WO2018181672A1 - Stable 1,3-dicarbamoylthio-2-(n,n-dimethylamino)propane hydrochloride and production method therefor - Google Patents

Stable 1,3-dicarbamoylthio-2-(n,n-dimethylamino)propane hydrochloride and production method therefor Download PDF

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WO2018181672A1
WO2018181672A1 PCT/JP2018/013133 JP2018013133W WO2018181672A1 WO 2018181672 A1 WO2018181672 A1 WO 2018181672A1 JP 2018013133 W JP2018013133 W JP 2018013133W WO 2018181672 A1 WO2018181672 A1 WO 2018181672A1
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dimethylamino
dicarbamoylthio
propane hydrochloride
week
acid
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PCT/JP2018/013133
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French (fr)
Japanese (ja)
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佐藤　誠
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住友化学株式会社
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Priority to BR112019020041-0A priority Critical patent/BR112019020041B1/en
Priority to JP2019510108A priority patent/JP7118049B2/en
Priority to CN201880022606.1A priority patent/CN110461817B/en
Publication of WO2018181672A1 publication Critical patent/WO2018181672A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the present invention relates to a stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride and a process for producing the same.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is known to be useful as an insecticide.
  • methods for producing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride methods described in Patent Documents 1 to 4 are known.
  • crystals of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride are obtained by filtering the reaction product.
  • the washing method of the crystal after filtration is a method of washing the crystal with methanol as described in Example 6 and Comparative Example 2 of Patent Document 1.
  • an object of the present invention is to provide 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having storage stability and a method for producing the same.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced by the following method. Specifically, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is washed with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid. It has been found that stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having the stability contains a strongly acidic inorganic acid salt or a strongly acidic organic acid.
  • Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride in the form of an adduct of the strong acid inorganic acid salt or strong acid organic acid, the strong acid inorganic acid salt or strong acid In the range of 0.05 to 10% by weight based on the weight of the 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride adduct I also found out.
  • the present invention is as follows, but is not limited thereto.
  • 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride used in step (A) is Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrogen chloride gas in methanol and an organic solvent that forms a two-layer system with methanol, or Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrochloric acid in water and an organic solvent that forms a two-layer system with water;
  • the organic solvent that forms a two-layer system with methanol is one or a mixture of two or more selected from the group consisting of tol
  • Strongly acidic inorganic acid salt or strong acid organic acid content is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strong acid 1,3-dicarbamoylthio-2- (N, N-dimethylamino)-described in the above item [6], in a range of 0.1 to 2% by weight based on the weight of the adduct of the organic acid Propane hydrochloride inorganic acid salt or organic acid adduct.
  • the strongly acidic inorganic acid salt or the strongly acidic organic acid is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, oxalic acid or citric acid.
  • stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced by an industrially feasible method.
  • the hydrochloride is excellent in thermal stability.
  • the present invention is a method for producing stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) by a method comprising the following step (A).
  • 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) used in the present invention is produced, for example, according to the methods described in the following production methods (1) to (3). be able to.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (hereinafter sometimes referred to as “compound (I)”) is also referred to as cartap hydrochloride.
  • compound (I) is also referred to as cartap hydrochloride.
  • Examples of the organic solvent that forms a two-layer system with methanol include one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene.
  • the reaction can be carried out according to the method described in Patent Document 1 or Patent Document 3.
  • the washing treatment in the following step (A), step (B) and step (C) refers to 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride
  • crystals of I ie, crystals of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) containing filtrate (eg wet crystals)
  • the crystal is washed with an exemplified aqueous solution or alcohol (for example, the crystal is immersed in the exemplified aqueous solution or alcohol, or the exemplified aqueous solution or alcohol is sprayed on the crystal).
  • the crystal contains Replacement of part or all of the filtrate with an aqueous solution or alcohol.
  • step (A) After the step (A) is performed, the following step (B) and / or step (C) is further performed to obtain 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (The amount of strongly acidic inorganic acid salt or strongly acidic organic acid contained in I) can be adjusted.
  • step (B) and / or step (C) either step (B) or step (C) may be carried out, and both step (B) and step (C) may be carried out. Also good.
  • step (A) 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is washed with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid.
  • 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) used in step (A) is prepared according to the method described in the above production methods (1) to (3).
  • the prepared product, or the following step (B) (including step (B) after the following step (C)) or the following step (C) (including step (C) after the following step (B)) It may be any product prepared after treatment.
  • a product prepared according to the method described in the above production methods (1) to (3) is preferred.
  • Examples of strongly acidic inorganic acid salts include sulfates and nitrates, and specific examples of sulfates include ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, and ammonium hydrogen sulfate.
  • Sodium bisulfate and potassium bisulfate can be produced by mixing sodium sulfate or potassium sulfate and concentrated hydrochloric acid, respectively. In this case, a mixture of sodium bisulfate and sodium chloride, and potassium bisulfate, respectively. A mixture of potassium chloride and potassium chloride can be used as it is.
  • Ammonium hydrogen sulfate may be prepared by mixing ammonium sulfate and concentrated hydrochloric acid, or one containing ammonium chloride may be used.
  • the strongly acidic inorganic acid salt include ammonium hydrogen sulfate and sodium hydrogen sulfate.
  • strongly acidic organic acids include organic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, glycolic acid, lactic acid, glyceric acid, tartaric acid, and citric acid.
  • strongly acidic organic acids include oxalic acid and citric acid.
  • an acid having low volatility that can remain during long-term storage for example, at a high temperature
  • a strongly acidic inorganic acid salt is more preferable.
  • An aqueous solution containing a strong acid inorganic acid salt or a strong acid organic acid is prepared by mixing the above strong acid inorganic acid salt or strong acid organic acid, or the acid or salt used to prepare them with water. By doing so, an aqueous solution can be prepared.
  • An aqueous solution of ammonium hydrogen sulfate is typically prepared by mixing concentrated sulfuric acid and aqueous ammonia. It can also be used as an aqueous solution of a mixture of ammonium hydrogen sulfate and ammonium chloride.
  • the aqueous solution of sodium hydrogensulfate is typically prepared by mixing concentrated sulfuric acid and sodium hydroxide, or by mixing concentrated sulfuric acid and aqueous sodium hydroxide.
  • aqueous solution of sodium hydrogen sulfate one prepared as an aqueous solution of a mixture of sodium hydrogen sulfate and sodium chloride may be used as it is.
  • the aqueous solution of potassium hydrogen sulfate is typically prepared by mixing concentrated sulfuric acid and potassium hydroxide, or by mixing concentrated sulfuric acid and aqueous potassium hydroxide solution.
  • the aqueous solution of potassium hydrogen sulfate one prepared as an aqueous solution of a mixture of potassium hydrogen sulfate and potassium chloride may be used.
  • the concentration of the inorganic acid salt or organic acid in the aqueous solution containing the strong acid inorganic acid salt or the strong acid organic acid is usually in the range of 0.5 to 30% by weight with respect to the weight of the aqueous solution, preferably 1 It is in the range of ⁇ 15% by weight.
  • the temperature of the aqueous solution containing a strongly acidic inorganic acid salt or strongly acidic organic acid used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
  • the amount of the aqueous solution containing a strongly acidic inorganic acid salt or a strongly acidic organic acid used for washing is usually in the range of 5 to 70% by weight, preferably 30 to 50% by weight, based on the weight of the wet crystals. It is a range.
  • Crude compositions containing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I), including those with reduced content and / or with reduced quality ) Is made into a slurry solution with water, hydrochloric acid, an aqueous solution of a strong acid inorganic acid salt or an aqueous solution of a strong acid organic acid, filtered, and further, water, hydrochloric acid, an aqueous solution of a strong acid inorganic acid salt or a strong acid
  • a stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) is obtained by subjecting a solution obtained by heating and dissolving in an aqueous solution of a basic organic acid to cooling crystallization and then filtering to the production method of the present invention.
  • -Propane hydrochloride can be prepared.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) obtained in step (A) can be further prepared by the following steps (B) and / or ( You may use for C) and may adjust content of the strongly acidic inorganic acid salt or strong acid organic acid to contain.
  • Step (B) will be described.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is washed with a weakly acidic aqueous inorganic salt solution.
  • the weakly acidic inorganic salt examples include ammonium chloride, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, and preferably ammonium chloride.
  • the weakly acidic inorganic salt aqueous solution can be prepared by mixing a weakly acidic inorganic salt and water, and examples thereof include an ammonium chloride aqueous solution.
  • the concentration of the weakly acidic inorganic salt aqueous solution is usually in the range of 0.5 to 30% by weight, preferably in the range of 1 to 20% by weight, based on the weight of the aqueous solution.
  • the temperature of the weakly acidic inorganic salt aqueous solution used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
  • the amount of the weakly acidic inorganic salt aqueous solution used for washing is usually in the range of 5 to 60% by weight, preferably in the range of 10 to 30% by weight, based on the weight of the wet crystals.
  • Step (C) will be described.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is washed with a lower alcohol.
  • it is preferably applied to the product obtained by the treatment of the step (A) or the step (B), more preferably applied to the product obtained by the treatment of the step (A).
  • the lower alcohol means an alcohol having 1 to 3 carbon atoms, and examples thereof include methanol, ethanol, and isopropyl alcohol, and methanol is preferable.
  • the temperature of the lower alcohol used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
  • the amount of the lower alcohol used for washing is usually in the range of 5 to 60% by weight, preferably in the range of 10 to 30% by weight, based on the weight of the wet crystals.
  • step (A) After the final step of step (A), step (B) or step (C), the desired 1,3-dicarbamoylthio-2- (N, N-dimethylamino) is obtained by passing through a drying step.
  • Propane hydrochloride (I) can be obtained.
  • All operations of the production method of the present invention can be performed at room temperature. However, in order to suppress the decrease of the target product in the cleaning liquid, it is preferable to perform cleaning using a cooled cleaning liquid.
  • Step (A) of the present invention comprises a composition comprising 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) having reduced content and / or reduced quality
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) having reduced content and / or reduced quality
  • a stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) can also be prepared.
  • the salt of formula (I) having a reduced content and / or a reduced quality was slurried with water, hydrochloric acid, etc., filtered, and further heated and dissolved in water, hydrochloric acid, etc., and then cooled and crystallized. What is obtained by post-filtration may be subjected to step (A).
  • Compound (I) as an acid adduct It is contained in the strong acid inorganic acid salt or strong acid organic acid adduct of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride produced by the production method of the present invention.
  • the amount of the strongly acidic inorganic acid salt or the strongly acidic organic acid is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strongly acidic acid.
  • Is usually in the range of 0.05 to 10% by weight, preferably in the range of 0.1 to 2% by weight, more preferably in the range of 0.1 to 1.5% by weight, based on the weight of the organic acid adduct. %, More preferably in the range of 0.1 to 1.1% by weight.
  • the pH of the aqueous solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride adduct is not more than 4.5, and usually not less than 3.0 and not more than 4.5 It is preferably 3.0 or more and 4.2 or less, more preferably 3.3 or more and 4.0 or less, still more preferably 3.7 or less, and still more preferably 3.
  • the pH of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is a solution in which 1 g of the dry hydrochloride is dissolved in 100 ml of water (hereinafter referred to as “pH”). "1% aqueous solution”) was prepared, and the pH of this aqueous solution was measured.
  • the pH in a 1% aqueous solution is usually 3.0 to 4.5, but when 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is decomposed, ammonia is dissolved.
  • the pH value is an important indicator for determining the presence or absence of decomposition as the content decreases. It is not preferred if the pH is greater than 4.5 (especially 3.7).
  • the stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the production method of the present invention is obtained by using 1,3-dicarbamoyl obtained by the conventional method.
  • thio-2- (N, N-dimethylamino) -propane hydrochloride (I) high purity and improved stability (eg thermal stability) enable long-term storage It is.
  • the produced 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) has a strong insecticidal action as described in Patent Document 3 and Patent Document 4, It can be used as an agricultural insecticidal composition.
  • Inorganic acid salt for example, NH 4 + contained in the inorganic acid salt or organic acid adduct of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) And SO 4 2 ⁇ ions
  • organic acid eg oxalic acid
  • HIC high-speed ion chromatograph
  • the content of sodium hydrogen sulfate was determined from the analytical value of sulfate ion (SO 4 2 ⁇ ) and the analytical value of sodium ion (Na + ) by the following calculation formula.
  • symbols represent the following meanings.
  • the pH of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is a 1% aqueous solution of the dry hydrochloride. The pH of the aqueous solution is measured.
  • Example 1 138.0 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (as the concentration of Compound II) 21.4%), 53.3 g of methanol was added, and 55 g (1.496 mol) of hydrogen chloride gas was blown in over 6 hours while cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added.
  • II 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride
  • Example 2 137.6 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (concentration of compound (II))
  • II 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride
  • 53.3 g of methanol was added to 21.5%, and 47 g (1.358 mol) of hydrogen chloride gas was blown in over 7 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours.
  • the reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added.
  • Example 3 137.6 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (concentration of compound (II))
  • II 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride
  • 53.3 g of methanol was added to 21.5%, and 47 g (1.358 mol) of hydrogen chloride gas was blown in over 7 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours.
  • the reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 46 g of water was added.
  • the internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. 1,2-Dichloroethane was distilled off, and the mixture was gradually cooled to 5 ° C. or lower.
  • the precipitated crystals were filtered, and 8.9 g of a mixed aqueous solution of 5.2% NH 4 HSO 4 and 2.4% NH 4 Cl separately prepared. After washing with 12.4 g of methanol.
