WO2014069668A1 - Method for producing compound - Google Patents

Method for producing compound Download PDF

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Publication number
WO2014069668A1
WO2014069668A1 PCT/JP2013/080055 JP2013080055W WO2014069668A1 WO 2014069668 A1 WO2014069668 A1 WO 2014069668A1 JP 2013080055 W JP2013080055 W JP 2013080055W WO 2014069668 A1 WO2014069668 A1 WO 2014069668A1
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weight
formula
parts
salt
compound represented
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PCT/JP2013/080055
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French (fr)
Japanese (ja)
Inventor
遠山　芳伴
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住友化学株式会社
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Priority to CN201380056227.1A priority Critical patent/CN104755476B/en
Priority to JP2014544627A priority patent/JP6217646B2/en
Publication of WO2014069668A1 publication Critical patent/WO2014069668A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a method for producing a compound.
  • Patent Document 1 discloses the following formula (3) represented by 2-chloro-5- (aminomethyl) thiazole.
  • X 1 represents a hydrogen atom or a halogen atom.
  • the thiazole compound shown by these is a compound useful as an intermediate of a medicine and an agrochemical.
  • the following formula (1) (Wherein X 1 represents the same meaning as described above, and X 2 represents a halogen atom.)
  • a method of simultaneously mixing and reacting a compound represented by the following formula with ammonia and formaldehyde, followed by hydrolysis treatment is described.
  • X 1 represents the same meaning as described above.
  • the compound represented by is by-produced.
  • the present invention includes the following inventions.
  • [1] A reaction between ammonia and formaldehyde, and the formula (8) A mixture containing the compound represented by formula (8) was obtained, and the resulting mixture containing the compound represented by formula (8) and formula (1) (In formula (1), X 1 represents a hydrogen atom or a halogen atom. X 2 represents a halogen atom. ) Or a salt thereof in the presence of a base, the compound of formula (2) (In formula (2), X 1 represents the same meaning as described above.) Or a salt thereof.
  • [2] The production method according to [1], wherein the base is a bicarbonate.
  • [3] The production method according to [2], wherein the bicarbonate is sodium bicarbonate.
  • the thiazole compound represented by the formula (3) can be obtained with high yield, and the amount of by-products generated can be suppressed.
  • a step of obtaining a compound represented by formula (2) or a salt thereof hereinafter sometimes referred to as compound (2)
  • step of obtaining compound (2) hereinafter, sometimes referred to as “step of obtaining compound (2)”
  • an organic solvent solution of ammonia dissolved in an organic solvent capable of dissolving ammonia such as ammonia gas, liquid ammonia, aqueous ammonia, and methanol can be used, and an organic solvent solution of ammonia is preferably used.
  • formaldehyde gas can be used, but from the viewpoint of handling, it is preferable to use paraformaldehyde or formalin, and it is more preferable to use paraformaldehyde.
  • the amount of formaldehyde used is usually 1.0 to 1.4 mol, preferably 1.01 to 1.1 mol, per 1 mol of ammonia.
  • examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom.
  • Compound (1) can be produced according to a known method described in, for example, JP-A-4-234864.
  • Compound (1) includes a salt of the compound represented by Formula (1), and the salt is, for example, an acid addition salt.
  • the acid of the acid addition salt include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and perchloric acid, and organic acids such as acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
  • the compound (1) 5- (chloromethyl) thiazole, 2-chloro-5- (chloromethyl) thiazole, 2-chloro-5- (bromomethyl) thiazole, 2-bromo-5- (bromomethyl) thiazole, 2 -Chloro-5- (iodomethyl) thiazole, 2-bromo-5- (iodomethyl) thiazole, 2-iodo-5- (iodomethyl) thiazole and the like.
  • the salt of the said compound is mentioned.
  • the amount of compound (1) to be used is generally 0.2-1 mol, preferably 0.5-1 mol, more preferably 0.66-0.84 mol, per 1 mol of ammonia.
  • the amount of compound (1) to be used is generally 0.2 to 1 mol, preferably 0.5 to 1 mol, more preferably 0.5 to 0.77 mol, per 1 mol of formaldehyde.
  • the amount of the salt of the compound represented by the formula (1) may be determined in consideration of the acid in the acid addition salt.
  • the base does not contain ammonia.
  • Examples of the base include carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; and organic bases such as triethylamine and diisopropylethylamine. Is preferred, and sodium bicarbonate is more preferred.
  • the amount of the base to be used is generally 0.9 to 1.5 mol, preferably 1 to 1.2 mol, more preferably 1.05 to 1.15 mol, per 1 mol of compound (1).
  • the amount of the base used may be determined in consideration of the acid in the acid addition salt.
  • the reaction temperature in the step of reacting ammonia and formaldehyde is usually ⁇ 20 to 60 ° C., preferably ⁇ 20 to 50 ° C., more preferably 5 to 50 ° C., further preferably 5 to 25 ° C., and particularly preferably 5 ⁇ 15 ° C.
  • the step of reacting ammonia and formaldehyde may be performed in the presence of a base or compound (1).
  • the reaction temperature in the step of obtaining the compound (2) is usually 15 to 100 ° C., preferably 40 to 70 ° C.
  • the step of obtaining the compound (2) may be performed under normal pressure conditions, or may be performed under pressurized conditions of 0.5 MPa (gauge pressure) or less.
  • the step of reacting ammonia and formaldehyde and the step of obtaining compound (2) are preferably performed in a solvent inert to the reaction between the mixture containing compound (8) and compound (1).
  • Solvents include alcohols such as methanol, ethanol, n-propanol and isopropanol, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene and dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane and cyclohexane, Examples include ethers such as diethyl ether, tetrahydrofuran and dioxane, aprotic polar solvents such as acetonitrile, propionitrile, dimethyl sulfoxide, N, N-dimethylacetamide, and water, and a combination of two or more solvents.
  • the amount of the solvent to be used is generally 0.5 to 5 parts by weight, preferably 0.7 to 2.0 parts by weight, more preferably 0.95 to 1 part per 1 part by weight of the compound (1). .5 parts by weight.
  • quaternary ammonium such as triethylbenzylammonium chloride, tri-n-octylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium bromide, tetra-n-butylammonium bromide, if necessary.
  • the reaction may be carried out in the presence of a phase transfer catalyst such as a salt or a crown ether.
  • the reaction mixture containing the compound (2) can be obtained by mixing the mixture containing the compound (8) and the compound (1) in the presence of a base.
  • Compound (2) can be taken out by concentrating the reaction mixture as necessary. After concentrating the mixture containing the compound (2) as necessary, water and a hydrophobic organic solvent are mixed, extracted, and the resulting organic layer is concentrated to extract the compound (2).
  • hydrophobic organic solvent examples include halogenated hydrocarbon solvents such as chlorobenzene and dichlorobenzene, esters such as ethyl acetate and butyl acetate, ketones such as methyl ethyl ketone and methyl isobutyl ketone, and aromatic hydrocarbons such as toluene and xylene. Two or more solvents may be combined.
  • halogenated hydrocarbon solvents such as chlorobenzene and dichlorobenzene
  • esters such as ethyl acetate and butyl acetate
  • ketones such as methyl ethyl ketone and methyl isobutyl ketone
  • aromatic hydrocarbons such as toluene and xylene. Two or more solvents may be combined.
  • Compound (2) includes a salt of the compound represented by formula (2), and the salt is, for example, an acid addition salt.
  • the acid of the acid addition salt include the same as described above.
  • examples of the compound (2) include salts of the above compounds.
  • hydroxylamines include hydroxylamine salts such as hydroxylamine, hydroxylamine sulfate and hydroxylamine hydrochloride, preferably hydroxylamine sulfate or hydroxylamine hydrochloride.
  • hydroxylamines commercially available ones may be used as they are, or those in a solution state such as an aqueous solution may be used.
  • the amount of hydroxylamine to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, more preferably 0.5 to 2 mol, per 1 mol of compound (2).
  • the acid examples include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and hydrochloric acid or sulfuric acid is preferable.
  • the acid may be used as an aqueous solution.
  • the amount of the acid to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of compound (2).
  • hydroxylamines may be added to the mixture of compound (2) and acid, or acid may be added to the mixture of compound (2) and hydroxylamine.
  • acid or hydroxylamine may be added all at once, or it may be dropped continuously or intermittently, and it is preferably dropped continuously or intermittently.
  • the step of obtaining the compound (3) is preferably performed in the presence of a solvent.
  • a solvent it is preferable to use a mixed solvent of water and an organic solvent that does not affect the reaction for obtaining the compound (3) or water.
  • the amount of water used is usually 0.5 to 10 parts by weight, preferably 0.5 to 5 parts by weight, more preferably 0.5 to 2 parts by weight with respect to 1 part by weight of the compound (2).
  • organic solvent examples include aromatic hydrocarbons such as toluene, xylene and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofuran, and alcohols such as methanol, ethanol and isopropanol, preferably toluene. It is.
  • the amount of the organic solvent to be used is generally 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, more preferably 2 to 6 parts by weight with respect to 1 part by weight of the compound (2).
  • the reaction temperature in the step of obtaining the compound (3) is usually 0 to 100 ° C., preferably 0 to 50 ° C.
  • the reaction time in this step is usually 0.5 to 24 hours.
  • the resulting reaction solution is adjusted to pH 8 to 14, preferably pH 10 to 14, with an aqueous alkali solution such as sodium hydroxide to liberate compound (3).
  • the compound (3) can be taken out by adding an organic solvent insoluble in water and performing an extraction treatment or filtration.
  • the organic layer containing the free form of the compound (3) and the aqueous solution containing formaldoxime are separated, and the obtained organic layer is concentrated to obtain the compound. (3) can be taken out.
  • the separated compound (3) may be further purified by ordinary purification means such as recrystallization, distillation, column chromatography and the like.
  • the organic layer obtained by the extraction treatment and the aqueous acid solution are mixed and then subjected to a liquid separation treatment, whereby the formula (3)
  • the salt of the compound shown by the chemical formula (3) can be taken out.
  • a poor solvent in which the salt of the compound represented by the formula (3) is difficult to dissolve is added to the aqueous solution containing the salt of the compound represented by the formula (3) to precipitate crystals of the salt of the compound represented by the formula (3). It can also be made.
  • An aqueous solution containing a salt of the compound represented by the formula (3) can also be used as a raw material for the next step as it is.
