JPH0219106B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing N,N'-disubstituted carbodiimides. Specifically, N,N′-disubstituted thiourea is reacted with N-substituted amine halide.
This invention relates to a new method for producing N'-disubstituted carbodiimides. In recent years, with the rapid development of pharmaceuticals and concentrates, N,N'-disubstituted carbodiimides have attracted attention for the production of intermediates for these organic compounds. For example, N,N'-dicyclohexylcarbodiimide has come to be widely used as a dehydrating agent in the synthesis of complex organic compounds such as peptide synthesis. Conventionally, the following methods are known as methods for producing N,N'-disubstituted carbodiimides. One method is based on the desulfurization reaction of N,N'-disubstituted thioureas, and the following compounds have been proposed as desulfurization agents. (i) Hypohalite salts such as sodium hypochlorite (Ger, No. 823445, Brit. No. 685970, Liebig
Annalen612, 11-22, 1958) (ii) Heavy metals such as mercury and lead (USP No. 3201463) (iii) Chlorinated sulfur compounds such as thionyl chloride (Fr. 1558856) (iv) Contains cyanuric chloride, pyridine chloride, etc. Nitrogen ring chlorides (Nikka-shi, 921005-7) (v) Quinones (Meka-shi, 92357-360) In the method using hypohalite salts in (i) above, since the salts are inorganic salts, Since it is used as an aqueous solution, the N,N'-disubstituted carbodiimide produced reacts with water to become a urea derivative. Therefore, the yield of N,N'-disubstituted carbodiimide is extremely low. On the other hand, there is a drawback that the range of N,N'-disubstituted thioureas to which hypohalites can be applied is also limited. The method (ii) using heavy metals such as mercury and lead cannot be adopted industrially due to problems with waste disposal, and the method (iii) using thionyl chloride is expensive and There is a problem in disposing of the by-product sulfur dioxide gas. The method of using nitrogen-containing ring chlorides (iv) and quinones (v) is expensive, and it is difficult to recover and reuse them after the reaction. There was a problem. On the other hand, there is a method of obtaining N,N'-disubstituted carbodiimide by decarboxylation reaction from two molecules of isocyanate, as disclosed in USP 3157622 and Ger. 255676, but this method is difficult to handle and requires an expensive phosphorus catalyst. Moreover, when the substituent of the isocyanate is an alkyl group, there is a drawback that the reaction hardly progresses. Furthermore, Ger.1173460 discloses a method for obtaining N,N'-disubstituted carbodiimide from S-methyl-i-thiourea, but it is unsuitable as an industrial production method because it is extremely difficult to remove the by-product mercaptan. be. The present inventor has conducted extensive research into a desulfurizing agent that is inexpensive, easy to handle, reusable through recycling, applicable to a wide range of N,N'-disubstituted thioureas, and provides high yields. The inventors discovered that aliphatic amine halide satisfies all of the above requirements as a desulfurizing agent, and completed the present invention. The present invention involves reacting an N,N'-disubstituted thiourea with an N-substituted amine halide in the presence of an inert solvent, and optionally reacting the by-produced N-substituted amine hydrohalide with a hypohalite. The present invention provides a method for producing an N,N'-disubstituted carbodiimide, which is reused as an N-substituted amine halide. The present invention preferably provides R ₁ −N=C=N−R ₂ () where R ₁ or R ₂ may be the same or different,
N represents an alkyl group that may have a substituent, a cycloalkyl group that may have a substituent, an aryl group that may have a substituent, and an aralkyl group that may have a substituent, respectively. , N'-disubstituted carbodiimide, which has the formula () where R ₁ or R ₂ has the above meaning, N,N'-disubstituted thiourea () Here, R ₃ and R ₄ may be the same or different,
Each represents hydrogen or an alkyl group having 1 to 8 carbon atoms, or R ₃ and R ₄ can be taken together to form a 5- to 6-membered alicyclic group which may be interrupted by O, and X is Cl or Br, provided that R ₃ and R ₄ do not both represent hydrogen at the same time, is reacted with the N-substituted amine halide in the presence of an inert solvent, and N-substituted amine hydrogen halide is produced as a by-product as necessary. By reacting the acid salt with the hypohalite salt, N
Reused as substituted amine halide, N,
This invention relates to a method for producing an N'-disubstituted carbodiimide. The reaction for producing a disubstituted carbodiimide according to the production method of the present invention involves the reaction of N,N'-dicyclohexylthiourea and diethylamine chloride in carbon tetrachloride for 50 min.
