WO2004067517A1 - Process for producing 2-alkoxy-6-trifluoromethylpyrimidin-4-ol - Google Patents

Abstract

A process for industrially producing a 2-alkoxy-6-trifluoropyrimidin-4-ol in a satisfactory yield without causing environmental pollution, in contrast to known processes for producing the target compound which have problems, for example, that they cause environmental pollution and are low in yield. The process comprises reacting cyanamide with a C1-8 alcohol in the presence of sulfuric acid to obtain an O-alkylisourea and reacting it with ethyl trifluoroacetoacetate in the presence of an alkali metal hydroxide.

Description

 Specification

2_Alkoxy-6-trifluoromethyl-1-pyrimidine-14-ol Production method

 The present invention relates to a method for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-1-ol from an alkoxysoureasulfuric acid sulfate or an alkoxysisourine sulfate, and particularly to 2-isopropoxy-6-ol. Trifluoromethyl-pyrimidine—4-ol

Background art

 An important intermediate in the production of insecticides is 2-alkoxy-6-trifluoromethyl-pyrimidin-14-ol, especially 2-isopropoxy-16-trifluoromethyl-pyrimidin-14-ol. As a production method, the reaction between O-isopropylpyrsourea hydrochloride and trifluoroacetate ethyl acetate is carried out.

 (1) A method in which methanol is used in the presence of sodium 'methoxide in methanol (see, for example, Japanese Patent Application Laid-Open No. 10-88088).

 (2) A method of conducting in an alcoholic solvent in the presence of at least one base selected from carbonates and bicarbonates of alkali metals (see, for example, Japanese Patent Application Publication No. Gazette) and

(3) A method in which the reaction is performed in water in the presence of an alkali metal hydroxide (for example, see Japanese Patent Application Laid-Open No. H10-29983) is known. Disclosure of the invention However, the method described in the above (1) has a problem that the usable separation device is limited because the target substance is separated from petroleum ether after the reaction. In the above method (2), a centrifugal separator cannot be used to isolate the target substance by recrystallization from a mixed organic solvent such as ethyl acetate / hexane. There is a problem that the operation rate is reduced in a production facility in which a reaction apparatus of the type and various separation apparatuses are combined. Further, in the above method (3) and the method (2), the cyanide and isopropanol are added at 70 ° C. to O-isopropylisoleurea hydrochloride in the presence of hydrogen chloride. Obtained by reacting at reflux temperature.

 However, this formulation is not suitable for the production of the product 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 chloride reacts with isopropanol 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 be released to the environment, so that they must be separated and removed. Was expensive and expensive.

 These problems make conventional methods unattractive, environmentally and economically, as industrial processes.

The present invention has been made in view of the above points, and reduces the facility load required to prevent the release of harmful gases into the environment, and is inexpensive. It is an object of the present invention to provide a method for producing o-methyl-pyrimidine-1-ol. The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, reacted alkoxysisourea hydrogensulfate or sulfate with trifluoroacetate alkyl acetate or sodium salt thereof, and crystallized in water. The present inventors have found that 2-alkoxy-6-trifluoromethyl-pyrimidin-14-ol can be easily obtained by the conversion, and thus completed the present invention.

 The compound produced by the method of the present invention has the formula (I):

 R

(Wherein, R represents a C i -C ₈ linear or branched alkyl group). BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, detailed embodiments of the present invention will be described.

The present invention relates to an alkyl tris trifluoroacetate or a sodium alkyl sulfate thereof in the presence of an alkali metal hydroxide, which is a strong base, in the presence of an alkali metal hydroxide, which is a strong base. The reaction is carried out through the following three steps, that is, the reaction is carried out with a sulfuric acid salt in the presence of sulfuric acid to form an alkoxyisoureas hydrogen sulfate or a sulfate. In step 1, alkyl trifluoroacetate and alkyl acetic acid are subjected to alkali condensation to produce alkyl triacetate acetic acid ester, sodium phenol enolate or trifluoroacetate acetic acid alkyl ester. In the second step, the hydrogen sulfate of the alkoxysyurea or This is a third step of converting a sulfate into the target compound using an alkyl trifluoracetate or a sodium salt thereof in the presence of an alkali metal hydroxide.