  • the acid include aqueous solutions of acids such as hydrochloric acid, sulfuric acid, acetic acid, and methanesulfonic acid.
  • the amount of acid used is an amount such that the pH of the aqueous layer during the extraction treatment is usually in the range of 2.5 to 5.5, and preferably in the range of 3 to 5.
  • the aqueous solution may be decolorized with a decoloring agent such as activated carbon.
  • Compound (3) includes a salt of the compound represented by formula (3), and the salt is, for example, an acid addition salt.
  • the acid of the acid addition salt include the same as described above.
  • examples of the compound (3) include 5- (aminomethyl) thiazole, 2-chloro-5- (aminomethyl) thiazole, 2-bromo-5- (aminomethyl) thiazole and the like.
  • examples of the compound (3) include salts of the above compounds.
  • the compound (3) obtained and the compound represented by the formula (5) are reacted to obtain a compound represented by the formula (6) or a salt thereof, and a compound represented by the formula (6) or a salt thereof, and amines
  • the step of obtaining a thiazole compound represented by the formula (7) or a salt thereof by reacting with the salt thereof can be performed according to a known method described in JP-A-10-120666.
  • Example 1 A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight) and 89.2 parts by weight of methanol, and 115 parts by weight of a 12% by weight ammonia / methanol solution at an internal temperature of 15 ° C. or less over 4.9 hours. And dripped. To the obtained mixture, 45.4 parts by weight of sodium hydrogen carbonate and 95.7 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.9% by weight) were sequentially charged. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours.
  • Example 2 To the obtained toluene layer, 8.8 parts by weight of toluene and 142 parts by weight of water are added, and 190 parts by weight of an aqueous solution of hydroxylamine sulfate (sulfate content: 24% by weight) is charged over 0.5 hours and mixed. A solution was obtained. To the obtained mixed solution, 56.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 284 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.4, followed by liquid separation.
  • aqueous solution of hydroxylamine sulfate sulfate content: 24% by weight
  • the toluene solution was washed by adding 15.0 parts by weight of water and 17.0 parts by weight of a 27% by weight aqueous sodium hydroxide solution. Further, 122 parts by weight of water and 49.7 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 4.16. The solution was separated, and 251 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.8% by weight, yield: 92.6% (2-chloro-5- (chloromethyl ) Thiazole standard)). The yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the aqueous solution was 0.04% (based on 2-chloro-5- (chloromethyl) thiazole).
  • Example 3 A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 88.9 parts by weight of methanol, and 47.7 parts by weight of sodium bicarbonate in order, and cooled to 5 ° C. or lower, and then 2-chloro-5 93.5 parts by weight of (chloromethyl) thiazole (content: 96.6% by weight) was charged. To the resulting mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise over 5 hours at an internal temperature of 25 ° C. or lower. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C.
  • Example 4 142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution.
  • a hydroxylamine sulfate aqueous solution sulfate content: 24% by weight
  • hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C.
  • 284 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.1, and the liquids were separated.
  • An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene.
  • the obtained toluene layer and the previously obtained organic layer were mixed, and 987 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.1% by weight, yield: 90.6% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained.
  • the yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the toluene solution was 2.9% (based on 2-chloro-5- (chloromethyl) thiazole).
  • the toluene solution was washed with 15.3 parts by weight of water and 17.5 parts by weight of a 27% by weight aqueous sodium hydroxide solution.
  • Example 5 A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 89.1 parts by weight of methanol, and 47.8 parts by weight of sodium bicarbonate in order, and cooled to 5 ° C. or lower, and then 2-chloro-5 93.5 parts by weight of (chloromethyl) thiazole (content: 96.6% by weight) was charged. To the obtained mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise at an internal temperature of 20 ° C. or less over 5 hours. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C.
  • Example 6 142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution.
  • a hydroxylamine sulfate aqueous solution sulfate content: 24% by weight
  • hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C.
  • 283 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.3, followed by liquid separation.
  • An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene.
  • the obtained toluene layer and the previously obtained organic layer were mixed and 981 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.2% by weight, yield: 90.6% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained.
  • the yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the toluene solution was 3.1% (based on 2-chloro-5- (chloromethyl) thiazole).
  • Example 7 A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 88.8 parts by weight of methanol, 47.7 parts by weight of sodium hydrogen carbonate, and 2-chloro-5- (chloromethyl) thiazole (content: 96). .6 wt%) 93.5 parts by weight were charged in order. To the resulting mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise at an internal temperature of 50 ° C. or less over 5 hours. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours.
  • Example 8 142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution.
  • a hydroxylamine sulfate aqueous solution sulfate content: 24% by weight
  • hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C.
  • 283 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.2, and the liquids were separated.
  • An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene.
  • the obtained toluene layer and the previously obtained organic layer were mixed, and 990 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.1% by weight, yield: 90.7% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained.
  • the yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the toluene solution was 3.0% (based on 2-chloro-5- (chloromethyl) thiazole).
  • Example 9 A reaction vessel was charged with 4.0 parts by weight of paraformaldehyde (content: 92% by weight) and 14.0 parts by weight of methanol, and 17.1 parts by weight of an 11% by weight ammonia / methanol solution at an internal temperature of 15 ° C. or less over 4 hours. And dripped. To the obtained mixture, 7.1 parts by weight of sodium hydrogen carbonate and 14.8 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.9% by weight) were sequentially charged. The resulting mixture was stirred at an internal temperature of 50 ° C. for 8 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours.
  • Example 10 To the obtained toluene layer, 1.4 parts by weight of toluene and 22.1 parts by weight of water were added, and 29.6 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was added for 0.5 hour. The mixed solution was obtained. To the obtained mixed solution, 8.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 44.4 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.3, followed by liquid separation.
  • a hydroxylamine sulfate aqueous solution sulfate content: 24% by weight
  • the obtained aqueous layer was extracted with toluene three times.
  • the obtained toluene layer and the previously obtained organic layer were mixed and 1318 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content: 12.8% by weight, yield: 88.4). % (Based on 2-chloro-5- (chloromethyl) thiazole)).
  • the yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the toluene solution was 4.8% (based on 2-chloro-5- (chloromethyl) thiazole).
  • the toluene solution was washed by adding 29.3 parts of water and 31.5 parts by weight of a 27 wt% aqueous sodium hydroxide solution. Further, 229 parts by weight of water and 93.2 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 3.5 to 4.5. The solution was separated, and 455 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.0% by weight, yield: 85.8% (2-chloro-5- (chloromethyl ) Thiazole standard)). The yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the aqueous solution was 0.53% (based on 2-chloro-5- (chloromethyl) thiazole).
  • Comparative Example 3 A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight) and 88.8 parts by weight of methanol, and 195 parts by weight of a 12% by weight ammonia / methanol solution was added dropwise at an internal temperature of 15 ° C. or less over 2 hours. . The resulting mixture was charged with 97.0 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.5 wt%), and the internal temperature was 50 ° C. for 7 hours, then 60 ° C. for 1 hour, and further 68 Stir for 2 hours at ° C.
  • the toluene solution was washed by adding 15.4 parts by weight of water and 17.3 parts by weight of a 27% by weight aqueous sodium hydroxide solution. Further, 122 parts by weight of water and 52.9 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 4.03. The solution was separated, and 248 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 34.0% by weight, yield: 83.5% (2-chloro-5- (chloromethyl ) Thiazole standard)). The yield of bis ⁇ (2-chlorothiazol-5-yl) methyl ⁇ amine in the aqueous solution was 0.67% (based on 2-chloro-5- (chloromethyl) thiazole).
  • Example 11 269 parts by weight of O-methyl-N-nitroisourea mixed acid mixture (content: 19.2%) was added dropwise to 185 parts by weight of water cooled to 7 ° C while maintaining the temperature at 10 ° C or lower. To the obtained mixture, 551 parts by weight of 27% aqueous sodium hydroxide solution was added dropwise at 20 ° C. or lower. After adding 199 parts by weight (content: 36.2% by weight) of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride, the mixture was kept at an internal temperature of 18 to 24 ° C. for 42 hours. The temperature was raised to 35 ° C., followed by filtration.
  • Example 12 To 256 g of water, 50 parts by weight (content 96.1%) of O-methyl- (2-chloro-5-thiazolylmethyl) -N′-nitroisourea was added. To the obtained mixture, 22.3 parts by weight of methylamine aqueous solution (content 40%) was added and kept at 15 ° C. for 3 hours. To the obtained mixture, 38 parts by weight of methyl isopropyl ketone and 57 parts by weight of a 27% aqueous sodium hydroxide solution were added in order, and the mixture was stirred at 15 ° C. for 1 hour. After the liquid separation operation, 7.7 parts by weight of methanol was added to the aqueous layer.
  • methylamine aqueous solution content 40%
  • the thiazole compound represented by the formula (3) can be obtained with high yield. Moreover, the production amount of a by-product can be suppressed.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Provided is a method for producing a compound represented by formula (2), or a salt thereof, by reacting ammonia with formaldehyde so as to obtain a mixture that contains a compound represented by formula (8), and then mixing the obtained mixture that contains the compound represented by formula (8) with a compound represented by formula (1), or a salt thereof, in the presence of a base.

Description

化合物の製造方法Method for producing compound
　本発明は、化合物の製造方法に関する。 The present invention relates to a method for producing a compound.
　特許文献１には、２−クロロ−５−（アミノメチル）チアゾールに代表される下記式（３）
Figure JPOXMLDOC01-appb-I000008
（式中、Ｘ１は水素原子またはハロゲン原子を表す。）
で示されるチアゾール化合物は、医薬および農薬の中間体として有用な化合物であることが記載されている。その製造方法としては、下記式（１）
Figure JPOXMLDOC01-appb-I000009
（式中、Ｘ１は上記と同一の意味を表し、Ｘ２はハロゲン原子を表す。）
で示される化合物とアンモニアとホルムアルデヒドとを同時に混合して反応させ、次いで加水分解処理する方法が記載されており、反応時に下記式（４）
Figure JPOXMLDOC01-appb-I000010
（式中、Ｘ１は上記と同一の意味を表す。）
で示される化合物が副生されることも記載されている。 Patent Document 1 discloses the following formula (3) represented by 2-chloro-5- (aminomethyl) thiazole.
Figure JPOXMLDOC01-appb-I000008
(In the formula, X 1 represents a hydrogen atom or a halogen atom.)
