl 4,4,4-trifluoroacetoacetate In a 500 ml four-necked flask equipped with a thermometer, a reflux tube, and a stirrer, 69.1 g of toluene and 29.0 g of sodium ethoxide (purity 95.95) were stirred. 0%, 0.405 mol). Subsequently, 57.1 g of ethyl trifluoroacetate (purity 99.0%, 0.398 mol) was added over about 3 hours so that the liquid temperature did not exceed 25 ° C. Then, the mixture was heated to 50 ° C., and 71.0 g of ethyl acetate (purity 99.5%, 0.802 mol) was added over about three and a half hours, and stirring was continued overnight. Next, the mixture was heated under reduced pressure to distill a 123.0 g fraction. Next, 160.6 g of toluene was introduced to produce ethyl trifluoroacetoacetate sodium enolate.
Subsequently, the mixture containing ethyl trifluoroacetoacetate / sodium enolate was cooled to 40 ° C., 20.0 g of powdered sodium hydroxide (purity 99.0%, 0.495 mol) and viscous O-isopropylisourea hydrogen sulfate 97.0 g of a mixture containing salt was added. During this time, the temperature was kept below 50 ° C. Next, 194.6 g of distilled water was added, and stirring was continued overnight at a temperature of 80 to 85 ° C. Subsequently, 265 ml of the fraction was distilled off with a fractionator while adding distilled water. The amount of water added during this period was 160.4 g. Next, the reaction mixture was cooled to 40 ° C. while adding a small amount of diluted hydrochloric acid to the yellow suspended reaction solution, and the pH was adjusted to 5.0. When the yellow solid was separated by filtration at the temperature, the obtained granular wet solid was 63.6 g. This solid was dried in a vacuum drying oven overnight to obtain 55.1 g (yield 62.4%: based on the charged ethyl trifluoroacetate) of 2-isopropoxy-6-trifluoromethylpyrimidin-4-ol. It was.
The purity by HPLC analysis was 100%.