According to the present invention, in the first step, cyanamide is reacted in the presence of an alcohol and sulfuric acid to produce an alkoxyisourea hydrogen sulfate. C ₈ alcohols can be used, but C ₄ alcohols are preferred, and specific examples thereof include methyl alcohol, ethynoleanole cornole, propinoleanole cornole, isopropinole alcohol, Butanol, isobutanol and the like can be mentioned.

 The alcohol is preferably used in an amount of about 2 to 15 molar equivalents relative to cyanamide. The excess alcohol also acts as a solvent, and the excess alcohol can be recovered and reused.Also, the amount of alcohol used is reduced to reduce the load on the recovery operation. Alternatively, by adding an inert solvent such as toluene which forms two layers with the reaction solution, the reaction can be well controlled.

 By using an inert solvent, the inert solvent layer can be recovered only by separating the two layers, and the recovered inert solvent can be recycled for the formation of an additional alcoholoxyurea hydrogen sulfate described later. Is possible. As the sulfuric acid used in the first step, concentrated sulfuric acid is preferable, and it is more preferable to use sulfuric acid having a concentration of 95% or more from the viewpoint of obtaining a good yield. The amount of sulfuric acid is preferably 0.9 to 1.2 mol, more preferably 1.0 mol, per 1 mol of cyanamide.

 The reaction temperature is preferably from 110 to 90 ° (more preferably from 0 to 35 ° C. The reaction time is preferably from 1 to 20 hours, more preferably from 3 to 15 hours. .

The resulting bisulfate of alkoxyisourea is purified and isolated as usual. It can be obtained by operation. This alkoxyisourea hydrogen sulfate can be appropriately subjected to salt exchange to an alkoxyisourea sulfate. For example, half of the obtained alkoxyisourea hydrogen sulfate is treated with a metal alcohol or alcohol in anhydrous alcohol. Neutralized with metal hydroxide and the like, and the precipitated inorganic salts are removed by filtration, and then the remaining half of the solution is added to this solution by adding alkoxyisoureas hydrogensulfate. Can be.

 In addition, for example, a metal alcoholate or an alkali metal hydroxide of 1/2 mole equivalent of the contained sulfuric acid is added to the reaction liquid of the alkoxyisourea hydrogen sulfate, and the normal isolation operation is performed. It is also possible to obtain crystals of the alkoxy disurea sulfate.

 Both of the obtained crystalline alkoxyisourea hydrogen sulfate and the alkoxyisourea sulfate can be used in the third step of the present invention. It is preferable to use it directly in the third step without isolation from the reaction solution. According to the present invention, in the second step, the condensation of an alkyl ester of trifluoroacetic acid and an alkyl acetate is carried out in the presence of a strong base condensing agent containing sodium. , To form trifluoroacetate acetic acid alkyl ester and sodium methanolate. The produced trifluoroacetoacetic acid alkyl ester 'naturimuenolate' can be appropriately converted to a free trifluoroacetoacetic acid alkyl ester by using an acid described below.

In the above reaction, examples of the strong base condensing agent containing sodium include sodium hydride, sodium metal, sodium ethylate, sodium methylate, and the like. It is used in an equimolar equivalent to the alkyl trifluoroacetate. Among the above-mentioned condensing agents, powdery sodium alcoholate is preferable in terms of a reaction apparatus and safety management because it is easy to obtain and handle and does not generate hydrogen in the condensation reaction process.

 As the alkyl trifluoroacetate, methyl trifluoroacetate, ethyl tritrifluoroacetate, isopropyl trifluoroacetate and the like can be used, and ethyl trifluoroacetate is preferred.

 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 necessary to select an alkyl group according to the alkyl trifluoroacetate. There is no. The alkyl acetate is used in an amount of 1 mol or more, preferably 1.0 to 5.0 mol, per 1 mol of the trifluoroacetic acid alkyl ester.

 As a solvent that can be used in the above reaction, for example, an inert solvent such as cyclohexane or toluene is used, but a solvent is not necessarily used. In addition, it is not always necessary to isolate the formed alkyl ester of trifluoroacetate.

 The use of a solvent in the second step is not always necessary, but rather an excessive amount of the solvent is not preferable because it makes later recovery and the like complicated.

 The reaction is carried out at a temperature of preferably 0 to 110 ° C, more preferably 50 to 80 ° C, and the reaction time is preferably 1 to 20 hours, and more preferably 3 to 12 hours. Time.