It is described that the thiazole compound shown by these is a compound useful as an intermediate of a medicine and an agrochemical. As its production method, the following formula (1)
Figure JPOXMLDOC01-appb-I000009
(Wherein X 1 represents the same meaning as described above, and X 2 represents a halogen atom.)
A method of simultaneously mixing and reacting a compound represented by the following formula with ammonia and formaldehyde, followed by hydrolysis treatment is described.
Figure JPOXMLDOC01-appb-I000010
(Wherein X 1 represents the same meaning as described above.)
It is also described that the compound represented by is by-produced.
特開２００６−２９０７５８号公報JP 2006-290758 A
　特許文献１に記載された製造方法では、式（３）で示されるチアゾール化合物の収率と式（４）で示される化合物の副生量とは必ずしも十分満足し得るものではなかった。 In the production method described in Patent Document 1, the yield of the thiazole compound represented by the formula (3) and the by-product amount of the compound represented by the formula (4) were not necessarily satisfactory.
　本発明は、以下の発明を含む。
［１］アンモニアとホルムアルデヒドとを反応させ、式（８）
Figure JPOXMLDOC01-appb-I000011
で示される化合物を含む混合物を得、得られた式（８）で示される化合物を含む混合物と式（１）
Figure JPOXMLDOC01-appb-I000012
（式（１）中、Ｘ１は水素原子またはハロゲン原子を表す。
Ｘ２はハロゲン原子を表す。）
で示される化合物またはその塩とを、塩基の存在下に混合させる、式（２）
Figure JPOXMLDOC01-appb-I000013
（式（２）中、Ｘ１は上記と同一の意味を表す。）
で示される化合物またはその塩の製造方法。
［２］塩基が、炭酸水素塩である［１］に記載の製造方法。
［３］炭酸水素塩が、炭酸水素ナトリウムである［２］に記載の製造方法。
［４］塩基の使用量が、式（１）で示される化合物１モルに対して、０．９~１．５モルである［１］~［３］のいずれかの項に記載の製造方法。
［５］式（１）で示される化合物の使用量が、ホルムアルデヒド１モルに対して０．５~０．７７モルである［１］~［４］のいずれかの項に記載の製造方法。
［６］式（１）で示される化合物の使用量が、アンモニア１モルに対して０．６６~０．８４モルである［１］~［５］のいずれかに記載の製造方法。
［７］ホルムアルデヒドの使用量が、アンモニア１モルに対して、１．０~１．４モルである［１］~［６］のいずれかの項に記載の製造方法。
［８］アンモニアとホルムアルデヒドとの反応の反応温度が５~２５℃である［１］~［７］のいずれかの項に記載の製造方法。
［９］［１］~［８］のいずれかの項に記載の製造方法により、式（２）で示される化合物またはその塩を得、式（２）で示される化合物またはその塩とヒドロキシルアミン類とを酸性条件下で反応させる、式（３）
Figure JPOXMLDOC01-appb-I000014
（式（３）中、Ｘ１は上記と同一の意味を表す。）
で示される化合物またはその塩の製造方法。
［１０］［９］に記載の製造方法により、式（３）で示される化合物またはその塩を得、式（３）で示される化合物またはその塩と式（５）
Figure JPOXMLDOC01-appb-I000015
（式（５）中、Ｒ１は置換されていてもよい炭化水素基を表す。）
で示される化合物とを反応させ、式（６）
Figure JPOXMLDOC01-appb-I000016
（式（６）中、Ｒ１およびＸ１は上記と同一の意味を表す。）
で示される化合物またはその塩を得、式（６）で示される化合物またはその塩と、アミン類またはその塩とを反応させる、式（７）
Figure JPOXMLDOC01-appb-I000017
（式（７）中、Ｒ２は置換されていてもよいアミノ基を表す。）
で示されるチアゾール化合物またはその塩の製造方法。 The present invention includes the following inventions.
[1] A reaction between ammonia and formaldehyde, and the formula (8)
Figure JPOXMLDOC01-appb-I000011
A mixture containing the compound represented by formula (8) was obtained, and the resulting mixture containing the compound represented by formula (8) and formula (1)
Figure JPOXMLDOC01-appb-I000012
(In formula (1), X 1 represents a hydrogen atom or a halogen atom.
X 2 represents a halogen atom. )
Or a salt thereof in the presence of a base, the compound of formula (2)
Figure JPOXMLDOC01-appb-I000013
(In formula (2), X 1 represents the same meaning as described above.)
Or a salt thereof.
[2] The production method according to [1], wherein the base is a bicarbonate.
[3] The production method according to [2], wherein the bicarbonate is sodium bicarbonate.
[4] The production method according to any one of [1] to [3], wherein the amount of the base used is 0.9 to 1.5 mol with respect to 1 mol of the compound represented by formula (1). .
[5] The production method according to any one of [1] to [4], wherein the amount of the compound represented by the formula (1) is 0.5 to 0.77 mol per mol of formaldehyde.
[6] The production method according to any one of [1] to [5], wherein the amount of the compound represented by the formula (1) used is 0.66 to 0.84 mol with respect to 1 mol of ammonia.
[7] The production method according to any one of [1] to [6], wherein the amount of formaldehyde used is 1.0 to 1.4 mol per mol of ammonia.
[8] The production method according to any one of [1] to [7], wherein the reaction temperature of the reaction between ammonia and formaldehyde is 5 to 25 ° C.
[9] A compound represented by formula (2) or a salt thereof is obtained by the production method according to any one of items [1] to [8], and the compound represented by formula (2) or a salt thereof and hydroxylamine With an acid under acidic conditions, formula (3)
Figure JPOXMLDOC01-appb-I000014
(In formula (3), X 1 represents the same meaning as described above.)
Or a salt thereof.
[10] The compound represented by formula (3) or a salt thereof is obtained by the production method according to [9], and the compound represented by formula (3) or a salt thereof and formula (5)
Figure JPOXMLDOC01-appb-I000015
(In the formula (5), R 1 represents an optionally substituted hydrocarbon group.)
Is reacted with a compound represented by the formula (6)
Figure JPOXMLDOC01-appb-I000016
(In formula (6), R 1 and X 1 represent the same meaning as described above.)
A compound represented by the formula (6) or a salt thereof is obtained, and a compound represented by the formula (6) or a salt thereof is reacted with an amine or a salt thereof.
Figure JPOXMLDOC01-appb-I000017
(In Formula (7), R 2 represents an optionally substituted amino group.)
The manufacturing method of the thiazole compound or its salt shown by these.
　本発明によれば、高い収率で式（３）で示されるチアゾール化合物を得ることができ、副生成物の生成量を抑制することができる。 According to the present invention, the thiazole compound represented by the formula (3) can be obtained with high yield, and the amount of by-products generated can be suppressed.
　まず、アンモニアとホルムアルデヒドとを反応させて、式（８）で示される化合物（以下、化合物（８）という場合がある）を含む混合物を得る工程（以下、「アンモニアとホルムアルデヒドとを反応させる工程」という場合がある）と、得られた化合物（８）を含む混合物と式（１）で示される化合物またはその塩（以下、化合物（１）という場合がある。）とを塩基の存在下で反応させ、式（２）で示される化合物またはその塩（以下、化合物（２）という場合がある。）を得る工程（以下、「化合物（２）を得る工程」という場合がある。）について説明する。 First, a step of reacting ammonia and formaldehyde to obtain a mixture containing a compound represented by formula (8) (hereinafter sometimes referred to as compound (8)) (hereinafter, “a step of reacting ammonia and formaldehyde”) And a mixture containing the obtained compound (8) and a compound represented by formula (1) or a salt thereof (hereinafter sometimes referred to as compound (1)) in the presence of a base. And a step of obtaining a compound represented by formula (2) or a salt thereof (hereinafter sometimes referred to as compound (2)) (hereinafter, sometimes referred to as “step of obtaining compound (2)”) will be described. .
　アンモニアとしては、アンモニアガス、液体アンモニア、アンモニア水、メタノール等のアンモニアを溶解し得る有機溶媒に溶解させたアンモニアの有機溶媒溶液を用いることができ、アンモニアの有機溶媒溶液を用いることが好ましい。 As the ammonia, an organic solvent solution of ammonia dissolved in an organic solvent capable of dissolving ammonia such as ammonia gas, liquid ammonia, aqueous ammonia, and methanol can be used, and an organic solvent solution of ammonia is preferably used.
　ホルムアルデヒドとしては、ホルムアルデヒドガスを用いることができるが、取扱いの点から、パラホルムアルデヒドまたはホルマリンを用いることが好ましく、パラホルムアルデヒドを用いることがより好ましい。
　ホルムアルデヒドの使用量は、アンモニア１モルに対して、通常１．０~１．４モルであり、好ましくは１．０１~１．１モルである。 As formaldehyde, formaldehyde gas can be used, but from the viewpoint of handling, it is preferable to use paraformaldehyde or formalin, and it is more preferable to use paraformaldehyde.
The amount of formaldehyde used is usually 1.0 to 1.4 mol, preferably 1.01 to 1.1 mol, per 1 mol of ammonia.
　式（１）及び式（２）における、ハロゲン原子としては、塩素原子、臭素原子、ヨウ素原子等が挙げられる。 In the formulas (1) and (2), examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom.
　化合物（１）は、例えば特開平４−２３４８６４号公報等に記載された公知の方法に従い製造することができる。 Compound (1) can be produced according to a known method described in, for example, JP-A-4-234864.
　化合物（１）は、式（１）で示される化合物の塩を含み、当該塩は、例えば酸付加塩である。酸付加塩の酸としては、塩化水素、臭化水素、硫酸、過塩素酸等の無機酸、酢酸、メタンスルホン酸、トリフルオロメタンスルホン酸、ｐ−トルエンスルホン酸等の有機酸が挙げられる。 Compound (1) includes a salt of the compound represented by Formula (1), and the salt is, for example, an acid addition salt. Examples of the acid of the acid addition salt include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and perchloric acid, and organic acids such as acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
　化合物（１）としては、５−（クロロメチル）チアゾール、２−クロロ−５−（クロロメチル）チアゾール、２−クロロ−５−（ブロモメチル）チアゾール、２−ブロモ−５−（ブロモメチル）チアゾール、２−クロロ−５−（ヨードメチル）チアゾール、２−ブロモ−５−（ヨードメチル）チアゾール、２−ヨード−５−（ヨードメチル）チアゾール等が挙げられる。また、化合物（１）としては上記化合物の塩が挙げられる。
　化合物（１）の使用量は、アンモニア１モルに対して、通常０．２~１モル、好ましくは０．５~１モル、より好ましくは０．６６~０．８４モルである。
　化合物（１）の使用量は、ホルムアルデヒド１モルに対して、通常０．２~１モル、好ましくは０．５~１モル、より好ましくは０．５~０．７７モルである。
　式（１）で示される化合物の塩を用いる場合には、かかる酸付加塩中の酸を考慮して、式（１）で示される化合物の塩の使用量を決めればよい。 As the compound (1), 5- (chloromethyl) thiazole, 2-chloro-5- (chloromethyl) thiazole, 2-chloro-5- (bromomethyl) thiazole, 2-bromo-5- (bromomethyl) thiazole, 2 -Chloro-5- (iodomethyl) thiazole, 2-bromo-5- (iodomethyl) thiazole, 2-iodo-5- (iodomethyl) thiazole and the like. Moreover, as a compound (1), the salt of the said compound is mentioned.