  • a mixed aqueous solution of 5.2% NH 4 HSO 4 and 2.4% NH 4 Cl was prepared by dissolving 4.5 g of (NH 4 ) 2 SO 4 with 73.1 g of water, and then adding 3.8 g of 35% hydrochloric acid.
  • Example 4 The same reaction and treatment as in Example 1 were carried out, and 542.26 g of a slurry solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) 5 After cooling to around 0 ° C., it was centrifuged with a desktop small centrifuge. The obtained wet crystals were washed with 37.28 g of a mixed aqueous solution of 10.7% NH 4 HSO 4 and 5.0% NH 4 Cl prepared from (NH 4 ) 2 SO 4 and 36% hydrochloric acid, and then methanol 84. Washed with 00 g.
  • the obtained wet crystals (226.74 g) were dried under reduced pressure at 75 ° C. for 2 hours to obtain 168.11 g (purity 97.5%) as a dried product.
  • the appearance was white crystals, and the pH of the 1% aqueous solution was 3.51.
  • As a result of measurement by ion chromatography analysis of the product it was found that NH 4 HSO 4 contained 0.35% and NH 4 Cl contained 0.19%.
  • an accelerated test at 60 ° C. was performed and the progress was observed.
  • the results of the 60 ° C. acceleration test were as follows.
  • Example 5 The same reaction and treatment as in Example 1 were carried out, and 532.66 g of a slurry solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) before filtration was added to 5 After cooling to around 0 ° C., it was centrifuged with a desktop small centrifuge. The obtained wet crystals were washed with 51.31 g of a mixed solution of 10.7% NH 4 HSO 4 and 5.0% NH 4 Cl prepared from (NH 4 ) 2 SO 4 and 36% hydrochloric acid, and then 20% NH. Washed with 69.32 g of 4 Cl.
  • I 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride
  • Example 6 40 g (0.146 mol) of reduced 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (content: 95.8%, pH 5.20) After slurrying in 11.5% dilute hydrochloric acid (18.0 g of concentrated hydrochloric acid added to 28.0 g of water), the mixture was cooled to 5 ° C. or lower and stirred for 1 hour. Then, the mixture was washed with 9.4 g of a mixed aqueous solution of 7.1% NH 4 HSO 4 and 3.3% NH 4 Cl.
  • a mixed aqueous solution of 7.1% NH 4 HSO 4 and 2.4% NH 4 Cl was prepared by dissolving 0.79 g of (NH 4 ) 2 SO 4 with 78.0 g of water, and then adding 0.61 g of 35% hydrochloric acid.
  • the appearance was white crystals, and the pH of the 1% aqueous solution was 3.38.
  • Example 7 45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% oxalic acid aqueous solution (0.68 g of oxalic acid dissolved in 12.94 g of water).
  • Example 8 45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% aqueous citric acid solution (0.68 g of citric acid dissolved in 12.94 g of water).
  • Example 9 30 g (0.102 mol) (content: 93.1%, pH 5.00) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality
  • slurrying in 2.0% dilute hydrochloric acid 33.0 g of water plus 1.9 g of concentrated hydrochloric acid
  • the mixture was heated to 70 ° C. and completely dissolved.
  • 9.0 g of 36% hydrochloric acid at the same temperature, the mixture was cooled to 55 ° C. and methanol 12.0 was added. After gradually cooling to 10 ° C.
  • a 3.0% NH 4 HSO 4 water / methanol mixed solution was prepared by dissolving 0.30 g of NH 4 HSO 4 with 5.1 g of water and adding 4.50 g of methanol. After drying under reduced pressure at 60 ° C. for 2 hours, 25.3 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.6%, recovery rate 90% .7%).
  • Example 10 The slurry obtained by carrying out the same reaction and treatment as in Example 1 was centrifuged and filtered to collect 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I ) About 35 parts by weight of wet crystals were sprinkled and washed with about 7 parts by weight of methanol on a centrifuge, and further about 8.5 parts by weight of NH 4 HSO 4 -water-methanol mixed solution of about 4% w / w ( NH 4 HSO 4 0.35 parts by weight, 2.8 parts by weight of water, and washed sprinkled with methanol 5.3 parts by weight).
  • I 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride
  • Example 11 45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour.
  • dilute hydrochloric acid 28.0 g of water plus 13.1 g of concentrated hydrochloric acid
  • Comparative Example 1 133.4 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) 23.4%), 53.4 g of methanol was added, and 49.5 g (1.358 mol) of hydrogen chloride gas was blown in over 8 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added.
  • II 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride
  • the internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. After 1,2-dichloroethane was distilled off, the mixture was gradually cooled to 5 ° C. or lower, and the precipitated crystals were filtered and washed with 12.5 g of methanol. It was dried at 60 ° C. under reduced pressure for 2 hours, and 33.6 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.7%, yield 83) .2%).
  • Comparative Example 2 80 g (0.292 mol) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality (content: 95.8%, pH 5.20) Slurried in 11.5% dilute hydrochloric acid (56.0 g of water plus 26.3 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower, stirred for 1 hour, filtered the precipitated crystals, and filtered to 26.9 g of methanol. Washed with. After drying at 60 ° C.
  • Comparative Example 3 Unwashed wet crystal 224 of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the same method as in Comparative Example 1 except that methanol washing is not performed. .96 g was dried under reduced pressure at 75 ° C. for 2 hours to obtain 199.99 g (purity 98.0%) as a dried product. As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.95.
  • Comparative Example 4 Unwashed wet crystal 233 of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the same method as in Comparative Example 1 except that methanol washing is not performed. 0.000 g and the filtrate 233.00 g were mixed, and the reslurried solution was cooled to around 5 ° C. and then centrifuged with a desktop small centrifuge. The obtained wet crystals were washed while centrifuging with 64.0 g of methanol. 217.20 g of the obtained wet crystal was dried under reduced pressure at 75 ° C. for 2 hours to obtain 190.00 g (purity 98.0%) as a dried product.
  • Comparative Example 5 45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 12.87 g of methanol. It was dried under reduced pressure at 60 ° C.
  • Comparative Example 6 30 g (0.102 mol) (content: 93.1%, pH 5.00) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality
  • 1.0% diluted hydrochloric acid 30.0 g of water plus 0.9 g of concentrated hydrochloric acid
  • the mixture was heated to 70 ° C. and completely dissolved.
  • After adding 10.5 g of 36% hydrochloric acid at the same temperature the mixture was cooled to 55 ° C. and methanol 12.0 was added. After slowly cooling to 10 ° C.
  • Degraded 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is purified by recrystallization and is stable compared to conventional products (Padan (registered trademark)) The stability was improved, but the stability was poor as compared with that washed with a NH 4 HSO 4 water-containing methanol solution as in Example 9.
  • 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) having an excellent insecticidal action is considered to have good stability. It can be produced with good purity and yield.

Abstract

The present invention provides a production method for stable 1,3-dicarbamoylthio-2-(N,N-dimethylamino)propane hydrochloride, the method including step (A) in which 1,3-dicarbamoylthio-2-(N,N-dimethylamino)propane hydrochloride is washed with an aqueous solution of a salt of an inorganic strong acid or with an aqueous solution of an organic strong acid.

Description

安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩、およびその製造方法Stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride and process for producing the same
　本特許出願は、日本国特許出願２０１７－６７３５８号（２０１７年３月３０日出願）に基づくパリ条約上の優先権および利益を主張するものであり、ここに引用することによって、上記出願に記載された内容の全体が、本明細書中に組み込まれるものとする。
　本発明は、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩、およびその製造方法に関する。 This patent application claims priority and benefit under the Paris Convention based on Japanese Patent Application No. 2017-67358 (filed on March 30, 2017), and is incorporated herein by reference. The entire contents of which are incorporated herein are incorporated herein.
The present invention relates to a stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride and a process for producing the same.
　１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩は、殺虫剤として有用であることが知られる。１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の製造法としては、特許文献１乃至４に記載の方法が知られている。ここで、いずれの製法でも、反応生成物をろ過することにより１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の結晶を取得する。ろ過後の当該結晶の洗浄法とは、特許文献１の実施例６および比較例２に記載されている通り当該結晶をメタノールで洗浄する方法である。 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is known to be useful as an insecticide. As methods for producing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride, methods described in Patent Documents 1 to 4 are known. Here, in any production method, crystals of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride are obtained by filtering the reaction product. The washing method of the crystal after filtration is a method of washing the crystal with methanol as described in Example 6 and Comparative Example 2 of Patent Document 1.
中国特許第１０１５１９３７１号Chinese Patent No. 10151371 中国特許出願公開第１０１１０３７２５号Chinese Patent Application No. 10103725 特公昭４２－１０９６９号公報Japanese Patent Publication No.42-10969 特公昭４９－２７８５７号公報Japanese Patent Publication No.49-27857
　従来の製法で得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩は安定性が不十分であり、例えば長期間保管された場合に、分解による品質低下が見られる場合があった。そこで、本発明は、保存安定性を有する１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩、およびその製造方法を提供することを目的とする。 The 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride obtained by the conventional production method has insufficient stability, for example, when it is stored for a long period of time, the quality deteriorates due to decomposition. Was sometimes seen. Accordingly, an object of the present invention is to provide 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having storage stability and a method for producing the same.
　本発明者らは、前記課題を解決すべく検討した結果、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を以下の方法により製造できることを見出した。
　具体的には、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液で洗浄処理することにより、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を製造できることを見出した。また、当該安定性を有する１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩は、強酸性の無機酸塩または強酸性の有機酸を含有し、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の該強酸性の無機酸塩または強酸性の有機酸の付加物の形態であり、該強酸性の無機酸塩または強酸性の有機酸の含量が、前記の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の付加物の重量に対して、０．０５～１０重量％の範囲である、ことをも見出した。 As a result of studies to solve the above problems, the present inventors have found that stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced by the following method. .
Specifically, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is washed with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid. It has been found that stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced. Further, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having the stability contains a strongly acidic inorganic acid salt or a strongly acidic organic acid. Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride in the form of an adduct of the strong acid inorganic acid salt or strong acid organic acid, the strong acid inorganic acid salt or strong acid In the range of 0.05 to 10% by weight based on the weight of the 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride adduct I also found out.
　本発明は以下のとおりであるが、これらに限定されるものではない。 The present invention is as follows, but is not limited thereto.
（製造方法）
［１］　工程（Ａ）を含む安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の製造方法：
工程（Ａ）：１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液で洗浄する工程。
［２］　工程（Ａ）に供される１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩が、
　メタノールおよびメタノールと二層系を形成する有機溶媒中で２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩と塩化水素ガスとを反応させるか、あるいは、
　水および水と二層系を形成する有機溶媒中で２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩と塩酸とを反応させる、
ことにより得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩である、前項［１］に記載の製造方法。
［３］　メタノールと二層系を形成する有機溶媒が、トルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物であり、
　水と二層系を形成する有機溶媒が、トルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物である、前項［２］に記載の製造方法。
［４］　工程（Ａ）に供される１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩が、２－Ｎ，Ｎ－ジメチルアミノ－１，３－プロパンジチオールとシアン酸塩とを塩酸の存在下で反応させることにより得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩である、前項［１］～［３］のいずれか１つに記載の製造方法。
［５］　強酸性の無機酸塩が、硫酸水素アンモニウム、硫酸水素ナトリウム、硫酸水素カリウム、または硫酸水素アンモニウムであり、強酸性の有機酸が、シュウ酸またはクエン酸である、前項［１］～［４］のいずれか１つに記載の製造方法。 (Production method)
[1] Method for producing stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride comprising step (A):
Step (A): A step of washing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid.
[2] 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride used in step (A) is
Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrogen chloride gas in methanol and an organic solvent that forms a two-layer system with methanol, or
Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrochloric acid in water and an organic solvent that forms a two-layer system with water;
The production method of the above-mentioned [1], which is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride obtained by
[3] The organic solvent that forms a two-layer system with methanol is one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene,
The organic solvent that forms a two-layer system with water is one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene. Manufacturing method.
[4] 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride used in step (A) is converted to 2-N, N-dimethylamino-1,3-propanedithiol. And [3], which are 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride obtained by reacting benzene with cyanate in the presence of hydrochloric acid The manufacturing method as described in any one of these.
[5] The above [1] to [1], wherein the strongly acidic inorganic acid salt is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, or ammonium hydrogen sulfate, and the strongly acidic organic acid is oxalic acid or citric acid. [4] The production method according to any one of [4].
（酸付加物としての化合物（Ｉ））
［６］　下記（ａ）および（ｂ）を満たす、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物：
　（ａ）強酸性の無機酸塩または強酸性の有機酸の含量が、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物の重量に対して、０．０５～１０重量％の範囲である、
　（ｂ）１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物の水溶液のｐＨが３．７以下である。
［７］　強酸性の無機酸塩または強酸性の有機酸の含量が、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物の重量に対して、０．１～２重量％の範囲である、前項［６］記載の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物。
［８］　強酸性の無機酸塩または強酸性の有機酸が、硫酸水素アンモニウム、硫酸水素ナトリム、硫酸水素カリウム、シュウ酸またはクエン酸である、前項［６］または［７］のいずれか１項に記載の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物。 (Compound (I) as an acid adduct)
[6] A strongly acidic inorganic acid salt of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride or a strongly acidic organic acid satisfying the following (a) and (b): Addendum:
(A) A strongly acidic inorganic acid salt or a strong acid containing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having a content of a strongly acidic inorganic acid salt or a strongly acidic organic acid Is in the range of 0.05 to 10% by weight based on the weight of the adduct of the organic acid.