The acid which neutralizes the obtained alkyl ester of trifluoroacetate and sodium enolate is selected from the group consisting of an organic acid, an inorganic mineral acid and an inorganic salt of a strong inorganic acid. It is preferred that the acidity is greater than the acidity of the enol to be neutralized and not too high to cause the decomposition of the alkyl trifluoracetate acetate. Acids that satisfy the above conditions include glacial acetic acid, formic acid, and sulfuric acid. Salt and the like.

 The temperature at the time of neutralization can be preferably 20 to 70 ° C, more preferably 40 to 60 ° C, and the time required for neutralization is about 0.5 to 3 hours. is there.

 In the method of the present invention, any of the trifluoroacetate acetate alkyl ester or trifluoroacetate alkyl ester sodium sodium enolate produced in the second step may be used in the third step. it can. In addition, each of them can be isolated by distillation, filtration and purification, but it is preferable to use it as it is in the third step without isolation irrespective of its form industrially.

 According to the method of the present invention, in the third step, the alkoxyisourea hydrogensulfate or sulfate obtained in the first step is produced in the second step in the presence of an alkali metal hydroxide. The above-mentioned target compound is synthesized by using trifluoroacetyl acetate alkyl ester or its sodium salt.

 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 alkyl ester of trifluoroacetate.

 Alkali metal hydroxide is used in an amount of 1.9 to 3.3 moles, based on 1 mole of the alkyl ester of trifluoroacetate acetate, and alkyl ester of triacetone acetate sodium acetate. The amount is preferably about 0.55 to 2.3 mol per mol of the rate, and the reaction can be carried out in this range to obtain the desired product in a good yield.

 Examples of the alkali metal hydroxide include potassium hydroxide, sodium hydroxide, and the like, with sodium hydroxide being more preferred.

The reaction is carried out in an aqueous medium, but the amount of water used is usually Approximately 500 m 1 per mole of alkyl fluoroacetate

2 00 0 m 1. In a preferred embodiment of the reaction, the alkyl trifluoracetoacetate or the sodium salt thereof produced in the second step is used without being isolated as such and in a state of being dispersed in an inert solvent. The amount of the inert solvent at that time is about 200 m1 to 100 m1 per 1 mol of the alkyl ester of trifluoroacetate, and the amount of the aqueous medium is 500 m1 to 2 m2. It is about 0.000 ml.

 In a more advantageous form of the present reaction, it is preferable that the inert solvent is immiscible with water, and toluene can be mentioned as an optimal example in terms of price 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, and more preferably 2 to 10 hours. Time. Example

 Hereinafter, the present invention will be described in more detail with reference to Examples and the like, but the present invention is not limited to these Examples and the like.

Example 1

 Preparation of O-isopropylisopropylisourea salt

 Under stirring in a 300 ml four-neck flask equipped with a thermometer and a stirrer, 99.4 g of isopropyl alcohol (purity: 99.5%, 1.65 mol) and 17.5 g of cyanamide (Purity 99.0%, 0.41

3 mo 1), dissolve, and add 41.8 g of concentrated sulfuric acid (concentration 97.5%, 0.415 mo 1) over 3 hours so that the liquid temperature does not exceed 25 ° C. did. 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 the concentrated viscous reaction solution was diluted by adding 125 ml of distilled water. Next, the mixture containing the generated O-isopropylpyrisourea hydrogensulfate was transferred to a 1000 ml square flask, and a 20% sodium hydroxide aqueous solution was added. 150.8 g of liquid (0.754 mol) was added at room temperature. During this time, the temperature was kept below 30 ° C. ·

 Preparation of 4,4,4-—Ethyl trifluoroacetate

 In a 500 ml square flask equipped with a thermometer, heat exchanger, reflux tube and stirrer, 69.2 g of toluene and 29.0 g of sodium ethoxide (purity 95.0%, 0.4 0 5 mo 1) was added under stirring. Next, 57.0 g (purity: 99.0%, 0.397 mol) of ethyl trifluoroacetate was added over about 5 hours so that the liquid temperature did not exceed 25 ° C. Then, the mixture was heated to 50 ° C, 71.0 g of ethyl acetate (purity 99.5%, 0.802 mo 1) was added over about 4 1/2 hours, and stirring was continued overnight. did. Then, after adding 10.0 g of toluene, the mixture was heated under reduced pressure to distill a fraction of 204 g, and 89.0 g of toluene was introduced again, and the reaction mixture was heated at 40 ° C. After cooling to C, formic acid (18.4 g, concentration 99.0%, 0.396 mo1) was added over about 1 hour and 40 minutes while maintaining the temperature at 40 ° C.