The amount of compound (1) to be used is generally 0.2-1 mol, preferably 0.5-1 mol, more preferably 0.66-0.84 mol, per 1 mol of ammonia.
The amount of compound (1) to be used is generally 0.2 to 1 mol, preferably 0.5 to 1 mol, more preferably 0.5 to 0.77 mol, per 1 mol of formaldehyde.
When the salt of the compound represented by the formula (1) is used, the amount of the salt of the compound represented by the formula (1) may be determined in consideration of the acid in the acid addition salt.
　塩基はアンモニアを含まない。塩基としては、炭酸リチウム、炭酸ナトリウム、炭酸カリウム等の炭酸塩、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等の炭酸水素塩、及びトリエチルアミン、ジイソプロピルエチルアミン等の有機塩基が挙げられ、炭酸水素塩が好ましく、炭酸水素ナトリウムがより好ましい。 The base does not contain ammonia. Examples of the base include carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; and organic bases such as triethylamine and diisopropylethylamine. Is preferred, and sodium bicarbonate is more preferred.
　塩基の使用量は、化合物（１）１モルに対して、通常０．９~１．５モル、好ましくは１~１．２モル、より好ましくは１．０５~１．１５モルである。
式（１）で示される化合物の塩を用いる場合には、かかる酸付加塩中の酸を考慮して塩基の使用量を決めればよい。 The amount of the base to be used is generally 0.9 to 1.5 mol, preferably 1 to 1.2 mol, more preferably 1.05 to 1.15 mol, per 1 mol of compound (1).
When the salt of the compound represented by the formula (1) is used, the amount of the base used may be determined in consideration of the acid in the acid addition salt.
　アンモニアとホルムアルデヒドとを反応させる工程における反応温度は、通常−２０~６０℃、好ましくは−２０~５０℃、より好ましくは５~５０℃、さらに好ましくは５~２５℃であり、特に好ましくは５~１５℃である。
　アンモニアとホルムアルデヒドとを反応させる工程は、塩基、化合物（１）の存在下で行ってもよい。
　化合物（２）を得る工程における反応温度は、通常１５~１００℃、好ましくは４０~７０℃である。
化合物（２）を得る工程は、常圧条件下で実施してもよいし、０．５ＭＰａ（ゲージ圧）以下の加圧条件下で実施してもよい。 The reaction temperature in the step of reacting ammonia and formaldehyde is usually −20 to 60 ° C., preferably −20 to 50 ° C., more preferably 5 to 50 ° C., further preferably 5 to 25 ° C., and particularly preferably 5 ~ 15 ° C.
The step of reacting ammonia and formaldehyde may be performed in the presence of a base or compound (1).
The reaction temperature in the step of obtaining the compound (2) is usually 15 to 100 ° C., preferably 40 to 70 ° C.
The step of obtaining the compound (2) may be performed under normal pressure conditions, or may be performed under pressurized conditions of 0.5 MPa (gauge pressure) or less.
　アンモニアとホルムアルデヒドとを反応させる工程及び化合物（２）を得る工程は、化合物（８）を含む混合物と化合物（１）との反応に不活性な溶媒中で行うことが好ましい。溶媒としては、メタノール、エタノール、ｎ−プロパノール、イソプロパノール等のアルコール、トルエン、キシレン等の芳香族炭化水素、クロロベンゼン、ジクロロベンゼン等のハロゲン化炭化水素、ヘキサン、ヘプタン、シクロヘキサン等の脂肪族炭化水素、ジエチルエーテル、テトラヒドロフラン、ジオキサン等のエーテル、アセトニトリル、プロピオニトリル、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルアセトアミド等の非プロトン性極性溶媒、及び水等が挙げられ、二種以上の溶媒を組み合わせて用いてもよい。アルコールまたは水が好ましく、アルコールがより好ましい。
溶媒の使用量は、化合物（１）１重量部に対して、通常０．５~５重量部であり、好ましくは０．７~２．０重量部であり、より好ましくは０．９５~１．５重量部である。 The step of reacting ammonia and formaldehyde and the step of obtaining compound (2) are preferably performed in a solvent inert to the reaction between the mixture containing compound (8) and compound (1). Solvents include alcohols such as methanol, ethanol, n-propanol and isopropanol, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as chlorobenzene and dichlorobenzene, aliphatic hydrocarbons such as hexane, heptane and cyclohexane, Examples include ethers such as diethyl ether, tetrahydrofuran and dioxane, aprotic polar solvents such as acetonitrile, propionitrile, dimethyl sulfoxide, N, N-dimethylacetamide, and water, and a combination of two or more solvents. Also good. Alcohol or water is preferred, and alcohol is more preferred.
The amount of the solvent to be used is generally 0.5 to 5 parts by weight, preferably 0.7 to 2.0 parts by weight, more preferably 0.95 to 1 part per 1 part by weight of the compound (1). .5 parts by weight.
　化合物（２）を得る工程において、必要に応じて、トリエチルベンジルアンモニウムクロリド、トリ−ｎ−オクチルメチルアンモニウムクロリド、トリメチルデシルアンモニウムクロリド、テトラメチルアンモニウムブロミド、テトラ−ｎ−ブチルアンモニウムブロミド等の四級アンモニウム塩、クラウンエーテル等の相間移動触媒の存在下で、反応を行ってもよい。 In the step of obtaining the compound (2), quaternary ammonium such as triethylbenzylammonium chloride, tri-n-octylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium bromide, tetra-n-butylammonium bromide, if necessary. The reaction may be carried out in the presence of a phase transfer catalyst such as a salt or a crown ether.
　化合物（８）を含む混合物と化合物（１）とを塩基の存在下に混合させることにより、化合物（２）を含む反応混合物を得られる。該反応混合物を、必要に応じて濃縮することにより、化合物（２）を取り出すことができる。化合物（２）を含む混合物を必要に応じて濃縮した後、水および疎水性有機溶媒を混合し、抽出処理し、得られる有機層を濃縮することにより、化合物（２）を取り出すことができる。 The reaction mixture containing the compound (2) can be obtained by mixing the mixture containing the compound (8) and the compound (1) in the presence of a base. Compound (2) can be taken out by concentrating the reaction mixture as necessary. After concentrating the mixture containing the compound (2) as necessary, water and a hydrophobic organic solvent are mixed, extracted, and the resulting organic layer is concentrated to extract the compound (2).
　疎水性有機溶媒としては、クロロベンゼン、ジクロロベンゼン等のハロゲン化炭化水素系溶媒、酢酸エチル、酢酸ブチル等のエステル、メチルエチルケトン、メチルイソブチルケトン等のケトン、トルエン、キシレン等の芳香族炭化水素等が挙げられ、二種以上の溶媒を組み合わせてもよい。 Examples of the hydrophobic organic solvent include halogenated hydrocarbon solvents such as chlorobenzene and dichlorobenzene, esters such as ethyl acetate and butyl acetate, ketones such as methyl ethyl ketone and methyl isobutyl ketone, and aromatic hydrocarbons such as toluene and xylene. Two or more solvents may be combined.
　化合物（２）を含む反応液をそのまま次の工程に用いてもよい。
　化合物（２）は、式（２）で示される化合物の塩を含み、当該塩は、例えば酸付加塩である。酸付加塩の酸としては、上記と同じものが挙げられる。 You may use the reaction liquid containing a compound (2) for the next process as it is.
Compound (2) includes a salt of the compound represented by formula (2), and the salt is, for example, an acid addition salt. Examples of the acid of the acid addition salt include the same as described above.
　化合物（２）としては、１，３，５−トリス｛（チアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジン、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジン、１，３，５−トリス｛（２−ブロモチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジン等が挙げられる。また、化合物（２）としては上記化合物の塩が挙げられる。 As the compound (2), 1,3,5-tris {(thiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, 1,3,5-tris {(2-chlorothiazole-5 -Yl) methyl} -1,3,5-hexahydrotriazine, 1,3,5-tris {(2-bromothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine and the like. . In addition, examples of the compound (2) include salts of the above compounds.
　続いて、得られた化合物（２）とヒドロキシルアミン類とを酸性条件下で反応させ、式（３）で示されるチアゾール化合物またはその塩（以下、化合物（３）という場合がある。）を製造する工程（以下、「化合物（３）を得る工程」という場合がある。）について説明する。 Subsequently, the obtained compound (2) and hydroxylamines are reacted under acidic conditions to produce a thiazole compound represented by formula (3) or a salt thereof (hereinafter sometimes referred to as compound (3)). Will be described (hereinafter sometimes referred to as “a step of obtaining compound (3)”).
　ヒドロキシルアミン類としては、ヒドロキシルアミン、硫酸ヒドロキシルアミン、塩酸ヒドロキシルアミン等のヒドロキシルアミン塩が挙げられ、好ましくは、硫酸ヒドロキシルアミンまたは塩酸ヒドロキシルアミンである。 Examples of hydroxylamines include hydroxylamine salts such as hydroxylamine, hydroxylamine sulfate and hydroxylamine hydrochloride, preferably hydroxylamine sulfate or hydroxylamine hydrochloride.
　ヒドロキシルアミン類は、通常市販されているものをそのまま用いてもよく、水溶液等の溶液状態のものを用いてもよい。
　ヒドロキシルアミン類の使用量は、化合物（２）１モルに対して、通常０．５~１０モル、好ましくは０．５~５モル、より好ましくは０．５~２モルである。 As hydroxylamines, commercially available ones may be used as they are, or those in a solution state such as an aqueous solution may be used.
