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WO2004067517A1 - Procede de production de 2-alcoxy-6-trifluoromethylpyridin-4-ole - Google Patents

Procede de production de 2-alcoxy-6-trifluoromethylpyridin-4-ole Download PDF

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Publication number
WO2004067517A1
WO2004067517A1 PCT/JP2004/000359 JP2004000359W WO2004067517A1 WO 2004067517 A1 WO2004067517 A1 WO 2004067517A1 JP 2004000359 W JP2004000359 W JP 2004000359W WO 2004067517 A1 WO2004067517 A1 WO 2004067517A1
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WO
WIPO (PCT)
Prior art keywords
reaction
trifluoroacetate
alkyl
sodium
production method
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2004/000359
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English (en)
Japanese (ja)
Inventor
Shinichi Kakinuma
Youichi Fukunishi
Masahiro Murotani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Carbide Industries Co Inc
Original Assignee
Nippon Carbide Industries Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nippon Carbide Industries Co Inc filed Critical Nippon Carbide Industries Co Inc
Priority to JP2005504672A priority Critical patent/JPWO2004067517A1/ja
Publication of WO2004067517A1 publication Critical patent/WO2004067517A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms

Definitions

  • 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.
  • An important intermediate in the production of insecticides is 2-alkoxy-6-trifluoromethyl-pyrimidin-14-ol, especially 2-isopropoxy-16-trifluoromethyl-pyrimidin-14-ol.
  • the reaction between O-isopropylpyrsourea hydrochloride and trifluoroacetate ethyl acetate is carried out.
  • 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.
  • 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.
  • 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.
  • 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):
  • 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.
  • 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.
  • step 2 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.
  • 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.
  • an inert solvent such as toluene which forms two layers with the reaction solution, the reaction can be well controlled.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a strong base condensing agent containing sodium containing sodium.
  • trifluoroacetoacetic acid alkyl ester and sodium methanolate 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.
  • 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.
  • 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.
  • alkyl trifluoroacetate methyl trifluoroacetate, ethyl tritrifluoroacetate, isopropyl trifluoroacetate and the like can be used, and ethyl trifluoroacetate is preferred.
  • alkyl acetate methyl acetate, ethyl acetate, isopropyl acetate and the like can be used, but ethyl acetate is preferable.
  • 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.
  • an inert solvent such as cyclohexane or toluene is used, but a solvent is not necessarily used.
  • a solvent is not necessarily used.
  • 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.
  • 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.
  • 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.
  • 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.
  • alkali metal hydroxide examples include potassium hydroxide, sodium hydroxide, and the like, with sodium hydroxide being more preferred.
  • 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
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • GC gas chromatography
  • 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.
  • 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.
  • 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.
  • a target substance in a production

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production industrielle d'une 2-alcoxy-6-trifluorométhylpiridin-4-ole avec un rendement satisfaisant sans entraîner de pollution de l'environnement, contrairement aux procédés connus de production du composé cible qui sont source de problèmes, par exemple, qui entraînent une pollution de l'environnement et présentent un faible rendement. Ledit procédé consiste à faire réagir du cyanamide avec un alcool C1-8 en présence d'acide sulfurique afin d'obtenir une O-alkylisourée et à la faire réagir avec du trifluoroacétoacétate d'éthyle en présence d'un hydroxyde métallique alcalin.
PCT/JP2004/000359 2003-01-29 2004-01-19 Procede de production de 2-alcoxy-6-trifluoromethylpyridin-4-ole Ceased WO2004067517A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2005504672A JPWO2004067517A1 (ja) 2003-01-29 2004-01-19 ２−アルコキシ−６−トリフルオロメチル−ピリミジン−４−オールの製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003-019620 2003-01-29
JP2003019620 2003-01-29

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WO2004067517A1 true WO2004067517A1 (fr) 2004-08-12

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1029983A (ja) * 1996-03-26 1998-02-03 Lonza Ag ２−アルコキシ−６−（トリフルオロメチル）ピリミジン−４−オルの製造方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH1029983A (ja) * 1996-03-26 1998-02-03 Lonza Ag ２−アルコキシ−６−（トリフルオロメチル）ピリミジン−４−オルの製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MOSS R A, KACZMARCZYK G M, JOHNSON L A: "Preparation of sec-alkyl isouronium salts", SYNTHETIC COMMUNICATIONS, vol. 30, no. 17, 2000, pages 3233 - 3240, XP002976465 *

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