 Next, the mixture containing this 4,4,4-trifluoroacetoethyl acetate 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, to a mixture containing O-isopropyl urea in a 1000 ml square flask was added dropwise 16.96 g of a mixture of 4,4,4-trifluoroacetoethyl acetate at room temperature. 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. Then, the organic layer was distilled off in a fractionator until the distillation temperature reached about 95 ° C. Then, the reaction mixture was cooled to 40 ° C while adding dilute hydrochloric acid of the yellow suspended reaction solution, and the pH was lowered. Adjusted to 3.0. Thereafter, the pale yellow solid was separated by filtration to obtain 62.lg of a wet solid. The solid was dried overnight in a vacuum drying oven to obtain 57.7 g (yield 6 5.4%: 2-isopropoxy-6-trifluoromethyl-pyrimidin-1-ol (based on the charged trifluoroacetate) was obtained. The purity by HPLC analysis was 100%.

Example 2

 Preparation of O-isopropylisopropylisourea salt

 While stirring in a 100 ml four-necked flask equipped with a thermometer and a stirrer, isopropyl alcohol 48.5 g (purity 99.5%, 8.03 mol) and cyanamide 85.0 g (purity 9.9%, 2.00 mo 1), and after dissolution, 201.8 g of concentrated sulfuric acid (concentration 97.5%, 2.0 OO mol) was cooled to 2 ml for 2 hours. It was added not to exceed 5 ° 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. Then, the reaction mixture was transferred to a 300-mL ml flask, and 640 mL of distilled water was added. Subsequently the concentration is 20. /. 76.8 g (3.59 mO 1) of a solution of sodium hydroxide in water was added at room temperature. During this time, the temperature was kept below 30 ° C.

 Preparation of 4,4,4—Trifluoroacetate Ethyl Acetate

 Under stirring in a 300 ml square flask equipped with a thermometer, heat exchanger, reflux tube, and stirrer, cyclohexane 372.0 g, sodium methoxide 156.3 g (purity 95%, 2.18 m 01) was injected. Next, 307.3 g (purity: 9.9%, 2.14 mol) of ethyl trifluoroacetate was added over about 4.5 hours so that the liquid temperature did not exceed 25 ° C. Then, the mixture was heated to 50 ° C., and 2.8 g of ethyl acetate (purity 99.5%, 4.32 mo 1) was added over about 4 hours, and stirring was continued overnight. .

Next, 71.7 g of cyclohexane was added, and a fraction of 1280.9 g was distilled off while heating under atmospheric pressure, and then cyclohexane was again added. Hexane (3.58 g) was introduced, and the reaction mixture was cooled to 40 ° C. Then, 99.3 g of formic acid (concentration 99.0%, 2.14 mo 1) and ethyl acetate? 34.8 g of the mixture was added over about 1 hour and 50 minutes while maintaining 40 ° C. Then, the mixture was cooled to 15 ° C., filtered, and the residue was washed with 301.9 g of cyclohexane. The washing liquid was mixed with the filtrate.

 130.9.7 g of the obtained filtrate containing trifluoroacetate ethyl acetate 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 fraction contained ethyl acetate, which was recycled to the next production.

 The distillation of the second fraction starts with an initial pressure of 2200 Pa absolute and an evaporation temperature of 48 ° C, and evaporates to a temperature of 62 ° C at 130 Pa absolute. When reached, it was terminated.

 Distillation of the third fraction starts at an initial pressure of 1300 Pa absolute and an evaporation temperature of 62 ° C and a final pot of 1300 ° C absolute at 900 Pa absolute. The process was terminated when the temperature reached.

 The obtained third fraction was 32.4 g. Later, 38.0 g of a residue having a tar-like appearance remained. This third fraction contained 95.0% by weight of ethyl trifluoroacetate. This corresponds to a yield of 75.3%.