The amount of hydroxylamine to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, more preferably 0.5 to 2 mol, per 1 mol of compound (2).
　酸としては、塩酸、硫酸、リン酸、硝酸等の無機酸が挙げられ、塩酸または硫酸が好ましい。酸は水溶液として用いられてもよい。
　酸の使用量は、化合物（２）１モルに対して、通常０．５~１０モル、好ましくは０．５~５モルである。 Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and hydrochloric acid or sulfuric acid is preferable. The acid may be used as an aqueous solution.
The amount of the acid to be used is generally 0.5 to 10 mol, preferably 0.5 to 5 mol, per 1 mol of compound (2).
　化合物（３）を得る工程は、化合物（２）と酸との混合物中に、ヒドロキシルアミン類を加えてもよいし、化合物（２）とヒドロキシルアミン類との混合物中に酸を加えてもよい。酸もしくはヒドロキシルアミン類を加える際は一度に加えてもよいし、連続的もしくは間欠的に滴下してもよく、連続的もしくは間欠的に滴下することが好ましい。 In the step of obtaining compound (3), hydroxylamines may be added to the mixture of compound (2) and acid, or acid may be added to the mixture of compound (2) and hydroxylamine. . When the acid or hydroxylamine is added, it may be added all at once, or it may be dropped continuously or intermittently, and it is preferably dropped continuously or intermittently.
化合物（３）を得る工程は、溶媒の存在下で行われることが好ましい。溶媒として、化合物（３）を得る反応に影響を及ぼさない有機溶媒と水との混合溶媒又は水を用いることが好ましい。 The step of obtaining the compound (3) is preferably performed in the presence of a solvent. As the solvent, it is preferable to use a mixed solvent of water and an organic solvent that does not affect the reaction for obtaining the compound (3) or water.
　水の使用量は、化合物（２）１重量部に対して、通常０．５~１０重量部、好ましくは０．５~５重量部、より好ましくは０．５~２重量部である。 The amount of water used is usually 0.5 to 10 parts by weight, preferably 0.5 to 5 parts by weight, more preferably 0.5 to 2 parts by weight with respect to 1 part by weight of the compound (2).
　有機溶媒としては、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素、ジエチルエーテル、ジイソプロピルエーテル、メチルｔｅｒｔ−ブチルエーテル、テトラヒドロフラン等のエーテル、またはメタノール、エタノール、イソプロパノール等のアルコール等が挙げられ、好ましくはトルエンである。
有機溶媒の使用量は、化合物（２）１重量部に対して、通常０．５~２０重量部、好ましくは１~１０重量部、より好ましくは２~６重量部である。 Examples of the organic solvent include aromatic hydrocarbons such as toluene, xylene and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether and tetrahydrofuran, and alcohols such as methanol, ethanol and isopropanol, preferably toluene. It is.
The amount of the organic solvent to be used is generally 0.5 to 20 parts by weight, preferably 1 to 10 parts by weight, more preferably 2 to 6 parts by weight with respect to 1 part by weight of the compound (2).
　化合物（３）を得る工程の反応温度は、通常０~１００℃、好ましくは０~５０℃である。該工程の反応時間は、通常０．５時間~２４時間である。 The reaction temperature in the step of obtaining the compound (3) is usually 0 to 100 ° C., preferably 0 to 50 ° C. The reaction time in this step is usually 0.5 to 24 hours.
　反応終了後、得られた反応液を、水酸化ナトリウム等のアルカリ水溶液等でｐＨ８~１４、好ましくはｐＨ１０~１４に調整することにより、化合物（３）が遊離する。必要に応じて水に不溶の有機溶媒を加えて抽出処理または濾過を行なうことにより、化合物（３）を取り出すことができる。
　化合物（３）を式（３）で示される化合物として得る場合、化合物（３）のフリー体を含む有機層とホルムアルドキシムを含む水溶液とに分離し、得られた有機層を濃縮すると、化合物（３）を取り出すことができる。分離した化合物（３）は、再結晶、蒸留、カラムクロマトグラフィー等の通常の精製手段によりさらに精製してもよい。
　化合物（３）を式（３）で示される化合物の塩として得る場合、抽出処理して得られた有機層と酸の水溶液とを混合した後、分液処理することで、式（３）で示される化合物の塩を含む水溶液を得、該水溶液を必要に応じて濃縮処理することにより、化式（３）で示される化合物の塩をとして取り出すことができる。また、式（３）で示される化合物の塩を含む水溶液に、式（３）で示される化合物の塩が溶解しにくい貧溶媒を加え、式（３）で示される化合物の塩の結晶を析出させることもできる。式（３）で示される化合物の塩を含む水溶液をそのまま次工程の原料として使用することもできる。
　酸としては、塩酸、硫酸、酢酸、メタンスルホン酸等の酸の水溶液が挙げられる。酸の使用量としては、抽出処理時の水層のｐＨが、通常２．５~５．５の範囲となる量であり、好ましくは３~５の範囲となる量である。
　得られた式（３）で示される化合物の塩を含む水溶液が着色している場合には、活性炭等の脱色剤により、該水溶液を脱色処理してもよい。 After completion of the reaction, the resulting reaction solution is adjusted to pH 8 to 14, preferably pH 10 to 14, with an aqueous alkali solution such as sodium hydroxide to liberate compound (3). If necessary, the compound (3) can be taken out by adding an organic solvent insoluble in water and performing an extraction treatment or filtration.
When obtaining the compound (3) as a compound represented by the formula (3), the organic layer containing the free form of the compound (3) and the aqueous solution containing formaldoxime are separated, and the obtained organic layer is concentrated to obtain the compound. (3) can be taken out. The separated compound (3) may be further purified by ordinary purification means such as recrystallization, distillation, column chromatography and the like.
When the compound (3) is obtained as a salt of the compound represented by the formula (3), the organic layer obtained by the extraction treatment and the aqueous acid solution are mixed and then subjected to a liquid separation treatment, whereby the formula (3) By obtaining an aqueous solution containing a salt of the compound shown and concentrating the aqueous solution as necessary, the salt of the compound shown by the chemical formula (3) can be taken out. Further, a poor solvent in which the salt of the compound represented by the formula (3) is difficult to dissolve is added to the aqueous solution containing the salt of the compound represented by the formula (3) to precipitate crystals of the salt of the compound represented by the formula (3). It can also be made. An aqueous solution containing a salt of the compound represented by the formula (3) can also be used as a raw material for the next step as it is.
Examples of the acid include aqueous solutions of acids such as hydrochloric acid, sulfuric acid, acetic acid, and methanesulfonic acid. The amount of acid used is an amount such that the pH of the aqueous layer during the extraction treatment is usually in the range of 2.5 to 5.5, and preferably in the range of 3 to 5.
When the obtained aqueous solution containing the salt of the compound represented by the formula (3) is colored, the aqueous solution may be decolorized with a decoloring agent such as activated carbon.
　化合物（３）は、式（３）で示される化合物の塩を含み、当該塩は、例えば酸付加塩である。酸付加塩の酸としては、上記と同じものが挙げられる。
　化合物（３）としては、５−（アミノメチル）チアゾール、２−クロロ−５−（アミノメチル）チアゾール、２−ブロモ−５−（アミノメチル）チアゾール等が挙げられる。また、化合物（３）としては上記化合物の塩が挙げられる。 Compound (3) includes a salt of the compound represented by formula (3), and the salt is, for example, an acid addition salt. Examples of the acid of the acid addition salt include the same as described above.
Examples of the compound (3) include 5- (aminomethyl) thiazole, 2-chloro-5- (aminomethyl) thiazole, 2-bromo-5- (aminomethyl) thiazole and the like. In addition, examples of the compound (3) include salts of the above compounds.
　得られた化合物（３）と式（５）で示される化合物とを反応させ、式（６）で示される化合物またはその塩を得て式（６）で示される化合物またはその塩と、アミン類またはその塩とを反応させて式（７）で示されるチアゾール化合物またはその塩を得る工程は、特開平１０−１２０６６６号公報等に記載された公知の方法に従い行うことができる。 The compound (3) obtained and the compound represented by the formula (5) are reacted to obtain a compound represented by the formula (6) or a salt thereof, and a compound represented by the formula (6) or a salt thereof, and amines Alternatively, the step of obtaining a thiazole compound represented by the formula (7) or a salt thereof by reacting with the salt thereof can be performed according to a known method described in JP-A-10-120666.
　以下、実施例により本発明をさらに詳細に説明する。なお、分析には、高速液体クロマトグラフィ（ＬＣ）法を用いた。 Hereinafter, the present invention will be described in more detail with reference to examples. In the analysis, a high performance liquid chromatography (LC) method was used.
実施例１
　反応容器に、パラホルムアルデヒド（含量：９２重量％）２５．２重量部およびメタノール８９．２重量部を仕込み、内温１５℃以下で１２重量％アンモニア／メタノール溶液１１５重量部を４．９時間かけて滴下した。得られた混合物に炭酸水素ナトリウム４５．４重量部、２−クロロ−５−（クロロメチル）チアゾール（含量：９４．９重量％）９５．７重量部を順に仕込んだ。得られた混合物を内温５０℃で７時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール１１．５重量部を加えた後、減圧条件下で得られた混合物からメタノール１２０重量部を留去した。得られた濃縮残渣に水２２６重量部及びトルエン３７９重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層４３７重量部を得た。 Example 1
A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight) and 89.2 parts by weight of methanol, and 115 parts by weight of a 12% by weight ammonia / methanol solution at an internal temperature of 15 ° C. or less over 4.9 hours. And dripped. To the obtained mixture, 45.4 parts by weight of sodium hydrogen carbonate and 95.7 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.9% by weight) were sequentially charged. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours. After adding 11.5 parts by weight of methanol to the resulting reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, the pressure was reduced. 120 parts by weight of methanol was distilled off from the mixture obtained under the conditions. 226 parts by weight of water and 379 parts by weight of toluene were added to the resulting concentrated residue, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1, 437 parts by weight of a toluene layer containing 3,5-hexahydrotriazine was obtained.