(B) The pH of the aqueous solution of an inorganic acid salt of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride or an adduct of an organic acid is 3.7 or lower.
[7] Strongly acidic inorganic acid salt or strong acid organic acid content is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strong acid 1,3-dicarbamoylthio-2- (N, N-dimethylamino)-described in the above item [6], in a range of 0.1 to 2% by weight based on the weight of the adduct of the organic acid Propane hydrochloride inorganic acid salt or organic acid adduct.
[8] Any one of [6] or [7] above, wherein the strongly acidic inorganic acid salt or the strongly acidic organic acid is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, oxalic acid or citric acid. An inorganic acid salt or an organic acid adduct of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride as described in 1. above.
　本発明によれば、工業的に実施可能な方法で、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を製造することができる。当該塩酸塩は、熱安定性に優れる。 According to the present invention, stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride can be produced by an industrially feasible method. The hydrochloride is excellent in thermal stability.
（製造方法）
　本発明は、下記工程（Ａ）を含む方法により、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を製造する方法である。
　本発明に用いる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）は、例えば下記製法（１）乃至（３）に記載の方法に準じて製造することができる。
　ここで、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）（以下、「化合物（Ｉ）」と称することがある）とは、カルタップ塩酸塩とも呼称され、下記式：
Figure JPOXMLDOC01-appb-C000001
 で示される化合物のことをいう。また、該化合物は、例えばＴｈｅ　Ｐｅｓｔｉｃｉｄｅ　Ｍａｎｕａｌ　１７ｔｈ　ｅｄｉｔｉｏｎの１７０－１７１ページに記載されている。 (Production method)
The present invention is a method for producing stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) by a method comprising the following step (A).
1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) used in the present invention is produced, for example, according to the methods described in the following production methods (1) to (3). be able to.
Here, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (hereinafter sometimes referred to as “compound (I)”) is also referred to as cartap hydrochloride. The following formula:
Figure JPOXMLDOC01-appb-C000001
 The compound shown by these. The compound is described, for example, on pages 170-171 of The Pesticide Manual 17th edition.
製法（１）
　メタノールおよびメタノールと二層系を形成する有機溶媒中で、２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（以下、「化合物（II）」と称することがある）と塩化水素ガスとを反応させることにより、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を得ることができる。
　メタノールと二層系を形成する有機溶媒としては、例えば、トルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物が挙げられる。
　反応は、特許文献１または特許文献３に記載の方法に準じて実施することができる。 Manufacturing method (1)
2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (hereinafter referred to as “compound (II)” in methanol and an organic solvent that forms a two-layer system with methanol. 1) and hydrogen chloride gas can be reacted to give 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I).
Examples of the organic solvent that forms a two-layer system with methanol include one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene.
The reaction can be carried out according to the method described in Patent Document 1 or Patent Document 3.
製法（２）
　水および水と二層系を形成する有機溶媒中で２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（II）と塩酸とを反応させることにより、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を得ることができる。
　水と二層系を形成する有機溶媒としては、例えばトルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物が挙げられる。
　反応は、特許文献２に記載の方法に準じて実施することができる。 Manufacturing method (2)
By reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) with hydrochloric acid in water and an organic solvent that forms a two-layer system with water, 3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) can be obtained.
Examples of the organic solvent that forms a two-layer system with water include one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene.
The reaction can be carried out according to the method described in Patent Document 2.
製法（３）
　２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－プロパンジチオール（以下、「化合物（III）」と称することがある）とシアン酸塩とを酸の存在下で反応させることにより、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を得ることができる。
　反応は、特許文献４に記載の方法に準じて実施することができる。 Manufacturing method (3)
By reacting 2- (N, N-dimethylamino) -1,3-propanedithiol (hereinafter sometimes referred to as “compound (III)”) with cyanate in the presence of an acid, 1, 3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) can be obtained.
The reaction can be carried out according to the method described in Patent Document 4.
　本明細書中、下記工程（Ａ）、工程（Ｂ）および工程（Ｃ）における洗浄の処理とは、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の結晶、即ち、ろ液を含有している１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の結晶（例えば、湿結晶）について、該結晶を例示する水溶液またはアルコールで洗浄する（例えば、例示する水溶液またはアルコールに該結晶を浸す、あるいは例示する水溶液またはアルコールを該結晶に散布する）ことをいい、結果、該結晶が含有しているろ液の一部または全部を水溶液またはアルコールで置換することである。 In the present specification, the washing treatment in the following step (A), step (B) and step (C) refers to 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride ( For crystals of I), ie, crystals of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) containing filtrate (eg wet crystals) The crystal is washed with an exemplified aqueous solution or alcohol (for example, the crystal is immersed in the exemplified aqueous solution or alcohol, or the exemplified aqueous solution or alcohol is sprayed on the crystal). As a result, the crystal contains Replacement of part or all of the filtrate with an aqueous solution or alcohol.
　工程（Ａ）の実施後に、更に下記工程（Ｂ）および／または工程（Ｃ）を実施することにより、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）に含有される強酸性の無機酸塩または強酸性の有機酸の量を調整することができる。工程（Ｂ）および／または工程（Ｃ）とは、工程（Ｂ）または工程（Ｃ）のいずれか一方のみを実施してもよく、工程（Ｂ）および工程（Ｃ）の両方を実施してもよい。 After the step (A) is performed, the following step (B) and / or step (C) is further performed to obtain 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride ( The amount of strongly acidic inorganic acid salt or strongly acidic organic acid contained in I) can be adjusted. With step (B) and / or step (C), either step (B) or step (C) may be carried out, and both step (B) and step (C) may be carried out. Also good.
　まず、工程（Ａ）を説明する。
　工程（Ａ）では、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液で洗浄する。
　工程（Ａ）で使用する１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）は、上記製法（１）乃至（３）に記載の方法に準じて調製した生成物、あるいは下記工程（Ｂ）（下記工程（Ｃ）の後の工程（Ｂ）を含む）または下記工程（Ｃ）（下記工程（Ｂ）の後の工程（Ｃ）を含む）の処理後に調製した生成物のいずれでもあってもよい。上記製法（１）乃至（３）に記載の方法に準じて調製した生成物が好ましい。 First, the step (A) will be described.
In step (A), 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is washed with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid. To do.
1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) used in step (A) is prepared according to the method described in the above production methods (1) to (3). The prepared product, or the following step (B) (including step (B) after the following step (C)) or the following step (C) (including step (C) after the following step (B)) It may be any product prepared after treatment. A product prepared according to the method described in the above production methods (1) to (3) is preferred.
　強酸性の無機酸塩としては、例えば、硫酸塩および硝酸塩が挙げられ、硫酸塩の具体例としては、硫酸水素アンモニウム、硫酸水素ナトリウム、硫酸水素カリウム、硫酸水素アンモニウムが例示される。硫酸水素ナトリウムおよび硫酸水素カリウムは、それぞれ硫酸ナトリウムまたは硫酸カリウムと濃塩酸を混合して生成したものを使用することができ、この場合、それぞれ硫酸水素ナトリウムと塩化ナトリウムとの混合物、および硫酸水素カリウムと塩化カリウムとの混合物をそのまま使用することができる。硫酸水素アンモニウムは、硫酸アンモニウムと濃塩酸を混合して調製してもよく、塩化アンモニウムを含むものを使用してもよい。 Examples of strongly acidic inorganic acid salts include sulfates and nitrates, and specific examples of sulfates include ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, and ammonium hydrogen sulfate. Sodium bisulfate and potassium bisulfate can be produced by mixing sodium sulfate or potassium sulfate and concentrated hydrochloric acid, respectively. In this case, a mixture of sodium bisulfate and sodium chloride, and potassium bisulfate, respectively. A mixture of potassium chloride and potassium chloride can be used as it is. Ammonium hydrogen sulfate may be prepared by mixing ammonium sulfate and concentrated hydrochloric acid, or one containing ammonium chloride may be used.
　強酸性の無機酸塩の好ましい具体例は、硫酸水素アンモニウムおよび硫酸水素ナトリウムを挙げられる。
　強酸性の有機酸としては、シュウ酸、マロン酸、コハク酸、グルタル酸、グリコール酸、乳酸、グリセリン酸、酒石酸、およびクエン酸等の有機酸が挙げられる。強酸性の有機酸の好ましい具体例としては、シュウ酸およびクエン酸を挙げられる。
　強酸性の無機酸塩または強酸性の有機酸としては、長期間保管の間（例えば、高温下で）に残留し得る揮発性の低い酸が好ましく、また強酸性の無機酸塩がより好ましい。 Preferable specific examples of the strongly acidic inorganic acid salt include ammonium hydrogen sulfate and sodium hydrogen sulfate.
Examples of strongly acidic organic acids include organic acids such as oxalic acid, malonic acid, succinic acid, glutaric acid, glycolic acid, lactic acid, glyceric acid, tartaric acid, and citric acid. Specific examples of strongly acidic organic acids include oxalic acid and citric acid.
As the strongly acidic inorganic acid salt or the strongly acidic organic acid, an acid having low volatility that can remain during long-term storage (for example, at a high temperature) is preferable, and a strongly acidic inorganic acid salt is more preferable.
　強酸性の無機酸塩または強酸性の有機酸を含有する水溶液は、前記の強酸性の無機酸塩または強酸性の有機酸、あるいは、それらを調製するために用いた酸や塩を水と混合することにより水溶液を調製することができる。
　硫酸水素アンモニウムの水溶液は、典型的には、濃硫酸とアンモニア水とを混合して調製される。硫酸水素アンモニウムと塩化アンモニウムとの混合物の水溶液として使用することもできる。
　硫酸水素ナトリウムの水溶液は、典型的には、濃硫酸と水酸化ナトリウムとを混合して調製するか、あるいは、濃硫酸と水酸化ナトリウム水溶液とを混合して調製される。硫酸水素ナトリウムの水溶液は、硫酸水素ナトリウムと塩化ナトリウムとの混合物の水溶液として調製されるものをそのまま使用してもよい。
　硫酸水素カリウムの水溶液は典型的には、濃硫酸と水酸化カリウムとを混合して調製するか、あるいは、濃硫酸と水酸化カリウム水溶液とを混合して調製される。硫酸水素カリウムの水溶液は、硫酸水素カリウムと塩化カリウムとの混合物の水溶液として調製されるものを使用してもよい。 An aqueous solution containing a strong acid inorganic acid salt or a strong acid organic acid is prepared by mixing the above strong acid inorganic acid salt or strong acid organic acid, or the acid or salt used to prepare them with water. By doing so, an aqueous solution can be prepared.
An aqueous solution of ammonium hydrogen sulfate is typically prepared by mixing concentrated sulfuric acid and aqueous ammonia. It can also be used as an aqueous solution of a mixture of ammonium hydrogen sulfate and ammonium chloride.
The aqueous solution of sodium hydrogensulfate is typically prepared by mixing concentrated sulfuric acid and sodium hydroxide, or by mixing concentrated sulfuric acid and aqueous sodium hydroxide. As the aqueous solution of sodium hydrogen sulfate, one prepared as an aqueous solution of a mixture of sodium hydrogen sulfate and sodium chloride may be used as it is.
The aqueous solution of potassium hydrogen sulfate is typically prepared by mixing concentrated sulfuric acid and potassium hydroxide, or by mixing concentrated sulfuric acid and aqueous potassium hydroxide solution. As the aqueous solution of potassium hydrogen sulfate, one prepared as an aqueous solution of a mixture of potassium hydrogen sulfate and potassium chloride may be used.
　強酸性の無機酸塩または強酸性の有機酸を含有する水溶液における当該無機酸塩または有機酸の濃度は、水溶液の重量に対し、通常０．５～３０重量％の範囲であり、好ましくは１～１５重量％の範囲である。
　洗浄に用いる強酸性の無機酸塩または強酸性の有機酸を含有する水溶液の温度は、通常０～３０℃の範囲であり、好ましくは０～１０℃の範囲である。
　洗浄に用いる強酸性の無機酸塩または強酸性の有機酸を含有する水溶液の使用量は、湿結晶の重量に対し、通常５～７０重量％の範囲であり、好ましくは３０～５０重量％の範囲である。 The concentration of the inorganic acid salt or organic acid in the aqueous solution containing the strong acid inorganic acid salt or the strong acid organic acid is usually in the range of 0.5 to 30% by weight with respect to the weight of the aqueous solution, preferably 1 It is in the range of ˜15% by weight.
The temperature of the aqueous solution containing a strongly acidic inorganic acid salt or strongly acidic organic acid used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
The amount of the aqueous solution containing a strongly acidic inorganic acid salt or a strongly acidic organic acid used for washing is usually in the range of 5 to 70% by weight, preferably 30 to 50% by weight, based on the weight of the wet crystals. It is a range.
　１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を含有する粗組成物（例えば、含量が低下したもの、および／または品質が低下したものを含む）を、水、塩酸、強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液でスラリー液とした後、濾過し、及び更に、水、塩酸、強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液中に加熱溶解後、冷却晶析した後濾過したものを本発明の製造方法に供することにより、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を製造することができる。 Crude compositions containing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I), including those with reduced content and / or with reduced quality ) Is made into a slurry solution with water, hydrochloric acid, an aqueous solution of a strong acid inorganic acid salt or an aqueous solution of a strong acid organic acid, filtered, and further, water, hydrochloric acid, an aqueous solution of a strong acid inorganic acid salt or a strong acid A stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) is obtained by subjecting a solution obtained by heating and dissolving in an aqueous solution of a basic organic acid to cooling crystallization and then filtering to the production method of the present invention. ) -Propane hydrochloride can be prepared.