Taking as an example the case where the reaction was carried out at ℃ for 1 hour, it is shown as follows. The by-produced diethylamine hydrochloride is regenerated into diethylamine chloride by reacting with sodium hypochlorite as shown in the following formula. (C ₂ H ₅ ) ₂ NH・HCl＋NaOCl→(C ₂ H ₅ ) ₂ NCl
+NaCl+H ₂ O Preferred substituents of the compound of formula () used in the method for producing N,N'-substituted carbodiimide of the present invention
R ₁ and R ₂ are an alkyl group having 1 to 18 carbon atoms which may have a substituent of an OH group or an alkoxy group; a 5 carbon number which may have a substituent of an alkyl group having 1 to 4 carbon atoms; -8 cycloalkyl group; phenyl group or naphthyl group which may have a substituent of halogen, C1-4 alkyl group, C1-4 alkoxy group or nitro group; or substituted with halogen It is a good aralkyl group having 7 to 8 carbon atoms. Among such substituents R ₁ and R ₂ , particularly preferred substituents R ₁ and R ₂ are alkyl groups having 2 to 4 carbon atoms, which may have an OH group or an alkoxy group substituent; Cycloalkyl group having 6 carbon atoms which may have ~4 alkyl groups as substituents; Cl,
Br, alkyl group having 1 to 2 carbon atoms, 1 to 2 carbon atoms
a phenyl group which may have a substituent of an alkoxy group or a nitro group; or an aralkyl group having 7 to 8 carbon atoms. Examples of substituents R ₁ and R ₂ include isopropyl,
n-butyl, sec-butyl, tert-butyl, n-
octyl, ethyl, methyl, n-octadecyl,
2-hydroxyethyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, ethoxymethyl, 3-methoxypropyl, cyclohexyl, 4-methyl-cyclohexyl, 2-ethyl-cyclohexyl, phenyl, o-tolyl, m-
Tolyl, p-tolyl, o-methoxyphenyl, p
-methoxyphenyl, p-ethoxyphenyl, p
-Chlorphenyl, m-chlorphenyl, p-bromphenyl, o-chlorophenyl, p-nitrophenyl, o-orthophenyl, α-naphthyl,
Examples include β-naphthylbenzyl, p-chlorobenzyl, and the most preferred substituents R ₁ and R ₂ are cyclohexyl, tert-butyl and iso-propyl, with cyclohexyl being the most preferred. Preferred N,N'- used in the production method of the present invention
Examples of compounds of formula () which are disubstituted thioureas include N,N'-dicyclohexylthiourea, N,
N'-diisopropylthiourea, N,N'-di-n-
Octylthiourea, N,N'-diisooctylthiourea, N,N'-di-n-octadecylthiourea,
N-cyclohexyl-N'-nbutylthiourea,
N-cyclohexyl-N'-t-butylthiourea,
Nt-butyl-N'-methylthiourea, N,N'-
di(2-hydroxy)ethylthiourea, N,
N'-di(2-methoxy)ethylthiourea, N-
Methoxymethyl-N'methylthiourea, N,N'-
Diphenylthiourea, N,N'-diptolylthiourea, N,N'-diptolylthiourea, N,N'-
Dip methoxyphenylthiourea, N,N'-dip
Chlorphenylthiourea, N,N'-diotolylthiourea, N,N'-di-pnitrophenylthiourea, N-phenyl-N'-cyclohexylthiourea, N-phenyl-N'-t-butylthio urea,
Examples include N-benzyl-N'-t-butylthiourea. Among the above N,N'-disubstituted thioureas, N,
N′-substituent has moderate steric hindrance,
N'-disubstituted thioureas are particularly suitable for the present invention because they cause fewer side reactions and are easy to react.As such N,N'-disubstituted thioureas, R ₁ and R ₂ are cyclohexyl groups, t -N,N'-substituted thiourea which is butyl group, isopropyl group, e.g. N,N'-
Mention may be made of dicyclohexylthiourea, N,N'-dit-butylthiourea, and N,N'-diisopropylthiourea. On the other hand, the N,N'-disubstituted thiourea to which the production method of the present invention is applied has the formula Here, n represents an integer of 1 or more, and it can also be applied to polythiourea. Substituents R ₃ and R ₄ of the N-substituted amine halide of formula () used in the production method of the present invention include hydrogen,
Methyl, ethyl, n-propyl, isopropyl,
n-butyl, seebutyl, t-butyl, hexyl,
Examples include n-octyl, 2-ethyl-hexyl, etc. Among these, alkyl groups having 1 to 4 carbon atoms are more preferred, and ethyl and methyl are most preferred. R ₃ and R ₄ can also be taken together to form a 5- or 6-membered alicyclic group optionally interrupted with O, such examples include morpholine, piperidine, pyrrolidine, and the like. Also, the substituent X is
Of Cl and Br, Cl is most preferred. As the N-substituted amine halide of formula (),
N,N-dimethylamine chloride, N-ethylamine chloride, N,N-diethylamine chloride, N,N-di-n-propylamine chloride, N,N-di-n-propylamine chloride,
N,N-di-t-butylamine chloride, etc.