実施例２
　得られたトルエン層に、トルエン８．８重量部及び水１４２重量部を加え、さらに、硫酸ヒドロキシルアミンの水溶液（硫酸塩含量：２４重量％）１９０重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸５６．８重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液２８４重量部を加え、ｐＨを１３．４とし、分液した。有機層と水層をそれぞれ得、さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液９７７重量部（塩酸塩換算含量：９．７重量％、収率：９５．２％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は３．１％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。
　該トルエン溶液に水１５．０重量部及び２７重量％水酸化ナトリウム水溶液１７．０重量部を加え洗浄した。さらに水１２２重量部及び３５重量％塩酸４９．７重量部を加え、ｐＨを４．１６に調整した。分液し、２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液２５１重量部（含量：３６．８重量％、収率：９２．６％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。
　該水溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は０．０４％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Example 2
To the obtained toluene layer, 8.8 parts by weight of toluene and 142 parts by weight of water are added, and 190 parts by weight of an aqueous solution of hydroxylamine sulfate (sulfate content: 24% by weight) is charged over 0.5 hours and mixed. A solution was obtained. To the obtained mixed solution, 56.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 284 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.4, followed by liquid separation. An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene. The obtained toluene layer and the previously obtained organic layer were mixed, and 977 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.7% by weight, yield: 95.2% (based on 2-chloro-5- (chloromethyl) thiazole) was obtained. The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 3.1% (based on 2-chloro-5- (chloromethyl) thiazole).
The toluene solution was washed by adding 15.0 parts by weight of water and 17.0 parts by weight of a 27% by weight aqueous sodium hydroxide solution. Further, 122 parts by weight of water and 49.7 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 4.16. The solution was separated, and 251 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.8% by weight, yield: 92.6% (2-chloro-5- (chloromethyl ) Thiazole standard)).
The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the aqueous solution was 0.04% (based on 2-chloro-5- (chloromethyl) thiazole).
実施例３
　反応容器に、パラホルムアルデヒド（含量：９２重量％）２５．２重量部、メタノール８８．９重量部および炭酸水素ナトリウム４７．７重量部を順に仕込み、５℃以下に冷却後、２−クロロ−５−（クロロメチル）チアゾール（含量：９６．６重量％）９３．５重量部を仕込んだ。得られた混合物に内温２５℃以下で１１重量％アンモニア／メタノール溶液１１５重量部を５時間かけて滴下した。得られた混合物を内温５０℃で７時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール１１．２重量部を加えた後、減圧条件下で得られた混合物からメタノール１５１重量部を留去した。得られた濃縮残渣に水２２６重量部及びトルエン３８０重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層４７５重量部を得た。 Example 3
A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 88.9 parts by weight of methanol, and 47.7 parts by weight of sodium bicarbonate in order, and cooled to 5 ° C. or lower, and then 2-chloro-5 93.5 parts by weight of (chloromethyl) thiazole (content: 96.6% by weight) was charged. To the resulting mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise over 5 hours at an internal temperature of 25 ° C. or lower. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours. After adding 11.2 parts by weight of methanol to the resulting reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, the pressure was reduced. Under the conditions, 151 parts by weight of methanol was distilled off from the mixture obtained. To the obtained concentrated residue, 226 parts by weight of water and 380 parts by weight of toluene were added, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1, 475 parts by weight of a toluene layer containing 3,5-hexahydrotriazine was obtained.
実施例４
　得られたトルエン層に水１４２重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）１９０重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸５７．７重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液２８４重量部を加え、ｐＨを１３．１とし、分液した。有機層と水層をそれぞれ得、さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液９８７重量部（塩酸塩換算含量：９．１重量％、収率：９０．６％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は２．９％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。
　該トルエン溶液に水１５．３重量部及び２７重量％水酸化ナトリウム水溶液１７．５重量部を加え洗浄した。さらに水１２２重量部及び３５重量％塩酸４９．６重量部を加え、ｐＨを４．１６に調整した。分液し、２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液２４６重量部（含量：３６．１重量％、収率：８９．２％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。
　該水溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は０．１２％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Example 4
142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution. To the obtained mixed solution, 57.7 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 284 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.1, and the liquids were separated. An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene. The obtained toluene layer and the previously obtained organic layer were mixed, and 987 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.1% by weight, yield: 90.6% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained. The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 2.9% (based on 2-chloro-5- (chloromethyl) thiazole).
The toluene solution was washed with 15.3 parts by weight of water and 17.5 parts by weight of a 27% by weight aqueous sodium hydroxide solution. Further, 122 parts by weight of water and 49.6 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 4.16. The solution was separated and 246 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.1% by weight, yield: 89.2% (2-chloro-5- (chloromethyl ) Thiazole standard)).
The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the aqueous solution was 0.12% (based on 2-chloro-5- (chloromethyl) thiazole).
実施例５
　反応容器に、パラホルムアルデヒド（含量：９２重量％）２５．２重量部、メタノール８９．１重量部および炭酸水素ナトリウム４７．８重量部を順に仕込み、５℃以下に冷却後、２−クロロ−５−（クロロメチル）チアゾール（含量：９６．６重量％）９３．５重量部を仕込んだ。得られた混合物に内温２０℃以下で１１重量％アンモニア／メタノール溶液１１５重量部を５時間かけて滴下した。得られた混合物を内温５０℃で７時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール１１．２重量部を加えた後、減圧条件下で得られた混合物からメタノール１５１重量部を留去した。得られた濃縮残渣に水２２６重量部及びトルエン３８０重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層４７６重量部を得た。 Example 5
A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 89.1 parts by weight of methanol, and 47.8 parts by weight of sodium bicarbonate in order, and cooled to 5 ° C. or lower, and then 2-chloro-5 93.5 parts by weight of (chloromethyl) thiazole (content: 96.6% by weight) was charged. To the obtained mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise at an internal temperature of 20 ° C. or less over 5 hours. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours. After adding 11.2 parts by weight of methanol to the resulting reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, the pressure was reduced. Under the conditions, 151 parts by weight of methanol was distilled off from the mixture obtained. To the obtained concentrated residue, 226 parts by weight of water and 380 parts by weight of toluene were added, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1, As a result, 476 parts by weight of a toluene layer containing 3,5-hexahydrotriazine was obtained.
実施例６
得られたトルエン層に水１４２重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）１９０重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸５６．８重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液２８３重量部を加え、ｐＨを１３．３とし、分液した。有機層と水層をそれぞれ得、さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液９８１重量部（塩酸塩換算含量：９．２重量％、収率：９０．６％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は３．１％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Example 6
142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution. To the obtained mixed solution, 56.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 283 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.3, followed by liquid separation. An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene. The obtained toluene layer and the previously obtained organic layer were mixed and 981 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.2% by weight, yield: 90.6% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained. The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 3.1% (based on 2-chloro-5- (chloromethyl) thiazole).
実施例７
　反応容器に、パラホルムアルデヒド（含量：９２重量％）２５．２重量部、メタノール８８．８重量部、炭酸水素ナトリウム４７．７重量部および２−クロロ−５−（クロロメチル）チアゾール（含量：９６．６重量％）９３．５重量部を順に仕込んだ。得られた混合物に内温５０℃以下で１１重量％アンモニア／メタノール溶液１１５重量部を５時間かけて滴下した。得られた混合物を内温５０℃で７時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール１１．０重量部を加えた後、減圧条件下で得られた混合物からメタノール１５２重量部を留去した。得られた濃縮残渣に水２２６重量部及びトルエン３８０重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層４７６重量部を得た。 Example 7
A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight), 88.8 parts by weight of methanol, 47.7 parts by weight of sodium hydrogen carbonate, and 2-chloro-5- (chloromethyl) thiazole (content: 96). .6 wt%) 93.5 parts by weight were charged in order. To the resulting mixture, 115 parts by weight of an 11 wt% ammonia / methanol solution was added dropwise at an internal temperature of 50 ° C. or less over 5 hours. The resulting mixture was stirred at an internal temperature of 50 ° C. for 7 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours. After adding 11.0 parts by weight of methanol to the resulting reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, the pressure was reduced. Under a condition, 152 parts by weight of methanol was distilled off from the mixture obtained. To the obtained concentrated residue, 226 parts by weight of water and 380 parts by weight of toluene were added, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1, As a result, 476 parts by weight of a toluene layer containing 3,5-hexahydrotriazine was obtained.
実施例８
　得られたトルエン層に水１４２重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）１９０重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸５７．０重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液２８３重量部を加え、ｐＨを１３．２とし、分液した。有機層と水層をそれぞれ得、さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液９９０重量部（塩酸塩換算含量：９．１重量％、収率：９０．７％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は３．０％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Example 8
142 parts by weight of water was added to the obtained toluene layer, and 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours to obtain a mixed solution. To the obtained mixed solution, 57.0 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 283 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.2, and the liquids were separated. An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene. The obtained toluene layer and the previously obtained organic layer were mixed, and 990 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.1% by weight, yield: 90.7% (based on 2-chloro-5- (chloromethyl) thiazole)) was obtained. The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 3.0% (based on 2-chloro-5- (chloromethyl) thiazole).
実施例９
　反応容器に、パラホルムアルデヒド（含量：９２重量％）４．０重量部およびメタノール１４．０重量部を仕込み、内温１５℃以下で１１重量％アンモニア／メタノール溶液１７．１重量部を４時間かけて滴下した。得られた混合物に炭酸水素ナトリウム７．１重量部、２−クロロ−５−（クロロメチル）チアゾール（含量：９４．９重量％）１４．８重量部を順に仕込んだ。得られた混合物を内温５０℃で８時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール２．５重量部を加えた後、減圧条件下で得られた混合物からメタノール２４．０重量部を留去した。得られた濃縮残渣に水．３５．６重量部及びトルエン５９．７重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層７４．６重量部を得た。 Example 9
A reaction vessel was charged with 4.0 parts by weight of paraformaldehyde (content: 92% by weight) and 14.0 parts by weight of methanol, and 17.1 parts by weight of an 11% by weight ammonia / methanol solution at an internal temperature of 15 ° C. or less over 4 hours. And dripped. To the obtained mixture, 7.1 parts by weight of sodium hydrogen carbonate and 14.8 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.9% by weight) were sequentially charged. The resulting mixture was stirred at an internal temperature of 50 ° C. for 8 hours, then at 60 ° C. for 1 hour, and further at 68 ° C. for 2 hours. After adding 2.5 parts by weight of methanol to the resulting reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine, the pressure was reduced. 24.0 parts by weight of methanol were distilled off from the mixture obtained under the conditions. Water was added to the resulting concentrated residue. 35.6 parts by weight and 59.7 parts by weight of toluene were added, extracted at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5 -74.6 parts by weight of a toluene layer containing hexahydrotriazine was obtained.