　工程（Ａ）で得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）は、所望であれば、さらに下記の工程（Ｂ）および/または（Ｃ）に供して、含有する強酸性の無機酸塩または強酸性の有機酸の含有量を調整してもよい。 If desired, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) obtained in step (A) can be further prepared by the following steps (B) and / or ( You may use for C) and may adjust content of the strongly acidic inorganic acid salt or strong acid organic acid to contain.
　工程（Ｂ）を説明する。
　工程（Ｂ）では、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を弱酸性の無機塩水溶液で洗浄する。 Step (B) will be described.
In step (B), 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is washed with a weakly acidic aqueous inorganic salt solution.
　弱酸性の無機塩としては、例えば、塩化アンモニウム、リン酸２水素ナトリウム、リン酸２水素カリウムが挙げられ、好ましくは塩化アンモニウムが挙げられる。
　弱酸性の無機塩水溶液は、弱酸性の無機塩と水とを混合することにより調製することができ、塩化アンモニウム水溶液が挙げられる。
　弱酸性の無機塩水溶液の濃度は、水溶液の重量に対し、通常０．５～３０重量％の範囲であり、好ましくは１～２０重量％の範囲である。
　洗浄に用いる弱酸性の無機塩水溶液の温度は、通常０～３０℃の範囲であり、好ましくは０～１０℃の範囲である。
　洗浄に用いる弱酸性の無機塩水溶液の使用量は、湿結晶の重量に対し、通常５～６０重量％の範囲であり、好ましくは１０～３０重量％の範囲である。 Examples of the weakly acidic inorganic salt include ammonium chloride, sodium dihydrogen phosphate, and potassium dihydrogen phosphate, and preferably ammonium chloride.
The weakly acidic inorganic salt aqueous solution can be prepared by mixing a weakly acidic inorganic salt and water, and examples thereof include an ammonium chloride aqueous solution.
The concentration of the weakly acidic inorganic salt aqueous solution is usually in the range of 0.5 to 30% by weight, preferably in the range of 1 to 20% by weight, based on the weight of the aqueous solution.
The temperature of the weakly acidic inorganic salt aqueous solution used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
The amount of the weakly acidic inorganic salt aqueous solution used for washing is usually in the range of 5 to 60% by weight, preferably in the range of 10 to 30% by weight, based on the weight of the wet crystals.
　工程（Ｃ）を説明する。
　工程（Ｃ）では、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を低級アルコールで洗浄する。
　工程（Ｃ）では、工程（Ａ）または工程（Ｂ）の処理で得られた生成物に適用するのが好ましく、工程（Ａ）の処理で得られた生成物に適用するのがより好ましい。 Step (C) will be described.
In step (C), 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride is washed with a lower alcohol.
In the step (C), it is preferably applied to the product obtained by the treatment of the step (A) or the step (B), more preferably applied to the product obtained by the treatment of the step (A).
　低級アルコールとは、炭素数１乃至３のアルコールを意味し、例えば、メタノール、エタノール、イソプロピルアルコールが挙げられ、メタノールが好ましい。
　洗浄に用いる低級アルコールの温度は、通常０～３０℃の範囲であり、好ましくは０～１０℃の範囲である。
　洗浄に用いる低級アルコールの使用量は、湿結晶の重量に対し、通常５～６０重量％の範囲であり、好ましくは１０～３０重量％の範囲である。 The lower alcohol means an alcohol having 1 to 3 carbon atoms, and examples thereof include methanol, ethanol, and isopropyl alcohol, and methanol is preferable.
The temperature of the lower alcohol used for washing is usually in the range of 0 to 30 ° C, preferably in the range of 0 to 10 ° C.
The amount of the lower alcohol used for washing is usually in the range of 5 to 60% by weight, preferably in the range of 10 to 30% by weight, based on the weight of the wet crystals.
　工程（Ａ）、工程（Ｂ）または工程（Ｃ）のうちの最後の工程の後、乾燥工程を経ることにより、目的の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を得ることができる。 After the final step of step (A), step (B) or step (C), the desired 1,3-dicarbamoylthio-2- (N, N-dimethylamino) is obtained by passing through a drying step. Propane hydrochloride (I) can be obtained.
　本発明の製造方法の全ての操作は室温で行うことができる。ただし洗浄液への目的生成物の減少分を抑制するため、冷却した洗浄液を用いて洗浄するのが好ましい。 All operations of the production method of the present invention can be performed at room temperature. However, in order to suppress the decrease of the target product in the cleaning liquid, it is preferable to perform cleaning using a cooled cleaning liquid.
　本発明の工程（Ａ）は、含量が低下した、および／または品質が低下した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を含む組成物にも有効であり、含量が低下した、および／または品質が低下した式（Ｉ）の塩を本発明の製造方法に付すことにより、安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を製造することもできる。含量が低下した、および／または品質が低下した式（Ｉ）の塩は、水、塩酸等でスラリーにした後、濾過し、及び更に、水、塩酸等中に加熱溶解後、冷却晶析した後濾過して得られるものを、工程（Ａ）に供してもよい。 Step (A) of the present invention comprises a composition comprising 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) having reduced content and / or reduced quality By applying the salt of formula (I) having a reduced content and / or reduced quality to the production method of the present invention, a stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) can also be prepared. The salt of formula (I) having a reduced content and / or a reduced quality was slurried with water, hydrochloric acid, etc., filtered, and further heated and dissolved in water, hydrochloric acid, etc., and then cooled and crystallized. What is obtained by post-filtration may be subjected to step (A).
（酸付加物としての化合物（Ｉ））
　本発明の製造方法により製造される１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物に含有される、強酸性の無機酸塩または強酸性の有機酸の量は、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物の重量に対して、通常０．０５～１０重量％の範囲であり、好ましくは０．１～２重量％の範囲であり、より好ましくは０．１～１．５重量％の範囲であり、より一層好ましくは０．１～１．１重量％の範囲である。また、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩付加物の水溶液のｐＨは、４．５以下であって、通常３．０以上～４．５以下であり、好ましくは３．０以上～４．２以下であり、より好ましくは３．３以上～４．０以下、さらにより好ましくは、３．７以下であり、更に一層より好ましくは、３．３以上３．７以下である。ここで、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）のｐＨとは、当該乾燥塩酸塩１ｇを１００ｍｌの水に溶解させた溶液（以下、「１％水溶液」と記す。）を調製し、この水溶液のｐＨを測定したものである。１％水溶液におけるｐＨは、通常、３．０～４．５であるが、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）が分解するとアンモニアが副生し、ｐＨが上昇する傾向があるので、ｐＨ値は、含量低下とともに、分解存否判断の重要な指標である。ｐＨが４．５（特に、３．７）より大きい場合は好ましくない。 (Compound (I) as an acid adduct)
It is contained in the strong acid inorganic acid salt or strong acid organic acid adduct of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride produced by the production method of the present invention. The amount of the strongly acidic inorganic acid salt or the strongly acidic organic acid is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strongly acidic acid. Is usually in the range of 0.05 to 10% by weight, preferably in the range of 0.1 to 2% by weight, more preferably in the range of 0.1 to 1.5% by weight, based on the weight of the organic acid adduct. %, More preferably in the range of 0.1 to 1.1% by weight. The pH of the aqueous solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride adduct is not more than 4.5, and usually not less than 3.0 and not more than 4.5 It is preferably 3.0 or more and 4.2 or less, more preferably 3.3 or more and 4.0 or less, still more preferably 3.7 or less, and still more preferably 3. 3 or more and 3.7 or less. Here, the pH of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is a solution in which 1 g of the dry hydrochloride is dissolved in 100 ml of water (hereinafter referred to as “pH”). "1% aqueous solution") was prepared, and the pH of this aqueous solution was measured. The pH in a 1% aqueous solution is usually 3.0 to 4.5, but when 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is decomposed, ammonia is dissolved. As a by-product and the pH tends to increase, the pH value is an important indicator for determining the presence or absence of decomposition as the content decreases. It is not preferred if the pH is greater than 4.5 (especially 3.7).
　本発明の製造方法により製造された安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）は、従来の方法により得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）と比較して、高純度かつ、安定性（例えば、熱安定性）が向上しているため、長期間の保管が可能である。 The stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the production method of the present invention is obtained by using 1,3-dicarbamoyl obtained by the conventional method. Compared with thio-2- (N, N-dimethylamino) -propane hydrochloride (I), high purity and improved stability (eg thermal stability) enable long-term storage It is.
　製造された１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）は特許文献３および特許文献４に記載のように、強力な殺虫作用を有し、農業用殺虫組成物として用いることができる。 The produced 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) has a strong insecticidal action as described in Patent Document 3 and Patent Document 4, It can be used as an agricultural insecticidal composition.
以下、実施例（比較例を含む）を挙げて、本発明をさらに詳しく説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example (a comparative example is included) is given and this invention is demonstrated in more detail, this invention is not limited to these Examples.
　１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の含量分析は、ヨウ素滴定法により実施した。 The content analysis of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) was performed by an iodometric titration method.
　１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の該無機酸塩または有機酸の付加物に含有される、無機酸塩（例えば、NH4 ＋とSO4 2‐などのイオン）または有機酸（例えば、シュウ酸）の含有量は、高速イオンクロマトグラフ（HIC）を用いた絶対検量線法により求められるイオンの分析結果から下記のようにして算出することができる。有機酸がクエン酸である場合には、UV波長検出による液体クロマトグラフ（LC）を用いた絶対検量線法により求めることができる。 Inorganic acid salt (for example, NH 4 + contained in the inorganic acid salt or organic acid adduct of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) And SO 4 2− ions) or organic acid (eg oxalic acid) content is as follows from the analysis results of ions determined by the absolute calibration curve method using high-speed ion chromatograph (HIC) Can be calculated. When the organic acid is citric acid, it can be determined by an absolute calibration curve method using a liquid chromatograph (LC) with UV wavelength detection.
１）硫酸イオン（SO4 2‐）の分析方法
高速イオンクロマトグラフ（HIC）法
本体：　DX-120　Ion Chromatograph
　検出器：　電気伝導度検出器
　サプレッサー：　ASRS-ULTRA　4 mm
　　　　　　　　　P/N=061561
　カラム：　IonPac　AS4A‐SC（4×250 mm）
　　　　　　P/N=43174
　ガードカラム：　IonPac　AG14A（4×50 mm）
　　　　　　　　　P/N=46134
　溶離液：　1.8 mmol/L-Na2CO3
　　　　　　1.7 mmon/L-NaHCO3 の混合液
　サンプル注入量：　25 μL
　カラム温度：　35 ℃
　自動再生抑制器（Self Regeneration Suppressor（SRS））電流値：　50 mA
　流量：　1.0 mL/min
　圧：　1500 PSI程度 1) Analysis method of sulfate ion (SO 4 2- ) High-speed ion chromatograph (HIC) method body: DX-120 Ion Chromatograph
Detector: Electrical conductivity detector Suppressor: ASRS-ULTRA 4 mm
P / N = 061561
Column: IonPac AS4A-SC (4 x 250 mm)
P / N = 43174
Guard column: IonPac AG14A (4 x 50 mm)
P / N = 46134
Eluent: 1.8 mmol / L-Na 2 CO 3
1.7 mmon / L-NaHCO 3 mixture Sample injection volume: 25 μL
Column temperature: 35 ° C
Automatic regeneration suppressor (SRS) current value: 50 mA
Flow rate: 1.0 mL / min
Pressure: about 1500 PSI
２）アンモニウムイオン（NH4 ＋）及びナトリウムイオン（Na＋）イオンの分析方法
本体：　ICS-1000（日本ダイオネネクス）Ion Chromatograph
　検出器：　電気伝導度検出器
　カラム：　CG16/CS16（日本ダイオネネクス）
　溶離液：30 mmol　メタンスルホン酸
　サンプル注入量：　25μL 2) Ammonium ion (NH 4 + ) and sodium ion (Na + ) ion analysis methods Main body: ICS-1000 (Nippon Dionex) Ion Chromatograph
Detector: Electrical conductivity detector Column: CG16 / CS16 (Nippon Dionex)
Eluent: 30 mmol Methanesulfonic acid Sample injection volume: 25 μL
　硫酸水素ナトリウム塩の含有量は、硫酸イオン（SO4 2‐）の分析値およびナトリウムイオン（Na＋）の分析値から以下の計算式により求めた。
NaHSO4とNaCl含量の求め方
　NaHSO4 (wt%) = SO4 2- (%) ／96.07 × 120.06
　NaCl (wt%) = (Na+ (%) ／22.99 － SO4 2- (%) ／96.07) × 58.44
　式中、記号は以下の意味を表す。
　SO4 2- (%)：　イオンクロマトグラフでのSO4 2- の分析結果
　Na+ (%)：　イオンクロマトグラフでのNa+ の分析結果
　カリウムの場合は、Na+の代わりに、イオンクロマトグラフでのK+を分析した。 The content of sodium hydrogen sulfate was determined from the analytical value of sulfate ion (SO 4 2− ) and the analytical value of sodium ion (Na + ) by the following calculation formula.