The mixture containing O-isopropyluisourea in a 300 ml four-neck flask was then charged with 4,4,4-triethyl acetate ethyl 32.4 g (purity 95.0%, 1 6 1 mo 1) was added dropwise at room temperature. During this time the temperature rose to 28 ° C. After dropping, the mixed reaction solution is heated to the reflux temperature, maintained at that temperature for about 3 hours, and The organic layer was distilled off until the distillation temperature reached about 95 ° C. Then, the pale yellow suspension was cooled to 40 ° C. while adding dilute hydrochloric acid, and the pH was adjusted to 5.0.

 At a temperature of 40 ° C., a pale yellow to white solid was separated by filtration. 660 ml of distilled water was added to the obtained wet solid, and the mixture was placed under reflux for 1 hour. Subsequently, the mixture was cooled to room temperature, filtered and dried to obtain 275.7 g of 2-isopropoxy-6-trifluoromethylpyrimidine-1-ol. The yield from trifluoroacetate ethyl acetate was 76.2%. This equates to a yield of 57.4% from triethyl acetate. In addition, 11? 1 ^. Purity according to analysis was 98.9%.

Example 3

 Preparation of O-Sopropyruisourea Salt

 In a 300 ml four-necked flask equipped with a thermometer and a stirrer, 13.2 g (purity 99.5%, 1.87 mol) of isopropyl alcohol and 1.99 g of cyanamide were stirred. g (purity 97.0%, 0.46.0 mo 1), dissolve, and add 47.6 g of concentrated sulfuric acid (concentration 97.5%, 0.473 m01). The solution 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 the completion of the reaction, the solvent was distilled off using a rotary evaporator to obtain 97.0 g of a concentrated mixture containing viscous O-isopropylisourea hydrogen sulfate.

 Preparation of 4,4,4-1 trifluoroacetate ethyl ester

Under stirring in a 500 ml tetrafluoro flask equipped with a thermometer, a reflux tube, and a stirrer, 69.9 lg of toluene and 29.0 g of sodium ethoxide (purity 95.0%, 0 4 0 5 m 0 1) was introduced. Next, 57.1 g (purity: 99.0%, 0.398 mo1) of ethyl trifluoroacetate was added over about 3 hours so that the liquid temperature did not exceed 25 ° C. . Then, the mixture was heated to 50 ° C, 71.0 g of ethyl acetate (purity 99.5%, 0.802 mo 1) was added over about 3.5 hours, and stirring was continued overnight. . Then, the mixture was heated under reduced pressure to distill a fraction of 123.0 g. Next, 160.6 g of toluene was introduced to produce trifluoroacetate ethyl acetate.

 Then, the mixture containing trifluoroacetate / ethyl sodium enolate was cooled to 40 ° C, and 20.0 g of powdered sodium hydroxide (purity 99.0%, 0.495%) was added. 97.0 g of a mixture containing mo 1) and viscous O-isopropylisourea hydrogen sulfate was charged. 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. Next, while adding distilled water, a fraction of 26.5 ml was distilled off by a fractionating apparatus. The water added during this time was 160.4 g. Next, the reaction mixture was cooled to 40 ° C. while adding a small amount of dilute hydrochloric acid to the yellow suspension, and the pH was adjusted to 5.0. At that temperature, a yellow solid was separated by filtration, and the obtained granular wet solid was 63.6 g. The solid was dried overnight in a vacuum drying oven, yielding 5.5 g (yield 62.4%, based on the charged trifluoroacetate) of 2-isopropoxy-1 6-trifluoromethylpyrimidine. I got one forty-one.

 Incidentally, the purity by HPLC analysis was 100%.

Example 4

 Preparation of O-Sopropyruisourea Salt

Under stirring in a 100 ml four-necked flask equipped with a thermometer and a stirrer, 4.80.7 g of isopropyl alcohol (purity: 99.5%, 7.966 mol) and 85% of cyanamide 0.0 g (purity 99.0%, 2.00 m 0 1) was added, and after dissolution, concentrated sulfuric acid 200.2.7 g (concentration 97.5 ° /., 2.01 mo 1 ) For about 2 hours and 30 minutes. Was added so as not to exceed. The liquid temperature was kept at 25 ° C or lower, and stirring was continued overnight. After the completion of the reaction, the solvent was distilled off using a rotary evaporator. Next, the reaction mixture containing the concentrated O-isopropyl isopropyl urea bisulfate was transferred to a 30000 ml square flask, and 92.3 ml of distilled water was added. Subsequently, 754.0 g (3.77 mol) of a 20% aqueous sodium hydroxide solution was added at room temperature. During this time, the temperature was kept below 30 ° C.