実施例１０
　得られたトルエン層に、トルエン１．４重量部及び水２２．１重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）２９．６重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸８．８重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液４４．４重量部を加え、ｐＨを１３．３とし、分液した。有機層と水層をそれぞれ得、さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液１６０．０重量部（塩酸塩換算含量：９．３重量％、収率：９５．１％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は３．３％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。
　得られた該トルエン溶液１２８．８重量部に水２．０重量部及び２７重量％水酸化ナトリウム水溶液２．１重量部を加え洗浄した。さらに水１５．３重量部及び３５重量％塩酸６．５重量部を加え、ｐＨを３．７に調整した。分液し、２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液３１．３重量部（含量：３６．２重量％、収率：９１．５％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。 Example 10
To the obtained toluene layer, 1.4 parts by weight of toluene and 22.1 parts by weight of water were added, and 29.6 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was added for 0.5 hour. The mixed solution was obtained. To the obtained mixed solution, 8.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 44.4 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.3, followed by liquid separation. An organic layer and an aqueous layer were obtained, respectively, and the obtained aqueous layer was extracted three times with toluene. The obtained toluene layer and the previously obtained organic layer were mixed, and 160.0 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content in terms of hydrochloride: 9.3% by weight, yield) Rate: 95.1% (based on 2-chloro-5- (chloromethyl) thiazole) was obtained. The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 3.3% (based on 2-chloro-5- (chloromethyl) thiazole).
To 128.8 parts by weight of the obtained toluene solution, 2.0 parts by weight of water and 2.1 parts by weight of a 27% by weight aqueous sodium hydroxide solution were added and washed. Further, 15.3 parts by weight of water and 6.5 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 3.7. The solution was separated, and 31.3 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.2% by weight, yield: 91.5% (2-chloro-5- ( Chloromethyl) thiazole standard)).
比較例１
　反応容器に、パラホルムアルデヒド１００重量部（含量：９２重量％）、１２重量％アンモニア／メタノール溶液５７７重量部および２−クロロ−５−（クロロメチル）チアゾール１７７重量部（含量：９６．８重量％）を仕込んだ。得られた混合物を内温４０℃で３時間、次いで５０℃で３時間、さらに７０℃で１時間攪拌した。内温５０℃まで冷却し、得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応混合物にメタノール３１．８重量部を加えた。減圧条件下で、得られた混合物からメタノール３３９重量部を留去した。得られた濃縮残渣に水４２７重量部、トルエン７１５重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層９１４重量部を得た。 Comparative Example 1
In a reaction vessel, paraformaldehyde 100 parts by weight (content: 92% by weight), 12% by weight ammonia / methanol solution 577 parts by weight and 2-chloro-5- (chloromethyl) thiazole 177 parts by weight (content: 96.8% by weight) ). The resulting mixture was stirred at an internal temperature of 40 ° C. for 3 hours, then at 50 ° C. for 3 hours, and further at 70 ° C. for 1 hour. After cooling to an internal temperature of 50 ° C., the reaction mixture containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine was added to methanol 31.8. Part by weight was added. Under reduced pressure, 339 parts by weight of methanol was distilled off from the resulting mixture. To the obtained concentrated residue, 427 parts by weight of water and 715 parts by weight of toluene were added, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1, 914 parts by weight of a toluene layer containing 3,5-hexahydrotriazine was obtained.
比較例２
　得られたトルエン層に、トルエン１７．２重量部及び水２６５重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）３５５重量部を仕込み、反応混合溶液を得た。得られた反応混合溶液に、３５重量％塩酸１０６重量部を、内温２０~３０℃を保ちながら加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液５３３重量部を加え、ｐＨを１３以上に調整し、分液し、有機層と水層を得た。さらに、得られた水層をトルエンで３回抽出した。得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液１３１８重量部（含量：１２．８重量％、収率：８８．４％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は４．８％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。
　該トルエン溶液に水２９．３重両部及び２７重量％水酸化ナトリウム水溶液３１．５重量部を加え洗浄した。さらに、水２２９重量部及び３５重量％塩酸９３．２重量部を加え、ｐＨを３．５~４．５に調整した。分液し、２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液４５５重量部（含量：３６．０重量％、収率：８５．８％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該水溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は０．５３％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Comparative Example 2
To the obtained toluene layer, 17.2 parts by weight of toluene and 265 parts by weight of water were added, and 355 parts by weight of an aqueous solution of hydroxylamine sulfate (sulfate content: 24% by weight) was added to obtain a reaction mixed solution. . To the obtained reaction mixture solution, 106 parts by weight of 35% by weight hydrochloric acid was added while maintaining the internal temperature at 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 533 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13 or higher, and liquid separation was performed to obtain an organic layer and an aqueous layer. Furthermore, the obtained aqueous layer was extracted with toluene three times. The obtained toluene layer and the previously obtained organic layer were mixed and 1318 parts by weight of a toluene solution containing 2-chloro-5- (aminomethyl) thiazole (content: 12.8% by weight, yield: 88.4). % (Based on 2-chloro-5- (chloromethyl) thiazole)). The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 4.8% (based on 2-chloro-5- (chloromethyl) thiazole).
The toluene solution was washed by adding 29.3 parts of water and 31.5 parts by weight of a 27 wt% aqueous sodium hydroxide solution. Further, 229 parts by weight of water and 93.2 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 3.5 to 4.5. The solution was separated, and 455 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 36.0% by weight, yield: 85.8% (2-chloro-5- (chloromethyl ) Thiazole standard)). The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the aqueous solution was 0.53% (based on 2-chloro-5- (chloromethyl) thiazole).
比較例３
　反応容器に、パラホルムアルデヒド（含量：９２重量％）２５．２重量部及びメタノール８８．８重量部を仕込み、内温１５℃以下で１２重量％アンモニア／メタノール溶液１９５重量部を２時間で滴下した。得られた混合物に２−クロロ−５−（クロロメチル）チアゾール（含量：９４．５重量％）９７．０重量部を仕込み、内温５０℃で７時間、次いで６０℃で１時間、さらに６８℃で２時間攪拌した。得られた１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含む反応液にメタノール１１．０重量部を加えた後、減圧条件下で得られた混合物からメタノール１５７重量部を留去した。得られた濃縮残渣に、水２２６重量部及びトルエン３８０重量部を加え、内温７５℃で抽出処理し、１，３，５−トリス｛（２−クロロチアゾール−５−イル）メチル｝−１，３，５−ヘキサヒドロトリアジンを含むトルエン層を得た。 Comparative Example 3
A reaction vessel was charged with 25.2 parts by weight of paraformaldehyde (content: 92% by weight) and 88.8 parts by weight of methanol, and 195 parts by weight of a 12% by weight ammonia / methanol solution was added dropwise at an internal temperature of 15 ° C. or less over 2 hours. . The resulting mixture was charged with 97.0 parts by weight of 2-chloro-5- (chloromethyl) thiazole (content: 94.5 wt%), and the internal temperature was 50 ° C. for 7 hours, then 60 ° C. for 1 hour, and further 68 Stir for 2 hours at ° C. After adding 11.0 parts by weight of methanol to the reaction solution containing 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1,3,5-hexahydrotriazine obtained, the pressure was reduced. 157 parts by weight of methanol was distilled off from the mixture obtained under the conditions. To the resulting concentrated residue, 226 parts by weight of water and 380 parts by weight of toluene were added, followed by extraction at an internal temperature of 75 ° C., and 1,3,5-tris {(2-chlorothiazol-5-yl) methyl} -1 A toluene layer containing 3,5-hexahydrotriazine was obtained.
比較例４
　得られたトルエン層に、トルエン８．８重量部及び水１４２重量部を加え、さらに、ヒドロキシルアミンの硫酸塩水溶液（硫酸塩含量：２４重量％）１９０重量部を０．５時間かけて仕込み、混合溶液を得た。得られた混合溶液に、３５重量％塩酸５６．８重量部を、内温２０~３０℃を保ちながら０．５時間かけて加えた。同温度で３０分攪拌した後、２７重量％水酸化ナトリウム水溶液２８４重量部を加え、ｐＨを１３．０３と調整した。分液し、有機層と水層をそれぞれ得た。さらに、得られた水層をトルエンで３回抽出した後、得られたトルエン層と先に得た有機層とを混合し、２−クロロ−５−（アミノメチル）チアゾールを含むトルエン溶液９９２重量部（塩酸塩換算含量：８．６重量％、収率：８４．１％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該トルエン溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は７．７％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。
　該トルエン溶液に水１５．４重量部及び２７重量％水酸化ナトリウム水溶液１７．３重量部を加え洗浄した。さらに、水１２２重量部及び３５重量％塩酸５２．９重量部を加え、ｐＨを４．０３に調整した。分液し、２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液２４８重量部（含量：３４．０重量％、収率：８３．５％（２−クロロ−５−（クロロメチル）チアゾール基準））を得た。該水溶液中のビス｛（２−クロロチアゾール−５−イル）メチル｝アミンの収率は０．６７％（２−クロロ−５−（クロロメチル）チアゾール基準）であった。 Comparative Example 4
To the obtained toluene layer, 8.8 parts by weight of toluene and 142 parts by weight of water were added, and further 190 parts by weight of a hydroxylamine sulfate aqueous solution (sulfate content: 24% by weight) was charged over 0.5 hours. A mixed solution was obtained. To the obtained mixed solution, 56.8 parts by weight of 35% by weight hydrochloric acid was added over 0.5 hours while maintaining the internal temperature of 20 to 30 ° C. After stirring at the same temperature for 30 minutes, 284 parts by weight of a 27% by weight aqueous sodium hydroxide solution was added to adjust the pH to 13.03. Liquid separation was performed to obtain an organic layer and an aqueous layer, respectively. Furthermore, after extracting the obtained aqueous layer 3 times with toluene, the obtained toluene layer and the organic layer obtained previously were mixed, and a toluene solution 992 weight containing 2-chloro-5- (aminomethyl) thiazole. Part (hydrochloride conversion content: 8.6% by weight, yield: 84.1% (based on 2-chloro-5- (chloromethyl) thiazole)). The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the toluene solution was 7.7% (based on 2-chloro-5- (chloromethyl) thiazole).