Preparation of O-isopropylisourea salt In a 1000 ml four-necked flask equipped with a thermometer and a stirrer, 480.7 g of isopropyl alcohol (purity 99.5%, 7.96 mol) and 85.0 g of cyanamide (purity 99) were stirred. 2.0%, 2.00 mol) was added, and after dissolution, 202.7 g of concentrated sulfuric acid (concentration 97.5%, 2.01 mol) was added over about 2 hours 30 minutes so that the liquid temperature did not exceed 25 ° C. . The liquid temperature was kept at 25 ° C. or lower and stirring was continued overnight. After completion of the reaction, the solvent was distilled off using a rotary evaporator. Subsequently, the reaction mixture containing concentrated O-isopropylisourea hydrogen sulfate was transferred to a 3000 ml four-necked flask, and 923 ml of distilled water was added. Subsequently, 754.0 g (3.77 mol) of a 20% strength aqueous sodium hydroxide solution was added at room temperature. During this time, the temperature was kept below 30 ° C.
Preparation of ethyl 4,4,4-trifluoroacetoacetate In a 2000 ml four-necked flask equipped with a thermometer, heat exchanger, reflux tube, and stirring device, 841.8 g of cyclohexane and 108.0 g of sodium ethoxide were stirred. (Purity 95%, 1.90 mol) was added. Then, 245.9 g of ethyl trifluoroacetate (purity 98.0%, 1.88 mol) was added over about 1 hour so that the liquid temperature did not exceed 15 ° C. Next, 352.3 g (purity 98.0%, 4.66 mol) of methyl acetate was added at room temperature in about 15 minutes, and then the mixture was heated to 40 ° C. and further stirred overnight. Subsequently, 355 ml of a fraction was distilled while heating under atmospheric pressure. Thereafter, the reaction mixture was cooled to 40 ° C. and then heated again under reduced pressure to distill a total of 713.7 g of fractions. The reaction mixture was cooled again to 40 ° C., and a mixture of 88.0 g formic acid (concentration 99.0%, 1.89 mol) and 207.4 g of methyl acetate was added over about 2 hours while maintaining 40 ° C. . The mixture containing ethyl 4,4,4-trifluoroacetoacetate was cooled to 15 ° C. and filtered, and the residue was washed with 196 g of cyclohexane.
The washing liquid was mixed with the filtrate. 995.9 g of the filtrate containing ethyl trifluoroacetoacetate thus obtained was transferred to a distillation vessel, fractionally distilled under reduced pressure, and 262.8 g of methyl trifluoroacetoacetate having a purity of 96.0% by weight according to gas chromatography (GC) analysis. (Yield 78.8%: based on charged methyl trifluoroacetate).
Next, 262.8 g (purity 96.0%, 1.48 mol) of methyl 4,4,4-trifluoroacetoacetate was added dropwise at room temperature to the mixture containing O-isopropylisourea in a 3000 ml four-necked flask. During this time, the temperature rose to 35 ° C. After completion of the dropwise addition, the mixed reaction solution was heated to the reflux temperature and further stirred overnight. Next, the organic layer was distilled off with a distillation apparatus until the distillation temperature reached about 95 ° C. Thereafter, the pale yellow suspension was cooled to 40 ° C. while dilute hydrochloric acid was added, and the pH was adjusted to 5.0. Then, a pale yellow to white solid was separated by filtration to obtain 283.2 g of a granular wet solid.
This solid was dried in a vacuum drying oven overnight to give 237.5 g of 2-isopropoxy-6-trifluoromethylpyrimidin-4-ol. The yield based on methyl trifluoroacetoacetate was 72.0%. This corresponds to a yield of 56.7% from methyl trifluoroacetate. The purity by HPLC was 100%.
Comparative Example 1
Under stirring in a 200 ml four-necked flask equipped with a thermometer, heat exchanger, condenser, and stirrer, 78.0 g (purity 99.5%, 1.29 mol) of isopropyl alcohol and 5.6 g of cyanamide (purity 99) 0.03%, 0.13 mol) was added, and after dissolution, hydrogen chloride gas was passed through the blowing tube at about 50 ° C. for about 2 hours to absorb 10.0 g (0.28 mol) of hydrogen chloride. At this time, the hydrogen chloride gas that was not absorbed was absorbed in the aqueous sodium hydroxide solution. The reaction mixture was then reacted at 70 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and 40 ml of distilled water was added to the reaction mixture containing concentrated O-isopropylisourea hydrochloride. During this time, brine at −30 ° C. was passed through the cooling device so that the fraction containing easily volatile isopropyl chloride produced as a by-product was not escaped from the system as much as possible. Further, an excessive amount of hydrogen chloride gas distilled off together with the solvent from the reaction solution was similarly absorbed in the aqueous sodium hydroxide solution.
Thereafter, 59.0 g (0.206 mol) of a 14% concentration sodium hydroxide aqueous solution was added at room temperature to adjust the pH to 11.5. During this time, the temperature was kept below 30 ° C. Next, 23.3 g (purity 95.0%, 0.120 mol) of ethyl trifluoroacetoacetate was dropped into the mixture at room temperature, and the mixture was reacted at reflux temperature for 2 hours. Next, the organic layer was distilled off with a fractionator until the distillation temperature reached about 95 ° C., and then cooled to room temperature while dilute hydrochloric acid was added to the yellow suspended reaction solution, and the pH was adjusted to 5.0. Thereafter, the yellow solid was separated by filtration to obtain 21.4 g of a wet solid. The solid was immersed in distilled water of the same weight and refluxed for 1 hour, then cooled to room temperature, separated by filtration, and dried overnight in a vacuum drying oven. 16.8 g (yield 62.8%: charged 2-isopropoxy-6-trifluoromethyl-pyrimidin-4-ol (based on ethyl trifluoroacetoacetate) was obtained.