NaHSO 4 and Determination NaHSO 4 (wt%) of NaCl content = SO 4 2- (%) /96.07 × 120.06
NaCl (wt%) = (Na + (%) /22.99-SO 4 2- (%) /96.07) x 58.44
In the formula, symbols represent the following meanings.
SO 4 2- (%): ion chromatography SO 4 2-analysis results of the graph Na + (%): For analysis potassium Na + in ion chromatography, in place of Na +, the ion chromatograph K + was analyzed.
NH4HSO4とNH4Cl含量の求め方
　NH4HSO4 (wt%) = SO4 2- (%) ／96.07 × 115.11
　NH4Cl (wt%) = (NH4 + (%) ／18.04 － SO4 2- (%) ／96.07) × 53.49
　式中、記号は以下の意味を表す。
　SO4 2- (%)：　イオンクロマトグラフでのSO4 2- の分析結果
　NH4 + (%)：　イオンクロマトグラフでのNH4 + の分析結果 Determination of NH 4 HSO 4 and NH 4 Cl content NH 4 HSO 4 (wt%) = SO 4 2- (%) /96.07 × 115.11
NH 4 Cl (wt%) = (NH 4 + (%) /18.04-SO 4 2- (%) /96.07) × 53.49
In the formula, symbols represent the following meanings.
SO 4 2- (%): SO 4 2- analytical results NH 4 + (%) of the ion chromatograph: NH 4 + analysis of the ion chromatography
３）シュウ酸とクエン酸の分析法
３－１）シュウ酸の分析条件
　イオンクロマトグラフ法（HIC）によるSO4 2-分析条件と同じ。
　シュウ酸検出保持時間（RT）＝15.2分程度 3) Analytical method for oxalic acid and citric acid 3-1) Analytical conditions for oxalic acid Same as SO 4 2- analytical conditions by ion chromatography (HIC).
Oxalic acid detection retention time (RT) = about 15.2 minutes
３－２）液体クロマトグラフ（LC）による、クエン酸の分析条件は、以下の通り。
　LC-20A相当品を使用
　LCカラム：Mightysil RP-8GP（5μm×4.6mm×250mm）
　流量：1.0　mL/min
　検出器：UV波長210 nm
　温度：40 ℃
　注入量：2 μL
　移動相（3L）：アセトニトリル／水＝350 mL／2650 mL
　　　　　　　　1-ペンタンスルホン酸ナトリウム2.64 g／3 L
　　　　　　　　40％リン酸 0.80g／3L　（pH=3.0に調整）
　定量法：絶対検量線法（3点）
　クエン酸検出保持時間（RT）＝5.9分程度 3-2) Analytical conditions for citric acid by liquid chromatography (LC) are as follows.
Use LC-20A equivalent LC column: Mightysil RP-8GP (5μm × 4.6mm × 250mm)
Flow rate: 1.0 mL / min
Detector: UV wavelength 210 nm
Temperature: 40 ° C
Injection volume: 2 μL
Mobile phase (3 L): acetonitrile / water = 350 mL / 2650 mL
Sodium 1-pentanesulfonate 2.64 g / 3 L
40% phosphoric acid 0.80g / 3L (adjusted to pH = 3.0)
Quantitative method: Absolute calibration curve method (3 points)
Citric acid detection retention time (RT) = about 5.9 minutes
　以下の実施例においては、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）のｐＨとは、当該乾燥塩酸塩の１％水溶液を調製し、この水溶液のｐＨを測定したものである。 In the following examples, the pH of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is a 1% aqueous solution of the dry hydrochloride. The pH of the aqueous solution is measured.
　実施例において、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の安定性試験は５５℃及び６０℃の恒温槽で実施した。 In the examples, the stability test of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) was carried out in a constant temperature bath at 55 ° C. and 60 ° C.
実施例１
　２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（II）２９．６ｇ（０．１４７mol）の１，２－ジクロロエタン溶液１３８．０ｇ（化合物IIの濃度として、２１．４％）に、メタノール５３．３ｇを加え、０～５℃に冷却下、６時間かけて、５５ｇ（１．４９６mol）の塩化水素ガスを吹き込んだ。この後、０～５℃で１２時間撹拌した。反応液を内温６５℃まで、徐々に加温していき、塩化水素ガス、メタノールを留去後、水５５ｇを加えた。内温７５℃まで加温し、１，２－ジクロロエタンを水との共沸で留去した。１，２－ジクロロエタンを留去後、５℃以下まで徐冷し、析出した結晶をろ過し、別途調製した１０％NH4HSO4水溶液１２．４ｇで洗浄した後、メタノール６．２ｇで洗浄した。減圧下、６０℃で２時間乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３４．６g（純度９７．８％、収率８３．８％)を得た。外観は白色結晶であり、１％水溶液のｐＨは３．３０であった。
　生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4の含有量が０．６１％、NH4Clの含有量が０％であった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　３．４６、６週目　３．４６、９週目　３．６３、１２週目　４．３１
６０℃加速経過後の含量測定結果：
　３週目　９７．１％、６週目　９８．０％、９週目　９８．１％、１２週目　９７．９％
６０℃加速経過後の外観観察結果：
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目　アンモニア臭気なく、粉末状で固着の無い状態。
　９週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目までｐＨは４．５以下で、生成物の含量低下、外観の変化も見られなかった。 Example 1
138.0 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (as the concentration of Compound II) 21.4%), 53.3 g of methanol was added, and 55 g (1.496 mol) of hydrogen chloride gas was blown in over 6 hours while cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added. The internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. After 1,2-dichloroethane was distilled off, the mixture was gradually cooled to 5 ° C. or less, and the precipitated crystals were filtered, washed with 12.4 g of a 10% NH 4 HSO 4 aqueous solution prepared separately, and then washed with 6.2 g of methanol. . After drying under reduced pressure at 60 ° C. for 2 hours, 34.6 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 97.8%, yield 83) 8%). The appearance was white crystals, and the pH of the 1% aqueous solution was 3.30.
Measurements of the ion chromatographic analysis of the product, NH 4 content of HSO 4 0.61% and the content of NH 4 Cl was 0%.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 3.46, 6th week 3.46, 9th week 3.63, 12th week 4.31
Content measurement results after 60 ° C acceleration:
Week 37.1%, Week 6 98.0%, Week 9 98.1%, Week 12 97.9%
Appearance observation results after 60 ° C acceleration:
3rd week No ammonia odor, no powder and no sticking.
6th week Ammonia odor, powder and no sticking.
9th week No odor of ammonia, no powder and no sticking.
12th week No odor of ammonia, no powder and no sticking.
Until the 12th week, the pH was 4.5 or less, and the content of the product was not decreased and the appearance was not changed.
実施例２
　２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（II）２９．６ｇ（０．１４７mol）の１，２－ジクロロエタン溶液１３７．６ｇ（化合物（II）の濃度として、２１．５％）に、メタノール５３．３ｇを加え、０～５℃に冷却下、７時間かけて、４７ｇ（１．３５８mol）の塩化水素ガスを吹き込んだ。この後、０～５℃で１２時間撹拌した。反応液を内温６５℃まで、徐々に加温していき、塩化水素ガス、メタノールを留去後、水５５ｇを加えた。内温７５℃まで加温し、１，２－ジクロロエタンを水との共沸で留去した。１，２－ジクロロエタンを留去後、５℃以下まで徐冷し、析出した結晶をろ過し、別途調製した１０．７％NH4HSO4と５．０％NH4Clの混合物水溶液１２．４ｇで洗浄した後、メタノール８．０ｇで洗浄した。ここで、１０．７％NH4HSO4と５．０％NH4Clの混合物水溶液は、（NH4）2SO4 ５gを水３０．７ｇで溶解した後、３５％塩酸３．８ｇを加えて調製し、洗浄用として、当該混合物水溶液を１２．４ｇ使用した。減圧下、６０℃で２時間乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３５．９g（純度９７．５％、収率８６．４％)を得た。外観は白色結晶であり、１％水溶液のｐＨは３．０１であった。
　生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4が１．１２％、NH4Clが０．２８％含有されていることが分かった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　３．４１、６週目　３．２８、９週目　３．３４、１２週目　４．０７
６０℃加速経過後の含量測定結果：
　３週目　９７．１％、６週目　９８．０％、９週目　９８．１％、１２週目　９７．５％
６０℃加速経過後の外観観察結果：
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目　アンモニア臭気なく、粉末状で固着の無い状態。
　９週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目までｐＨは４．１以下で、生成物の含量低下、外観の変化も見られなかった。 Example 2
137.6 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (concentration of compound (II)) In addition, 53.3 g of methanol was added to 21.5%, and 47 g (1.358 mol) of hydrogen chloride gas was blown in over 7 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added. The internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. After distilling off the 1,2-dichloroethane, 5 ° C. was gradually cooled to below, and the precipitated crystals were filtered separately and 10.7% NH 4 HSO 4, prepared 5.0% NH 4 aqueous mixture 12.4g of Cl And then with 8.0 g of methanol. Here, a mixed aqueous solution of 10.7% NH 4 HSO 4 and 5.0% NH 4 Cl was prepared by dissolving 5 g of (NH 4 ) 2 SO 4 with 30.7 g of water and then adding 3.8 g of 35% hydrochloric acid. 12.4 g of the mixture aqueous solution was used for washing. It was dried at 60 ° C. under reduced pressure for 2 hours, and 35.9 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 97.5%, yield 86) .4%). The appearance was white crystals, and the pH of the 1% aqueous solution was 3.01.
As a result of measurement by ion chromatography analysis of the product, it was found that NH 4 HSO 4 contained 1.12% and NH 4 Cl 0.28%.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 3.41, 6th week 3.28, 9th week 3.34, 12th week 4.07
Content measurement results after 60 ° C acceleration:
3rd week 97.1%, 6th week 98.0%, 9th week 98.1%, 12th week 97.5%
Appearance observation results after 60 ° C acceleration:
3rd week No ammonia odor, no powder and no sticking.
6th week Ammonia odor, powder and no sticking.
9th week No odor of ammonia, no powder and no sticking.
12th week No odor of ammonia, no powder and no sticking.
Until the 12th week, the pH was 4.1 or less, and neither the content of the product decreased nor the appearance was changed.
実施例３
　２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（II）２９．６ｇ（０．１４７mol）の１，２－ジクロロエタン溶液１３７．６ｇ（化合物（II）の濃度として、２１．５％）に、メタノール５３．３ｇを加え、０～５℃に冷却下、７時間かけて、４７ｇ（１．３５８mol）の塩化水素ガスを吹き込んだ。この後、０～５℃で１２時間撹拌した。反応液を内温６５℃まで、徐々に加温していき、塩化水素ガス、メタノールを留去後、水４６ｇを加えた。内温７５℃まで加温し、１，２－ジクロロエタンを水との共沸で留去した。１，２－ジクロロエタンを留去後、５℃以下まで徐冷し、析出した結晶をろ過し、別途調製した５．２％NH4HSO4と２．４％NH4Clの混合物水溶液８．９ｇで洗浄した後、メタノール１２．４ｇで洗浄した。５．２％NH4HSO4と２．４％NH4Clの混合物水溶液は、（NH4）2SO4 ４．５gを水７３．１ｇで溶解した後、３５％塩酸３．８ｇを加えて調製し、洗浄用として、当該混合物水溶液を８．９ｇ使用した。減圧下、６０℃で２時間乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３５．２g（純度９８．９％、収率８７．２％)を得た。外観は白色結晶であり、１％水溶液のｐＨは３．８８であった。
　生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4が０．１１％、NH4Clが０．０７％含有されていることが分かった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　４．２３、６週目　４．１０、９週目　４．１３、１２週目　４．２１
６０℃加速経過後の含量測定結果：
　３週目 ９７．９％、６週目 ９８．５％、９週目 ９９．０％、１２週目 ９９．０％
６０℃加速経過後の外観観察結果：
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目　アンモニア臭気なく、粉末状で固着の無い状態。
　９週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目　アンモニア臭気なく、粉末状で固着の無い状態。
　１２週目までｐＨは４．３以下で、生成物の含量低下、外観の変化も見られなかった。 Example 3
137.6 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) (concentration of compound (II)) In addition, 53.3 g of methanol was added to 21.5%, and 47 g (1.358 mol) of hydrogen chloride gas was blown in over 7 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 46 g of water was added. The internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. 1,2-Dichloroethane was distilled off, and the mixture was gradually cooled to 5 ° C. or lower. The precipitated crystals were filtered, and 8.9 g of a mixed aqueous solution of 5.2% NH 4 HSO 4 and 2.4% NH 4 Cl separately prepared. After washing with 12.4 g of methanol. A mixed aqueous solution of 5.2% NH 4 HSO 4 and 2.4% NH 4 Cl was prepared by dissolving 4.5 g of (NH 4 ) 2 SO 4 with 73.1 g of water, and then adding 3.8 g of 35% hydrochloric acid. 8.9 g of the aqueous mixture was used for preparation and washing. After drying at 60 ° C. under reduced pressure for 2 hours, 35.2 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.9%, yield 87) .2%). The appearance was white crystals, and the pH of the 1% aqueous solution was 3.88.
As a result of measurement by ion chromatography analysis of the product, it was found that NH 4 HSO 4 was 0.11% and NH 4 Cl was 0.07%.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 4.23, 6th week 4.10, 9th week 4.13, 12th week 4.21
Content measurement results after 60 ° C acceleration:
97.9% at 3rd week, 98.5% at 6th week, 99.0% at 9th week, 99.0% at 12th week
Appearance observation results after 60 ° C acceleration:
3rd week No ammonia odor, no powder and no sticking.