The toluene solution was washed by adding 15.4 parts by weight of water and 17.3 parts by weight of a 27% by weight aqueous sodium hydroxide solution. Further, 122 parts by weight of water and 52.9 parts by weight of 35% by weight hydrochloric acid were added to adjust the pH to 4.03. The solution was separated, and 248 parts by weight of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride (content: 34.0% by weight, yield: 83.5% (2-chloro-5- (chloromethyl ) Thiazole standard)). The yield of bis {(2-chlorothiazol-5-yl) methyl} amine in the aqueous solution was 0.67% (based on 2-chloro-5- (chloromethyl) thiazole).
参考例１
硫酸５３３重量部に５℃以下で硫酸Ｏ—メチルイソ尿素２１８重量部を加え、得られた混合物に硝酸２８３重量部を１０℃以下を保ち滴下した。同温度にて６時間撹拌し、Ｏ—メチル—Ｎ−ニトロイソ尿素混酸混合物１０３３重量部（含量１９．２％、収率９５％）を得た。 Reference example 1
To 533 parts by weight of sulfuric acid, 218 parts by weight of O-methylisourea sulfate was added at 5 ° C. or lower, and 283 parts by weight of nitric acid was added dropwise at 10 ° C. or lower to the resulting mixture. The mixture was stirred at the same temperature for 6 hours to obtain 1033 parts by weight of O-methyl-N-nitroisourea mixed acid mixture (content: 19.2%, yield: 95%).
実施例１１
　Ｏ—メチル—Ｎ−ニトロイソ尿素混酸混合物２６９重量部（含量１９．２％）を７℃に冷却した水１８５重量部に１０℃以下を保ち滴下した。得られた混合物に、２７％水酸化ナトリウム水溶液５５１重量部を２０℃以下で滴下した。２−クロロ−５−（アミノメチル）チアゾール・塩酸塩を含む水溶液１９９重量部（含量：３６．２重量％）を加えたのち、内温１８~２４℃で４２時間保温した。３５℃に昇温後、ろ過した。得られた固体を７０℃の水２８８重量部で２回洗浄後、乾燥し、Ｏ−メチル−（２−クロロ−５−チアゾリルメチル）−Ｎ‘−ニトロイソ尿素７２重量部（収率７０．８％、含量９６．１％）を得た。 Example 11
269 parts by weight of O-methyl-N-nitroisourea mixed acid mixture (content: 19.2%) was added dropwise to 185 parts by weight of water cooled to 7 ° C while maintaining the temperature at 10 ° C or lower. To the obtained mixture, 551 parts by weight of 27% aqueous sodium hydroxide solution was added dropwise at 20 ° C. or lower. After adding 199 parts by weight (content: 36.2% by weight) of an aqueous solution containing 2-chloro-5- (aminomethyl) thiazole hydrochloride, the mixture was kept at an internal temperature of 18 to 24 ° C. for 42 hours. The temperature was raised to 35 ° C., followed by filtration. The obtained solid was washed twice with 288 parts by weight of water at 70 ° C. and dried, and then 72 parts by weight of O-methyl- (2-chloro-5-thiazolylmethyl) -N′-nitroisourea (yield 70.8%). Content 96.1%).
実施例１２
　水２５６ｇにＯ−メチル−（２−クロロ−５−チアゾリルメチル）−Ｎ’−ニトロイソ尿素５０重量部（含量９６．１％）を加えた。得られた混合物にメチルアミン水溶液２２．３重量部（含量４０％）を加え、１５℃にて３時間保温した。得られた混合物にメチルイソプロピルケトン３８重量部、２７％水酸化ナトリウム水溶液５７重量部を順に加え、１５℃で１時間撹拌した。分液操作後、水層にメタノール７．７重量部を加えた。同水層に３０％硫酸７９重量部を加えた後、１５℃に冷却し、ろ過した。残渣を２３１重量部の６５℃温水で洗浄した。得られた固体５１．２重量部を減圧条件下乾燥し、１−（２−クロロ−５−チアゾリルメチル）−３−メチル−２−ニトログアニジン４４．５重量部（収率９２．５％、含量９９．８％）を得た。 Example 12
To 256 g of water, 50 parts by weight (content 96.1%) of O-methyl- (2-chloro-5-thiazolylmethyl) -N′-nitroisourea was added. To the obtained mixture, 22.3 parts by weight of methylamine aqueous solution (content 40%) was added and kept at 15 ° C. for 3 hours. To the obtained mixture, 38 parts by weight of methyl isopropyl ketone and 57 parts by weight of a 27% aqueous sodium hydroxide solution were added in order, and the mixture was stirred at 15 ° C. for 1 hour. After the liquid separation operation, 7.7 parts by weight of methanol was added to the aqueous layer. After adding 79 parts by weight of 30% sulfuric acid to the aqueous layer, it was cooled to 15 ° C. and filtered. The residue was washed with 231 parts by weight of 65 ° C. warm water. 51.2 parts by weight of the obtained solid was dried under reduced pressure, and 44.5 parts by weight of 1- (2-chloro-5-thiazolylmethyl) -3-methyl-2-nitroguanidine (yield 92.5%, content) 99.8%) was obtained.
本発明によれば、高い収率で、式（３）で示されるチアゾール化合物を得ることができる。また、副生成物の生成量を抑制することができる。 According to the present invention, the thiazole compound represented by the formula (3) can be obtained with high yield. Moreover, the production amount of a by-product can be suppressed.

Claims (10)

  1. 　アンモニアとホルムアルデヒドとを反応させ、式（８）
    Figure JPOXMLDOC01-appb-I000001
    で示される化合物を含む混合物を得、得られた式（８）で示される化合物を含む混合物と式（１）
    Figure JPOXMLDOC01-appb-I000002
    （式（１）中、Ｘ１は水素原子またはハロゲン原子を表す。
    Ｘ２はハロゲン原子を表す。）
    で示される化合物またはその塩とを、塩基の存在下に混合させる、式（２）
    Figure JPOXMLDOC01-appb-I000003
    （式（２）中、Ｘ１は上記と同一の意味を表す。）
    で示される化合物またはその塩の製造方法。     Ammonia and formaldehyde are reacted to obtain the formula (8)
    Figure JPOXMLDOC01-appb-I000001
    A mixture containing the compound represented by formula (8) was obtained, and the resulting mixture containing the compound represented by formula (8) and formula (1)
    Figure JPOXMLDOC01-appb-I000002
    (In formula (1), X 1 represents a hydrogen atom or a halogen atom.
    X 2 represents a halogen atom. )
    Or a salt thereof in the presence of a base, the compound of formula (2)
    Figure JPOXMLDOC01-appb-I000003
    (In formula (2), X 1 represents the same meaning as described above.)
    Or a salt thereof.
  2. 　塩基が、炭酸水素塩である請求項１に記載の製造方法。 The production method according to claim 1, wherein the base is bicarbonate.
  3. 　炭酸水素塩が、炭酸水素ナトリウムである請求項２に記載の製造方法。 The production method according to claim 2, wherein the bicarbonate is sodium bicarbonate.
  4. 　塩基の使用量が、式（１）で示される化合物１モルに対して、０．９~１．５モルである請求項１~３のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 3, wherein the amount of the base used is 0.9 to 1.5 mol with respect to 1 mol of the compound represented by the formula (1).
  5. 　式（１）で示される化合物の使用量が、ホルムアルデヒド１モルに対して０．５~０．７７モルである請求項１~４のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 4, wherein the amount of the compound represented by the formula (1) is 0.5 to 0.77 mol per mol of formaldehyde.
  6. 　式（１）で示される化合物の使用量が、アンモニア１モルに対して０．６６~０．８４モルである請求項１~５のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 5, wherein the amount of the compound represented by the formula (1) is 0.66 to 0.84 mol per 1 mol of ammonia.
  7. 　ホルムアルデヒドの使用量が、アンモニア１モルに対して、１．０~１．４モルである請求項１~６のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 6, wherein the amount of formaldehyde used is 1.0 to 1.4 mol per 1 mol of ammonia.
  8. 　アンモニアとホルムアルデヒドとの反応の反応温度が５~２５℃である請求項１~７のいずれかに記載の製造方法。 The production method according to any one of claims 1 to 7, wherein the reaction temperature of the reaction between ammonia and formaldehyde is 5 to 25 ° C.
  9. 　請求項１~８のいずれかに記載の製造方法により、式（２）で示される化合物またはその塩を得、式（２）で示される化合物またはその塩とヒドロキシルアミン類とを酸性条件下で反応させる、式（３）
    Figure JPOXMLDOC01-appb-I000004
    （式（３）中、Ｘ１は水素原子またはハロゲン原子を表す。）
    で示される化合物またはその塩の製造方法。     A compound represented by the formula (2) or a salt thereof is obtained by the production method according to any one of claims 1 to 8, and the compound represented by the formula (2) or a salt thereof and hydroxylamines are subjected to acidic conditions. React, formula (3)
    Figure JPOXMLDOC01-appb-I000004
    (In formula (3), X 1 represents a hydrogen atom or a halogen atom.)
    Or a salt thereof.
  10. 　請求項９に記載の製造方法により、式（３）で示される化合物またはその塩を得、式（３）で示される化合物またはその塩と式（５）
    Figure JPOXMLDOC01-appb-I000005
    （式（５）中、Ｒ１は置換されていてもよい炭化水素基を表す。）
    で示される化合物とを反応させ、式（６）
    Figure JPOXMLDOC01-appb-I000006
    （式（６）中、Ｒ１およびＸ１は上記と同一の意味を表す。）
    で示される化合物またはその塩を得、式（６）で示される化合物またはその塩と、アミン類またはその塩とを反応させる、式（７）
    Figure JPOXMLDOC01-appb-I000007
    （式（７）中、Ｒ２は置換されていてもよいアミノ基を表す。）
    で示されるチアゾール化合物またはその塩の製造方法。     The compound represented by formula (3) or a salt thereof is obtained by the production method according to claim 9, and the compound represented by formula (3) or a salt thereof and formula (5)
    Figure JPOXMLDOC01-appb-I000005
    (In the formula (5), R 1 represents an optionally substituted hydrocarbon group.)
    Is reacted with a compound represented by the formula (6)
    Figure JPOXMLDOC01-appb-I000006
    (In formula (6), R 1 and X 1 represent the same meaning as described above.)
    A compound represented by the formula (6) or a salt thereof is obtained, and a compound represented by the formula (6) or a salt thereof is reacted with an amine or a salt thereof.
    Figure JPOXMLDOC01-appb-I000007
    (In Formula (7), R 2 represents an optionally substituted amino group.)
    The manufacturing method of the thiazole compound or its salt shown by these.
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