  ADVANTAGE OF THE INVENTION According to this invention, the target object can be easily manufactured in the production | generation process of an alkoxy isourea salt, without producing easily volatile hazardous gas.

Claims (17)

Formula (I):

(Wherein, R represents a linear or branched alkyl group of _C 1 -C ₈₎
In the process for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol of
First step of obtaining in the presence of sulfuric acid, by reacting an alcohol of cyanamide and C ₁ -C ₈ the O- alkylisourea salt,
Second step of condensing alkyl trifluoroacetate and alkyl acetate in the presence of a strong base condensing agent containing sodium, and the resulting trifluoroacetoacetic acid alkyl ester sodium enolate or free alkyl trifluoroacetoacetate A process for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol comprising a third step of reacting an ester with the O-alkylisourea salt obtained in the first step in the presence of an alkali metal hydroxide . The production method according to claim 1, wherein the molar ratio of sulfuric acid to cyanamide in the first step is 0.9 to 1.2 mol of sulfuric acid per 1 mol of cyanamide. The production method according to claim 1 or 2, wherein the O-alkylisourea salt in the first step is hydrogen sulfate or sulfate. The production method according to claim 1, wherein the trifluoroacetic acid alkyl ester and the acetic acid alkyl ester used in the second step are an ethyl ester or a methyl ester. The production method according to claim 1 or 4, wherein the strong base condensing agent containing sodium in the reaction in the second step is sodium ethylate or sodium methylate. The manufacturing method according to claim 1, wherein a molar ratio of the trifluoroacetoacetic acid alkyl ester and the alkali metal hydroxide in the third step is 1: 1.9 to 3.3. The production method according to claim 1 or 6, wherein a molar ratio of the trifluoroacetoacetic acid alkyl ester / sodium enolate to the alkali metal hydroxide in the third step is 1: 0.55 to 2.3. The production method according to claim 1, 6 or 7, wherein the alkali metal hydroxide used in the third step is sodium hydroxide. The production method according to any one of claims 1 and 6 to 8, wherein the reaction in the third step is carried out without isolating alkoxyisourea hydrogen sulfate. The process according to any one of claims 1 and 6 to 9, wherein the reaction in the third step is carried out without isolating trifluoroacetoacetic acid alkyl ester sodium enolate or free trifluoroacetoacetic acid alkyl ester. Method. The production according to any one of claims 1 and 4 to 10, wherein the trifluoroacetoacetic acid alkyl ester sodium enolate produced in the reaction of the second step is separated by filtration and used in the third step of the reaction. Method. The trifluoroacetoacetic acid alkyl ester sodium enolate produced in the reaction of the second step is neutralized with at least one acid selected from inorganic mineral acids, organic acids and iminium salts of strong inorganic acids, and the third The manufacturing method of any one of Claim 1 and 4-11 used by reaction of a process. The trifluoroacetoacetic acid alkyl ester / sodium enolate produced in the reaction in the second step is neutralized with an acid, and the produced sodium salt is removed by filtration and then used in the reaction in the third step. The manufacturing method of any one of 4-12. The trifluoroacetoacetic acid alkyl ester sodium enolate produced in the second step reaction is neutralized with an acid, and the free trifluoroacetoacetic acid alkyl ester is isolated by distillation and then used in the third step reaction. The manufacturing method according to any one of claims 1 and 4 to 13. The method according to any one of claims 1 and 6 to 10, wherein the reaction in the third step is performed in a two-layer system of water and an organic solvent immiscible with water. The manufacturing method according to any one of claims 1, 6 to 10, and 15, wherein the organic solvent immiscible with water is toluene. The reaction of the said 1st process is -10 degreeC-90 degreeC, the reaction of a 2nd process is 0 degreeC-110 degreeC, and the reaction of a 3rd process is performed in 35 degreeC-100 degreeC temperature conditions. 2. The production method according to item 1.