 4,4,4-1 Preparation of trifluoroacetate ethyl acetate

 Cyclohexane 841.4 g, sodium ethoxide 1048.0 g in a 200 ml four-neck flask equipped with a thermometer, heat exchanger, reflux tube, and stirrer, with stirring (Purity 95%, 1.90 mo 1). Next, 245.9 g (purity 98.0%, 1.88 mol) of ethyl trifluoroacetate was added over about 1 hour so that the liquid temperature did not exceed 15 ° C. Then, at room temperature, 352.3 g of methyl acetate (purity 98.0%, 4.66 m 01) was added in about 15 minutes, and the mixture was heated to 40 ° C and further overnight. Stirring was continued. Then, while heating at atmospheric pressure, a distillate of 355 ml was distilled off. Thereafter, the reaction mixture was cooled to 40 ° C., and then heated again under reduced pressure to distill a total of 73.7 g of a fraction. The reaction mixture was cooled again to 40 ° C, and then a mixture of 88.0 g of formic acid (concentration 99.0%, 1.89 mo 1) and methyl acetate 207.4 g was added to 40%. The addition was performed over about 2 hours while maintaining the ° C. The mixture containing this 4,4,4_ trifluoroacetoethyl acetate was cooled to 15 ° C, filtered, and the residue was washed with 1996 g of cyclohexane.

The washing liquid was mixed with the filtrate. 99.5.9 g of the obtained filtrate containing trifluoroacetate acetate was transferred to a distillation vessel, fractionally distilled under reduced pressure, and purified by gas chromatography (GC) analysis to 96.0% by weight. 26.2.8 g (yield: 78.8%, based on the charged methyl trifluoroacetate) was obtained.

 Then, to a mixture containing O-isopropyl urea in a 300 O ml tetrahedral flask, was added 26.2.8 g of methyl 4,4,4_trifluoroacetoacetate (96.0% purity, 16.0%). 48 mo 1) was added dropwise at room temperature. 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 stirring was continued overnight. Then, the organic layer was distilled off by a fractionator until the distillation temperature reached about 95 ° C. Thereafter, the pale yellow suspension was cooled to 40 ° C. while adding dilute hydrochloric acid, 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.

 The solid was dried in a vacuum drying oven overnight to give 27.5 g of 2-isopropoxy-l-6-trifluoromethylpyrimidin-l-ol. The yield from methyl trifluoroacetate acetate was 72.0%. This corresponds to a yield of 56.7% from methyl trifluoroacetate. The purity by HPLC was 100%. Comparative Example 1

Isopropyl alcohol 78.0 g (purity 99.5%, 1.29) was stirred in a 200 ml square flask equipped with a thermometer, heat exchanger, condenser, and stirring device. mo 1) and 5.6 g of cyanamide (purity 99.0%, 0.13 m 01) were added, and after dissolution, hydrogen chloride gas was introduced at 50 ° C for about 2 hours from a blowing tube. Aeration allowed the absorption of 10.0 g (0.28 mo1) of hydrogen chloride. At this time, the hydrogen chloride gas that had not been absorbed was absorbed into the aqueous sodium hydroxide solution. Then, the reaction mixture was 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 the concentrated O-isopropylisourea hydrochloride. During this time, brine was passed through the cooling device at 130 ° C so that a distillate containing by-produced volatile isopropyl chloride was not released to the outside of the system. Excess hydrogen chloride gas, which was distilled off together with the solvent from the reaction solution, was similarly absorbed into the sodium hydroxide aqueous solution.