6th week Ammonia odor, powder and no sticking.
9th week No odor of ammonia, no powder and no sticking.
12th week No odor of ammonia, no powder and no sticking.
Until the 12th week, the pH was 4.3 or less, and no decrease in product content or change in appearance was observed.
実施例４ 
　実施例１と同様の反応と処理を行い、ろ過を行う前の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）のスラリー液５４２．２６ｇを５℃付近まで冷却した後、卓上小型遠心分離機で遠心分離した。得られた湿結晶を（NH4）2SO4と３６％塩酸から調製した１０．７％NH4HSO4と５．０％NH4Clの混合物水溶液３７．２８ｇで洗浄した後、メタノール８４．００ｇで洗浄した。
　得られた湿結晶２２６．７４ｇを７５℃で２時間減圧下で乾燥し、乾燥品として１６８．１１ｇ（純度９７．５％）を得た。外観は白色結晶であり、１％水溶液のｐＨは３．５１であった。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4が０．３５％、NH4Clが０．１９％含有されていることが分かった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　３．５９、６週目　３．８１
６０℃加速経過後の含量測定結果：
　３週目　９７．５％、６週目　９７．７％
６０℃加速経過後の外観観察結果：
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目までｐＨは４．０以下で、生成物の含量低下、外観の変化も見られなかった。 Example 4
The same reaction and treatment as in Example 1 were carried out, and 542.26 g of a slurry solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) 5 After cooling to around 0 ° C., it was centrifuged with a desktop small centrifuge. The obtained wet crystals were washed with 37.28 g of a mixed aqueous solution of 10.7% NH 4 HSO 4 and 5.0% NH 4 Cl prepared from (NH 4 ) 2 SO 4 and 36% hydrochloric acid, and then methanol 84. Washed with 00 g.
The obtained wet crystals (226.74 g) were dried under reduced pressure at 75 ° C. for 2 hours to obtain 168.11 g (purity 97.5%) as a dried product. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.51. As a result of measurement by ion chromatography analysis of the product, it was found that NH 4 HSO 4 contained 0.35% and NH 4 Cl contained 0.19%.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 3.59, 6th week 3.81
Content measurement results after 60 ° C acceleration:
97.5% at 3 weeks, 97.7% at 6 weeks
Appearance observation results after 60 ° C acceleration:
3rd week No ammonia odor, no powder and no sticking.
6th week Ammonia odor, powder and no sticking.
Until the 6th week, the pH was 4.0 or less, and no decrease in product content or change in appearance was observed.
実施例５
　実施例１と同様の反応と処理を行い、ろ過を行う前の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）のスラリー液５３２．６８ｇを５℃付近まで冷却した後、卓上小型遠心分離機で遠心分離した。得られた湿結晶を（NH4）2SO4と３６％塩酸から調製した１０．７％NH4HSO4と５．０％NH4Clの混合物水溶液５１．３１ｇで洗浄した後、２０％NH4Cl ６９．３２ｇで洗浄した。
　得られた湿結晶２８９．６７ｇを７５℃で２時間減圧下で乾燥し、乾燥品として１８３．１３ｇ（純度９２．０％）を得た。外観は白色結晶であり、１％水溶液のｐＨは３．１１であった。安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　３．２８、６週目　３．８４
６０℃加速経過後の含量測定結果：
　３週目　９３．１％、６週目　９３．５％
６０℃加速経過後の外観観察結果：
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目　アンモニア臭気なく、粉末状で固着の無い状態。
　６週目までｐＨは４．０以下で、生成物の含量低下、外観の変化も見られなかった。 Example 5
The same reaction and treatment as in Example 1 were carried out, and 532.66 g of a slurry solution of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) before filtration was added to 5 After cooling to around 0 ° C., it was centrifuged with a desktop small centrifuge. The obtained wet crystals were washed with 51.31 g of a mixed solution of 10.7% NH 4 HSO 4 and 5.0% NH 4 Cl prepared from (NH 4 ) 2 SO 4 and 36% hydrochloric acid, and then 20% NH. Washed with 69.32 g of 4 Cl.
289.67 g of the obtained wet crystal was dried under reduced pressure at 75 ° C. for 2 hours to obtain 183.13 g (purity 92.0%) as a dried product. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.11. In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 3.28, 6th week 3.84
Content measurement results after 60 ° C acceleration:
Week 33.1%, Week 6 93.5%
Appearance observation results after 60 ° C acceleration:
3rd week No ammonia odor, no powder and no sticking.
6th week Ammonia odor, powder and no sticking.
Until the 6th week, the pH was 4.0 or less, and no decrease in product content or change in appearance was observed.
実施例６
　品質が低下した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）４０ｇ（０．１４６mol）（含量：９５．８％、ｐＨ ５．２０）を、１１．５％希塩酸（水２８．０ｇに濃塩酸１３．１ｇを加えたもの）にスラリー化した後、５℃以下で冷却し、１時間撹拌後、析出した結晶をろ過し、メタノール７．５gで洗浄した後、７．１％NH4HSO4と３．３％NH4Clの混合物水溶液９．４ｇで洗浄した。ここで、７．１％NH4HSO4と２．４％NH4Clの混合物水溶液は、（NH4）2SO4 ０．７９gを水７８．０ｇで溶解した後、３５％塩酸０．６１ｇを加えて調製した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３７．８ｇ（純度９９．２％、回収率９４．４％)を得た。外観は白色結晶であり、１％水溶液のｐＨは３．３８であった。
　生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4が０．９２％、NH4Clが０．４７％含有されていることが分かった。
６０℃加速経過後のｐＨ測定結果：
　２週目　３．５０、３週目　３．５６、５週目　３．６７
６０℃加速経過後の含量測定結果：
　２週目　９８．９％、３週目　９８．７％、５週目　９８．５％
６０℃加速経過後の外観観察結果：
　２週目　アンモニア臭気なく、粉末状で固着の無い状態。
　３週目　アンモニア臭気なく、粉末状で固着の無い状態。
　５週目まで、ｐＨは４．０以下で、生成物の含量低下、外観の変化も見られなかった。 Example 6
40 g (0.146 mol) of reduced 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (content: 95.8%, pH 5.20) After slurrying in 11.5% dilute hydrochloric acid (18.0 g of concentrated hydrochloric acid added to 28.0 g of water), the mixture was cooled to 5 ° C. or lower and stirred for 1 hour. Then, the mixture was washed with 9.4 g of a mixed aqueous solution of 7.1% NH 4 HSO 4 and 3.3% NH 4 Cl. Here, a mixed aqueous solution of 7.1% NH 4 HSO 4 and 2.4% NH 4 Cl was prepared by dissolving 0.79 g of (NH 4 ) 2 SO 4 with 78.0 g of water, and then adding 0.61 g of 35% hydrochloric acid. Was prepared. It was dried under reduced pressure at 60 ° C. for 2 hours, and 37.8 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 99.2%, recovery rate 94) .4%). The appearance was white crystals, and the pH of the 1% aqueous solution was 3.38.
Measurements of the ion chromatographic analysis of the product, NH 4 HSO 4 is 0.92%, NH 4 Cl was found to be contained 0.47%.
Results of pH measurement after 60 ° C acceleration:
2nd week 3.50, 3rd week 3.56, 5th week 3.67
Content measurement results after 60 ° C acceleration:
2nd week 98.9% 3rd week 98.7% 5th week 98.5%
Appearance observation results after 60 ° C acceleration:
2nd week No ammonia odor, no powder and no sticking.
3rd week No ammonia odor, no powder and no sticking.
Until the 5th week, the pH was 4.0 or less, and no decrease in product content or change in appearance was observed.
実施例７
　実施例１と同様の反応と処理を行い、濾過により取得した未洗浄の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶４５．０ｇ（含量：８４．１％、０．１３８mol）を、１１．５％希塩酸（水２８．０ｇに濃塩酸１３．１ｇを加えたもの）にスラリー化した後、５℃以下で冷却して１時間撹拌後、析出した結晶をろ過し、５．０％シュウ酸水溶液（シュウ酸０．６８ｇを水１２．９４ｇに溶解）１３．６２ｇで洗浄した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３３．９７ｇ（純度９７．６％、回収率８７．６％）を得た。生成物のイオンクロマトグラフ分析での測定結果、シュウ酸が０．２４％含有されていることが分かった。外観は白色結晶であり、１％水溶液のｐＨは３．１８であった。
５５℃加速経過後のｐＨ測定結果：
　２週目　３．２５、２週目　３．３８、６週目　３．５３、８週目　４．０２
５５℃加速経過後の含量測定結果：
　８週目　９７．３％
５５℃加速経過後の外観観察結果：
　８週目まで、ｐＨは４．０以下で、アンモニア臭気なく、粉末状で固着の無い状態。含量残存率は９９．７％で、不純物の増加や外観の変化も見られなかった。 Example 7
45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% oxalic acid aqueous solution (0.68 g of oxalic acid dissolved in 12.94 g of water). After drying under reduced pressure at 60 ° C. for 2 hours, 33.97 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 97.6%, recovery rate 87) .6%). As a result of measurement by ion chromatography analysis of the product, it was found that 0.24% of oxalic acid was contained. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.18.
Results of pH measurement after 55 ° C acceleration:
2nd week 3.25, 2nd week 3.38, 6th week 3.53, 8th week 4.02
Content measurement results after 55 ° C acceleration:
Week 8 97.3%
Appearance observation results after 55 ° C acceleration:
Up to the 8th week, pH is 4.0 or less, no ammonia odor, powder and no sticking. The residual content rate was 99.7%, and neither an increase in impurities nor a change in appearance was observed.
実施例８
　実施例１と同様の反応と処理を行い、濾過により取得した未洗浄の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶４５．０ｇ（含量：８４．１％、０．１３８mol）を、１１．５％希塩酸（水２８．０ｇに濃塩酸１３．１ｇを加えたもの）にスラリー化した後、５℃以下で冷却して１時間撹拌後、析出した結晶をろ過し、５．０％クエン酸水溶液（クエン酸０．６８ｇを水１２．９４ｇに溶解）１３．６２ｇで洗浄した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３５．２４ｇ（純度９８．２％、回収率９１．４％）を得た。生成物の分析の測定結果、クエン酸が０．３２％含有されていることが分かった。外観は白色結晶であり、１％水溶液のｐＨは３．５０であった。
５５℃加速経過後のｐＨ測定結果：
　２週目　３．５１、２週目　３．６１、６週目　３．６６、８週目　３．８０
５５℃加速経過後の含量測定結果：
　８週目　９８．１％
５５℃加速経過後の外観観察結果：
　８週目まで、ｐＨは４．０以下で、アンモニア臭気なく、粉末状で固着の無い状態。不純物の増加や外観の変化も見られなかった。 Example 8
45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 13.62 g of a 5.0% aqueous citric acid solution (0.68 g of citric acid dissolved in 12.94 g of water). After drying under reduced pressure at 60 ° C. for 2 hours, 35.24 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.2%, recovery rate 91 4%). As a result of measurement of analysis of the product, it was found that 0.32% of citric acid was contained. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.50.
Results of pH measurement after 55 ° C acceleration:
2nd week 3.51, 2nd week 3.61, 6th week 3.66, 8th week 3.80
Content measurement results after 55 ° C acceleration:
Week 8: 98.1%
Appearance observation results after 55 ° C acceleration:
Up to the 8th week, pH is 4.0 or less, no ammonia odor, powder and no sticking. There was no increase in impurities or change in appearance.
実施例９
　品質が低下した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３０ｇ（０．１０２mol）（含量：９３．１％、ｐＨ ５．００）を、２．０％希塩酸（水３３．０ｇに濃塩酸１．９ｇを加えたもの）にスラリー化した後、７０℃に加温し、完全に溶解させた。同温度で３６％塩酸９．０ｇを加えた後、５５℃まで冷却し、メタノール１２．０を加えた。１０℃以下まで、徐冷し、１時間撹拌後、析出した結晶をろ過し、７．５ｇのメタノールで洗浄後、３．０％NH4HSO4水／メタノール混合溶液で洗浄した。ここで、３．０％NH4HSO4水／メタノール混合溶液はNH4HSO4 ０．３０gを水５．１ｇで溶解した後、メタノール４．５０ｇを加えて調製した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）２５．３ｇ（純度９８．６％、回収率９０．７％)を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4が０．５４％、NH4Clの含有量が０％であることが分かった。外観は白色結晶であり、１％水溶液のｐＨは３．３３であった。
６０℃加速経過後のｐＨ測定結果：
　２週目 ３．３８、３週目 ３．３７、５週目 ３．２８、７週目 ３．４６、
　１０週目 ３．６０
６０℃加速経過後の外観観察結果：
　１０週目までｐＨは３．６以下で、アンモニア臭気なく、粉末状で固着の無い状態。比較例６と比べ、ｐＨ上昇はなく、安定性が向上していた。１０週目の含量残存率は９９．５%であった。 Example 9
30 g (0.102 mol) (content: 93.1%, pH 5.00) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality After slurrying in 2.0% dilute hydrochloric acid (33.0 g of water plus 1.9 g of concentrated hydrochloric acid), the mixture was heated to 70 ° C. and completely dissolved. After adding 9.0 g of 36% hydrochloric acid at the same temperature, the mixture was cooled to 55 ° C. and methanol 12.0 was added. After gradually cooling to 10 ° C. or lower and stirring for 1 hour, the precipitated crystals were filtered, washed with 7.5 g of methanol, and then washed with a 3.0% NH 4 HSO 4 water / methanol mixed solution. Here, a 3.0% NH 4 HSO 4 water / methanol mixed solution was prepared by dissolving 0.30 g of NH 4 HSO 4 with 5.1 g of water and adding 4.50 g of methanol. After drying under reduced pressure at 60 ° C. for 2 hours, 25.3 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.6%, recovery rate 90% .7%). As a result of measurement by ion chromatographic analysis of the product, it was found that NH 4 HSO 4 was 0.54% and NH 4 Cl content was 0%. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.33.