 Thereafter, 59.0 g (0.206 mol) of a 14% aqueous solution of sodium hydroxide was added at room temperature, and the pH was adjusted to 11.5. During this time, the temperature was kept below 30 ° C. Then, 23.3 g (purity 95.0%, 0.120 m 01) of trifluoroacetoethyl acetate was added dropwise to this mixture at room temperature, and the mixture was reacted at reflux temperature for 2 hours. . Then, the organic layer was distilled off in a fractionation apparatus until the distillation temperature reached about 95 ° C, and the yellow suspended reaction solution was cooled to room temperature while adding dilute hydrochloric acid, and the pH was adjusted to 5.0. Was adjusted to Thereafter, the yellow solid was separated by filtration to obtain 21.4 g of a wet solid. This solid was immersed in distilled water of the same weight and refluxed for 1 hour, cooled to room temperature, separated by filtration, and dried overnight in a vacuum drying oven to obtain 16.8 g (yield 62.8%). : 2-Trisopropoxy-6-trifluoromethyl-pyrimidin-1-ol (based on the charged trifluoroacetate acetate) was obtained. Industrial applicability

 ADVANTAGE OF THE INVENTION According to this invention, in a production | generation process of an alkoxyisourea salt, a target substance can be easily manufactured, without producing | generating a toxic gas which is easily volatile.

Claims

 (I)  11 1 11 blue (Wherein, R represents a C i C s linear or branched alkyl group)  of 2-alkoxy-6-trifluoromethyl-pyrimidine-14- A first step of reacting cyanamide with an alcohol having a ~ C range of _{8 in} the presence of sulfuric acid to obtain an O-alkylisourea salt,  A second step of condensing the alkyl trifluoracetate and the alkyl acetate in the presence of a strong base condensing agent containing sodium; and  The resulting trifluoroacetoacetate alkyl ester / natrium enolate or free trifluoroacetoacetate alkyl ester is combined with the O-alkylisourea salt obtained in the first step to form an alkali metal hydroxide. Third step to react in the presence A process for producing 2-alkoxy-6-trifluoromethyl-pyrimidin-4-ol, comprising:  2. The 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 per 1 mol of cyanamide.  3. The method according to claim 1, wherein the O-alkylisourea salt in the first step is a hydrogen sulfate or a sulfate. 4. The alkyl trifluoroacetate used in the second step. 2. The method according to claim 1, wherein the ester and the alkyl acetate are ethyl esters or methyl esters.  5. The production method according to claim 1, wherein the sodium-containing strong base condensing agent in the reaction in the second step is sodium ethylate or sodium methylate.  6. The production method according to claim 1, wherein the molar ratio of the alkyl ester of trifluoroacetate and the alkali metal hydroxide in the third step is 1: 1.9 to 3.3.  7. The molar ratio of the alkyl ester sodium acetate concentrate to the alkali metal hydroxide in the third step is 1: 0.55 to 2.3. Or the production method according to 6.  8. The production method according to claim 1, 6 or 7, wherein the metal hydroxide used in the third step is sodium hydroxide.  9. 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 the alkoxyisourea hydrogen sulfate.  10. The reaction of the third step is carried out without isolating the alkyl ester of sodium trifluoroacetate acetate or free alkyl esters of trifluoroacetate. The production method according to any one of the preceding claims.  11. The alkyl trifluoroacetate acetate / sodium enolate produced in the reaction of the second step is separated by filtration and used in the third step of the reaction. 3. The method according to claim 1. 12. Trifluoroacetate alkyl ester and sodium phenol enolate formed in the reaction of the second step are prepared by using at least one acid selected from the inorganic salts of inorganic mineral acids, organic acids and inorganic strong acids. Neutralize 12. The production method according to claim 1, which is used in the reaction of the third step.  13. After neutralizing the trifluoroacetate alkyl ester / naphthalene enolate produced in the reaction of the second step with an acid and removing the produced sodium salt by filtration, the third step is carried out. The production method according to any one of claims 1 and 4 to 12, which is used in the reaction of (1).  14. Alkyl trifluoroacetate acetate generated in the reaction of the second step ♦ Neutralized enolate is neutralized with an acid, and the liberated alkyl trifluoroacetate is isolated by distillation. The production method according to any one of claims 1 and 4 to 13, which is used in a three-step reaction.  15. The production 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. 16. The method according to any one of claims 1, 6 to 10, and 15, wherein the water-immiscible organic solvent is toluene.  17. The reaction of the first step is performed at 110 ° C. to 90 ° C., the reaction of the second step is performed at 0 ° C. to 110 ° C., and the reaction of the third step is performed at 35 ° C. to 100 ° C. The production method according to any one of claims 1 to 16, which is performed under a temperature condition of ° C.