Results of pH measurement after 60 ° C acceleration:
2nd week 3.38, 3rd week 3.37, 5th week 3.28, 7th week 3.46,
Week 10 3.60
Appearance observation results after 60 ° C acceleration:
Up to the 10th week, the pH is 3.6 or less, no ammonia odor, powder and no sticking. Compared to Comparative Example 6, there was no increase in pH and stability was improved. The residual content rate at 10 weeks was 99.5%.
実施例１０
　実施例１と同様の反応と処理を行って得られたスラリー液を遠心分離機にかけ、濾取した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶約３５重量部を、遠心分離機上でメタノール約７重量部により振り掛け洗浄した後、更に約４％w/wのNH4HSO4-水-メタノール混合溶液 約８．５重量部（NH4HSO4 ０．３５重量部、水 ２．８重量部、メタノール ５．３重量部）で振り掛け洗浄した。この操作を十数回バスケットを用いて実施し、得られた湿結晶を気流乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）（純度９８．１％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4の含有量が、０．３１％、NH4Clが０％であることが分かった。外観は白色結晶であり、１％水溶液のｐＨは３．５０であった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　１週目 ３．５１、２週目 ３．４８、４週目 ３．５０、７週目 ３．５７、
　８週目 ３．５４
６０℃加速経過後の含量測定結果：
　８週目 ９８．０％（含量残存率 ９９．８％）
６０℃加速経過後の外観観察結果：
　８週目までアンモニア臭気なく、粉末状で固着の無い状態で外観の変化も見られなかった。
　メタノールのみで洗浄した比較例７と比べ、安定性が大幅に向上した。 Example 10
The slurry obtained by carrying out the same reaction and treatment as in Example 1 was centrifuged and filtered to collect 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I ) About 35 parts by weight of wet crystals were sprinkled and washed with about 7 parts by weight of methanol on a centrifuge, and further about 8.5 parts by weight of NH 4 HSO 4 -water-methanol mixed solution of about 4% w / w ( NH 4 HSO 4 0.35 parts by weight, 2.8 parts by weight of water, and washed sprinkled with methanol 5.3 parts by weight). This operation was carried out ten times using a basket, and the obtained wet crystals were air-dried to give 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) ( Purity 98.1%) was obtained. Measurements of the ion chromatographic analysis of the product, the content of NH 4 HSO 4 is 0.31% was found that NH 4 Cl is 0%. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.50.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
1st week 3.51, 2nd week 3.48, 4th week 3.50, 7th week 3.57,
Week 8 3.54
Content measurement results after 60 ° C acceleration:
8th week 98.0% (content remaining rate 99.8%)
Appearance observation results after 60 ° C acceleration:
There was no ammonia odor until the 8th week, and no change in appearance was observed in a powdery state without sticking.
Compared with Comparative Example 7 washed only with methanol, the stability was greatly improved.
実施例１１
　実施例１と同様の反応と処理を行い、濾過により取得した未洗浄の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶４５．０ｇ（含量：８４．１％、０．１３８mol）を、１１．５％希塩酸（水２８．０ｇに濃塩酸１３．１ｇを加えたもの）にスラリー化した後、５℃以下で冷却して１時間撹拌後、析出した結晶をろ過し、１０．０％NaHSO4水溶液（９８％硫酸１．２８ｇを水１２．２ｇで希釈後、２７％NaOH １．９０ｇで中和して調製、ｐＨ ０．５２）１５．４２ｇで振りかけ洗浄した後、１０％ NaH2PO4 ７．７ｇ（ｐＨ ４．１３）で振りかけ洗浄した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３８．０７ｇ（純度９８．３％、回収率９８．９％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4の含有量が、０．４１％、NH4Clが０％であることが分かった。外観は白色結晶であり、１％水溶液のｐＨは３．２０であった。
５５℃加速経過後のｐＨ測定結果：
　２週目 ３．２８、２週目 ３．２９、６週目 ３．４４、８週目 ４．０６
５５℃加速経過後の含量測定結果：
　８週目　９７．８％
５５℃加速経過後の外観観察結果：
　８週目までｐＨは４．０以下で、アンモニア臭気なく、粉末状で固着の無い状態。含量残存率は９９．５％で、不純物の増加や外観の変化も見られなかった。 Example 11
45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. after the precipitated crystals were collected by filtration, 10.0% NaHSO 4 solution (diluted 98% sulfuric acid 1.28g water 12.2 g, prepared by neutralization with 27% NaOH 1.90g, pH 0.52) After washing by sprinkling with 15.42 g, it was washed with sprinkling with 7.7 g of 10% NaH 2 PO 4 (pH 4.13). After drying under reduced pressure at 60 ° C. for 2 hours, 38.07 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.3%, recovery rate 98) 0.9%). As a result of measurement by ion chromatography analysis of the product, it was found that the content of NH 4 HSO 4 was 0.41% and NH 4 Cl was 0%. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.20.
Results of pH measurement after 55 ° C acceleration:
2nd week 3.28, 2nd week 3.29, 6th week 3.44, 8th week 4.06
Content measurement results after 55 ° C acceleration:
87.8 weeks 97.8%
Appearance observation results after 55 ° C acceleration:
Until the 8th week, pH is 4.0 or less, no ammonia odor, powder and no sticking. The residual content rate was 99.5%, and neither an increase in impurities nor a change in appearance was observed.
比較例１
　２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩（II）２９．６ｇ（０．１４７mol）の１，２－ジクロロエタン溶液１３３．４ｇ（化合物IIの濃度として、２２．２％）に、メタノール５３．４ｇを加え、０～５℃に冷却下、８時間かけて、４９．５ｇ（１．３５８mol）の塩化水素ガスを吹き込んだ。この後、０～５℃で１２時間撹拌した。反応液を内温６５℃まで、徐々に加温していき、塩化水素ガス、メタノールを留去後、水５５ｇを加えた。内温７５℃まで加温し、１，２－ジクロロエタンを水との共沸で留去した。１，２－ジクロロエタンを留去後、５℃以下まで徐冷し、析出した結晶をろ過し、メタノール１２．５ｇで洗浄した。減圧下、６０℃で２時間乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３３．６g（純度９８．７％、収率８３．２％)を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶で、わずかな生成物の特異臭を発し、１％水溶液のｐＨは４．０３であった。安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　４．５１、６週目　４．７１、９週目　５．４８、１２週目　５．８６
６０℃加速経過後の含量測定結果：
　３週目 ９８．０％、６週目 ９８．５％、９週目 ９８．４％、１２週目 ９４．５％
６０℃加速経過後の外観観察結果：
　３週目　わずかなアンモニア臭気あり。
　６週目　わずかなアンモニア臭気あり。
　９週目　わずかなアンモニア臭気あり。
　１２週目　わずかなアンモニア臭気あり。
　３週目以降 ｐＨが徐々に上昇し、アンモニア臭を発するようになった。
　３週目以降でｐＨが４．５超と、異常値を示した。 Comparative Example 1
133.4 g of 1,2-dichloroethane solution of 29.6 g (0.147 mol) of 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride (II) 23.4%), 53.4 g of methanol was added, and 49.5 g (1.358 mol) of hydrogen chloride gas was blown in over 8 hours under cooling to 0 to 5 ° C. Thereafter, the mixture was stirred at 0 to 5 ° C. for 12 hours. The reaction solution was gradually heated to an internal temperature of 65 ° C., and after distilling off hydrogen chloride gas and methanol, 55 g of water was added. The internal temperature was raised to 75 ° C., and 1,2-dichloroethane was distilled off azeotropically with water. After 1,2-dichloroethane was distilled off, the mixture was gradually cooled to 5 ° C. or lower, and the precipitated crystals were filtered and washed with 12.5 g of methanol. It was dried at 60 ° C. under reduced pressure for 2 hours, and 33.6 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.7%, yield 83) .2%). As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, a slight odor of the product was generated, and the pH of 1% aqueous solution was 4.03. In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 4.51, 6th week 4.71, 9th week 5.48, 12th week 5.86
Content measurement results after 60 ° C acceleration:
3rd week 98.0%, 6th week 98.5%, 9th week 98.4%, 12th week 94.5%
Appearance observation results after 60 ° C acceleration:
3rd week Slight ammonia odor.
6th week Slight ammonia odor.
9th week Slight ammonia odor.
Week 12 Slight ammonia odor.
From the 3rd week onward, the pH gradually increased and an ammonia odor was emitted.
After the third week, the pH was over 4.5, indicating an abnormal value.
比較例２
　品質が低下した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）８０ｇ（０．２９２mol）（含量：９５．８％、ｐＨ ５．２０）を、１１．５％希塩酸（水５６．０ｇに濃塩酸２６．３ｇを加えたもの）にスラリー化した後、５℃以下で冷却し、１時間撹拌後、析出した結晶をろ過し、メタノール２６．９ｇで洗浄した。６０℃で２時間乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）７４．３ｇ（純度９９．２％、回収率９３．６％)を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは４．３６であった。安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　３週目　５．２８、６週目　５．６２
６０℃加速経過後の含量測定結果：
　３週目　９９．０％、６週目　９８．４％
６０℃加速経過後の外観観察結果：
　３週目　ややアンモニア臭気あり。固着はなかった。
　６週間目　ややアンモニア臭気あり。やや固着していたが、ほぐれやすかった。
　わずか３週間で、ｐＨが５．２超となり、異常値を示した。 Comparative Example 2
80 g (0.292 mol) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality (content: 95.8%, pH 5.20) Slurried in 11.5% dilute hydrochloric acid (56.0 g of water plus 26.3 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower, stirred for 1 hour, filtered the precipitated crystals, and filtered to 26.9 g of methanol. Washed with. After drying at 60 ° C. for 2 hours, 74.3 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 99.2%, recovery 93.6%) ) As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 4.36. In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
3rd week 5.28, 6th week 5.62
Content measurement results after 60 ° C acceleration:
39.0 weeks 99.0%, 6 weeks 98.4%
Appearance observation results after 60 ° C acceleration:
3rd week Slight ammonia odor. There was no sticking.
6th week Slight ammonia odor. It was a little stuck, but it was easy to loosen.
In just 3 weeks, the pH exceeded 5.2, indicating an abnormal value.
比較例３
　メタノール洗浄を行わないこと以外、比較例１と同様の方法で製造した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の未洗浄の湿結晶２２４．９６ｇを、７５℃で２時間、減圧下で乾燥し、乾燥品として１９７．９９ｇ（純度９８．０％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは３．９５であった。
６０℃加速経過後のｐＨ測定結果：
　２週目　４．２０、３週目　４．４５、６週目　４．６５、９週目　５．０２
６０℃加速経過後の含量測定結果：
　２週目　９８．０％、３週目　９８．１％、６週目　９７．４％、９週目　９６．３％
６０℃加速経過後の外観観察結果：
　２週目　ややアンモニア臭気あり。粉末状で固着はなかった。
　３週目　ややアンモニア臭気あり。粉末状で固着はなかった。
　６週目　アンモニア臭気あり。やや固着していた。
　９週目　アンモニア臭気あり。固着していた。
　わずか２週間からｐＨ上昇が始まり、３週目にはアンモニア臭が発生するとともに、含量低下が見られた。 Comparative Example 3
Unwashed wet crystal 224 of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the same method as in Comparative Example 1 except that methanol washing is not performed. .96 g was dried under reduced pressure at 75 ° C. for 2 hours to obtain 199.99 g (purity 98.0%) as a dried product. As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.95.
Results of pH measurement after 60 ° C acceleration:
2nd week 4.20, 3rd week 4.45, 6th week 4.65, 9th week 5.02
Content measurement results after 60 ° C acceleration:
2nd week 98.0%, 3rd week 98.1%, 6th week 97.4%, 9th week 96.3%
Appearance observation results after 60 ° C acceleration:
Second week There was a slight ammonia odor. It was powdery and did not stick.
3rd week Slight ammonia odor. It was powdery and did not stick.
Week 6 There was an ammonia odor. Slightly stuck.
9th week There was ammonia odor. It was stuck.
The pH started to increase from only 2 weeks, and ammonia odor was generated and the content was decreased in the 3rd week.
比較例４
　メタノール洗浄を行わないこと以外、比較例１と同様の方法で製造した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）の未洗浄品湿結晶２３３．００ｇとそのろ液２３３．００ｇを混合し、再スラリー化した溶液を５℃付近まで冷却した後、卓上小型遠心分離機で遠心分離した。得られた湿結晶をメタノール６４．０ｇで遠心分離しながら、洗浄を実施した。得られた湿結晶２１７．２０ｇを７５℃で２時間、減圧下で乾燥し、乾燥品として１９０．００ｇ（純度９８．０％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは４．２７であった。
６０℃加速経過後のｐＨ測定結果：
　３週目 ４．４６、６週目 ５．０８、９週目 ５．１２
６０℃加速経過後の含量測定結果：
　３週目 ９８．１％、６週目 ９６．２％、９週目 ９６．０％
６０℃加速経過後の外観観察結果：
　３週目 ややアンモニア臭気あり。粉末状で固着はなかった。
　６週目 アンモニア臭気あり。やや固着していた。
　９週目 アンモニア臭気あり。固着していた。
　わずか３週間からｐＨ上昇とともにアンモニア臭が発生し、６週目でｐＨが５．０以上と異常値となった。 Comparative Example 4
Unwashed wet crystal 233 of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) produced by the same method as in Comparative Example 1 except that methanol washing is not performed. 0.000 g and the filtrate 233.00 g were mixed, and the reslurried solution was cooled to around 5 ° C. and then centrifuged with a desktop small centrifuge. The obtained wet crystals were washed while centrifuging with 64.0 g of methanol. 217.20 g of the obtained wet crystal was dried under reduced pressure at 75 ° C. for 2 hours to obtain 190.00 g (purity 98.0%) as a dried product. As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 4.27.
Results of pH measurement after 60 ° C acceleration:
3rd week 4.46, 6th week 5.08, 9th week 5.12
Content measurement results after 60 ° C acceleration:
3rd week 98.1%, 6th week 96.2%, 9th week 96.0%
Appearance observation results after 60 ° C acceleration:
3rd week Slight ammonia odor. It was powdery and did not stick.
Week 6 There was an ammonia odor. Slightly stuck.
9th week There was ammonia odor. It was stuck.
Ammonia odor was generated as the pH increased from only 3 weeks, and the pH became an abnormal value of 5.0 or more at the 6th week.
比較例５
　実施例１と同様の反応と処理を行い、濾過により取得した未洗浄の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶４５．０ｇ（含量：８４．１％、０．１３８mol）を、１１．５％希塩酸（水２８．０ｇに濃塩酸１３．１ｇを加えたもの）にスラリー化した後、５℃以下で冷却して１時間撹拌後、析出した結晶をろ過し、メタノール１２．８７ｇで洗浄した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３４．５３ｇ（純度９９．２％、回収率９１．３％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは４．１４であった。
５５℃加速経過後のｐＨ測定結果：
　２週目　４．２４、４週目　４．３７、６週目　４．５１、８週目　４．９３
５５℃加速経過後の外観観察結果：
　ｐＨ６は２週目から徐々に上昇し、６週目以降、黄色斑点異物が見られ、臭気を発するようになった。８週目では臭気が強く分解が進行していた。 Comparative Example 5
45.0 g of unwashed 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystals obtained by filtration after the same reaction and treatment as in Example 1 ( Content: 84.1%, 0.138 mol) was slurried in 11.5% dilute hydrochloric acid (28.0 g of water plus 13.1 g of concentrated hydrochloric acid), cooled to 5 ° C. or lower and stirred for 1 hour. Thereafter, the precipitated crystals were filtered and washed with 12.87 g of methanol. It was dried under reduced pressure at 60 ° C. for 2 hours, and 34.53 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 99.2%, recovery rate 91 .3%) was obtained. As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 4.14.
Results of pH measurement after 55 ° C acceleration:
2nd week 4.24, 4th week 4.37, 6th week 4.51, 8th week 4.93
Appearance observation results after 55 ° C acceleration:
The pH 6 gradually increased from the 2nd week, and yellow spots were observed from the 6th week onward. In the 8th week, the odor was strong and the decomposition was progressing.
比較例６
　品質が低下した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）３０ｇ（０．１０２mol）（含量：９３．１％、ｐＨ ５．００）を、１．０％希塩酸（水３０．０ｇに濃塩酸　０．９ｇを加えたもの）にスラリー化した後、７０℃に加温し、完全に溶解させた。同温度で３６％塩酸１０．５ｇを加えた後、５５℃まで冷却し、メタノール１２．０を加えた。１０℃以下まで、徐冷し、１時間撹拌後、析出した結晶をろ過し、７．５ｇのメタノールで洗浄した。６０℃で２時間減圧下で乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）２６．９ｇ（純度９８．６％、回収率９０．８％)を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは４．１０であった。
６０℃加速経過後のｐＨ測定結果：
　２週目　４．１８、３週目　４．３０、５週目　４．３５、７週目　４．４０
　１０週目　４．５８
６０℃加速経過後の外観観察結果：
　３週目くらいからｐＨの上昇が見られ、５週目以降臭気発生が見られた。１０週目では臭気も強くなり、含量残存率は９７．５％であった。劣化１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を再結晶化で精製することで通常品（パダン（登録商標））と比較して、安定性が向上しているが、実施例９のようにNH4HSO4含水メタノール液で洗浄したものと比較して安定性が悪かった。 Comparative Example 6
30 g (0.102 mol) (content: 93.1%, pH 5.00) of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) with reduced quality After slurrying in 1.0% diluted hydrochloric acid (30.0 g of water plus 0.9 g of concentrated hydrochloric acid), the mixture was heated to 70 ° C. and completely dissolved. After adding 10.5 g of 36% hydrochloric acid at the same temperature, the mixture was cooled to 55 ° C. and methanol 12.0 was added. After slowly cooling to 10 ° C. or lower and stirring for 1 hour, the precipitated crystals were filtered and washed with 7.5 g of methanol. After drying under reduced pressure at 60 ° C. for 2 hours, 26.9 g of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) (purity 98.6%, recovery rate 90%) 8%). As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 4.10.
Results of pH measurement after 60 ° C acceleration:
2nd week 4.18, 3rd week 4.30, 5th week 4.35, 7th week 4.40
10th week 4.58
Appearance observation results after 60 ° C acceleration:
An increase in pH was observed from about the third week, and odor generation was observed after the fifth week. At 10 weeks, the odor became stronger and the residual content rate was 97.5%. Degraded 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) is purified by recrystallization and is stable compared to conventional products (Padan (registered trademark)) The stability was improved, but the stability was poor as compared with that washed with a NH 4 HSO 4 water-containing methanol solution as in Example 9.
比較例７
　実施例１と同様の反応と処理を行い、遠心分離機により濾取した１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）湿結晶約３５重量部を、遠心分離機上でメタノール約７重量部により振り掛け洗浄した。この操作を十数回バスケットを用いて実施し、得られた湿結晶を気流乾燥して、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）（純度９８．３％）を得た。生成物のイオンクロマトグラフ分析での測定結果、NH4HSO4およびNH4Clは、検出されなかった。外観は白色結晶であり、１％水溶液のｐＨは３．９４であった。
　安定性確認のため、６０℃の加速試験を実施し、経過を観察した。６０℃加速試験の結果は以下の通りであった。
６０℃加速経過後のｐＨ測定結果：
　１週目　４．０８、２週目　４．８３、４週目　５．５０、７週目　５．１５、
　８週目　５．３２
６０℃加速経過後の含量測定結果：
　８週目　９６．０％（含量残存率　９７．７％）
６０℃加速経過後の外観観察結果：
　２週目から強いアンモニア臭気を発し、８週目では完全に固結した。
Comparative Example 7
About 35 parts by weight of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) wet crystal, which was subjected to the same reaction and treatment as in Example 1 and collected by filtration with a centrifugal separator Was sprinkled and washed with about 7 parts by weight of methanol on a centrifuge. This operation was carried out ten times using a basket, and the obtained wet crystals were air-dried to give 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) ( Purity 98.3%) was obtained. As a result of measurement by ion chromatography analysis of the product, NH 4 HSO 4 and NH 4 Cl were not detected. The appearance was white crystals, and the pH of the 1% aqueous solution was 3.94.
In order to confirm the stability, an accelerated test at 60 ° C. was performed and the progress was observed. The results of the 60 ° C. acceleration test were as follows.
Results of pH measurement after 60 ° C acceleration:
1st week 4.08, 2nd week 4.83, 4th week 5.50, 7th week 5.15,
Week 8: 5.32
Content measurement results after 60 ° C acceleration:
8th week 96.0% (content remaining rate 97.7%)
Appearance observation results after 60 ° C acceleration:
A strong ammonia odor was emitted from the second week and solidified completely in the eighth week.
　本発明の製造方法によれば、優れた殺虫作用を有する１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩（Ｉ）を、安定性が良好なものとして、良好な純度および収率で製造することができる。 According to the production method of the present invention, 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride (I) having an excellent insecticidal action is considered to have good stability. It can be produced with good purity and yield.

Claims (8)

  1. 　工程（Ａ）を含む安定な１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の製造方法：
    工程（Ａ）：１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩を強酸性の無機酸塩の水溶液または強酸性の有機酸の水溶液で洗浄する工程。     Process for producing stable 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride comprising step (A):
    Step (A): A step of washing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride with an aqueous solution of a strongly acidic inorganic acid salt or an aqueous solution of a strongly acidic organic acid.
  2. 　工程（Ａ）に供される１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩が、
    　メタノールおよびメタノールと二層系を形成する有機溶媒中で２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩と塩化水素ガスとを反応させるか、あるいは、
    　水および水と二層系を形成する有機溶媒中で２－（Ｎ，Ｎ－ジメチルアミノ）－１，３－ジチオシアナート－プロパン塩酸塩と塩酸とを反応させる、
    ことにより得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩である、請求項１に記載の製造方法。     1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride used in step (A) is
    Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrogen chloride gas in methanol and an organic solvent that forms a two-layer system with methanol, or
    Reacting 2- (N, N-dimethylamino) -1,3-dithiocyanate-propane hydrochloride with hydrochloric acid in water and an organic solvent that forms a two-layer system with water;
    The production method according to claim 1, which is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride obtained by this method.
  3. 　メタノールと二層系を形成する有機溶媒が、トルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物であり、
    　水と二層系を形成する有機溶媒が、トルエン、キシレン、１，２－ジクロロエタン、クロロホルム、塩化メチレンおよびクロロベンゼンからなる群より選ばれる一種または二種以上の混合物である、請求項２に記載の製造方法。     The organic solvent that forms a two-layer system with methanol is one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene,
    The organic solvent that forms a two-layer system with water is one or a mixture of two or more selected from the group consisting of toluene, xylene, 1,2-dichloroethane, chloroform, methylene chloride, and chlorobenzene. Production method.
  4. 　工程（Ａ）に供される１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩が、２－Ｎ，Ｎ－ジメチルアミノ－１，３－プロパンジチオールとシアン酸塩とを塩酸の存在下で反応させることにより得られる１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩である、請求項１～３のいずれか１つに記載の製造方法。 1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride used in step (A) is converted to 2-N, N-dimethylamino-1,3-propanedithiol and cyanic acid. The compound according to any one of claims 1 to 3, which is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride obtained by reacting a salt with hydrochloric acid. The manufacturing method as described.
  5. 　強酸性の無機酸塩が、硫酸水素アンモニウム、硫酸水素ナトリウム、硫酸水素カリウム、または硫酸水素アンモニウムであり、強酸性の有機酸が、シュウ酸またはクエン酸である、請求項１～４のいずれか１つに記載の製造方法。 The strong acid inorganic acid salt is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, or ammonium hydrogen sulfate, and the strong acid organic acid is oxalic acid or citric acid. The manufacturing method as described in one.
  6. 　下記（ａ）および（ｂ）を満たす、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物：
    （ａ）強酸性の無機酸塩または強酸性の有機酸の含量が、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物の重量に対して、０．０５～１０重量％の範囲である、
    （ｂ）１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物の水溶液のｐＨが３．７以下である。     1,3-Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strongly acidic organic acid adduct satisfying the following (a) and (b):
    (A) A strongly acidic inorganic acid salt or a strong acid containing 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride having a content of a strongly acidic inorganic acid salt or a strongly acidic organic acid Is in the range of 0.05 to 10% by weight based on the weight of the adduct of the organic acid.
    (B) The pH of the aqueous solution of an inorganic acid salt of 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride or an adduct of an organic acid is 3.7 or lower.
  7. 　強酸性の無機酸塩または強酸性の有機酸の含量が、１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の強酸性の無機酸塩または強酸性の有機酸の付加物の重量に対して、０．１～２重量％の範囲である、請求項６記載の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物。 The strongly acidic inorganic acid salt or the strongly acidic organic acid content is 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride strongly acidic inorganic acid salt or strongly acidic organic acid. The 1,3-dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride according to claim 6, in the range of 0.1 to 2% by weight, based on the weight of the acid adduct. Inorganic acid salt or organic acid adduct.
  8. 　強酸性の無機酸塩または強酸性の有機酸が、硫酸水素アンモニウム、硫酸水素ナトリム、硫酸水素カリウム、シュウ酸またはクエン酸である、請求項６または７のいずれか１項に記載の１，３－ジカルバモイルチオ－２－（Ｎ，Ｎ－ジメチルアミノ）－プロパン塩酸塩の無機酸塩または有機酸の付加物。 The 1,3 according to any one of claims 6 and 7, wherein the strongly acidic inorganic acid salt or the strongly acidic organic acid is ammonium hydrogen sulfate, sodium hydrogen sulfate, potassium hydrogen sulfate, oxalic acid or citric acid. -Dicarbamoylthio-2- (N, N-dimethylamino) -propane hydrochloride inorganic acid salt or organic acid adduct.
PCT/JP2018/013133 2017-03-30 2018-03-29 Stable 1,3-dicarbamoylthio-2-(n,n-dimethylamino)propane hydrochloride and production method therefor WO2018181672A1 (en)

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