N,N-dimethylamine chloride and N,N-
Diethylamine chloride and N-chloropiperidine are preferably used. In addition, in the production method of the present invention, one type or a combination of two or more types of N-substituted amine halides may be used. The process for preparing N,N'-disubstituted carbodiimides of the present invention is carried out by reacting N,N'-disubstituted thioureas with N-substituted amine halides in the presence of an inert solvent. Here, "inert" means
It is used to indicate that it is chemically inert to N,N'-disubstituted thioureas, N-substituted amine halides, and N,N'-disubstituted carbodiimides that are produced. In addition, it is not necessary that the entire amount of the raw material N,N'-disubstituted thiourea be dissolved in the solvent at the start of the reaction; most of the N,N'-disubstituted thiourea is suspended in the solvent. It can react effectively with halides.
Therefore, any inert solvent can be used without any restrictions as the solvent used in the method for producing N,N'-disubstituted carbodiimides of the present invention.
In order to easily separate the by-produced N-substituted amine hydrohalide as an aqueous solution from the inert solvent solution of the N,N'-disubstituted carbodiimide, water was
Solvents that are immiscible in amounts greater than % by weight are preferred. Examples of such solvents include halogenated hydrocarbons such as methylene chloride, chlorokyrm, carbon tetrachloride, and ethylene chloride; n-hexane;
Cyclohexane, isooctane, petroleum ether,
Aliphatic hydrocarbons such as ligroin; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene;
Carbon tetrachloride, n-hexane, and toluene, which are easy to handle at ℃, are preferred. These inert solvents can be used alone or in combination of two or more. The reaction molar ratio of N,N'-disubstituted thiourea and N-substituted amine halide in the production method of the present invention can be appropriately determined in consideration of the reaction conditions and is not particularly limited. However, in order to improve the yield of N,N'-disubstituted carbodiimide and suppress side reactions, it is necessary to add N to 1 mole of N,N'-disubstituted thiourea.
Substituted amine halide preferably 0.9 to 1.5 mol,
More preferably, it is used in a range of 1.0 to 1.3 mol. At less than 0.9 mol, the amount of N,N'-disubstituted thiourea in the final reaction tends to increase, while at more than 1.5 mol, side reactions tend to occur and the yield of N,N'-disubstituted carbodiimide tends to decrease. There is. In the present invention, the N,N'-disubstituted thiourea and the N-substituted amine halide can be reacted in various ways in an inert solvent. Among these various reactions, N,N'-disubstituted thiourea is dissolved or suspended in an inert solvent, and an inert solvent solution of N-substituted amine halide is added into this solution or suspension. A method in which the reaction is carried out by dropping the mixture under stirring is preferred. The reaction temperature is appropriately determined depending on the properties of the inert solvent, N-substituted amine halide, and target N,N'-disubstituted carbodiimide, but is generally about 0°C to about 70°C, preferably about 30°C to about 70°C. The reaction is carried out at 60°C. If the temperature is below about 0°C or above about 70°C, side reactions occur and the yield of N,N'-disubstituted carbodiimide is undesirably reduced. Examples of N,N'-disubstituted carbodiimides obtained by the production method of the present invention include N,N'-dicyclohexylcarbodiimide (mp35-36°C);
N,N'-diisopropylcarbodiimide (bp50
~60℃/42mmHg), N,N'-dit-butylcarbodiimide (bp79~80℃/45mmHg), N-cyclohexyl-N'-nbutylcarbodiimide (b.
p.153-155℃/5mmHg), N,N'-di-t-octylcarbodiimide (bd140-142℃/7mmHg),
N,N'-di-otolylcarbodiimide (bp169
~174℃/4.5mmHg), N,N'-di-pmethoxyphenylcarbodiimide (bp162~163℃/0.08mm
Hg), N,N'-di-pchlorophenylcarbodiimide (bp130℃/0.018mmHg), N-phenyl-N'-cyclohexylcarbodiimide (bp169
~172℃/13mmHg), N-phenyl-N'-t-butylcarbodiimide (bp118~120℃/16mmHg)
etc. In the method for producing N,N'-disubstituted carbodiimides of the present invention, generally as the reaction progresses, the N-substituted amine halide is converted to the N-substituted amine hydrohalide and precipitated in the inert solvent. The by-produced N-substituted amine hydrohalide can be obtained by passing through the reaction suspension and dissolving the residue in water, or preferably by adding an appropriate amount of water to the reaction suspension. After thorough shaking, only the aqueous layer is separated, thereby separating the N,N'-disubstituted carbodiimide from the inert solvent solution in the form of an aqueous solution. The aqueous solution of the N-substituted amine hydrohalide thus obtained is placed in an aqueous hypohydrohalite solution at 5°C to 20°C, for example, to which an inert solvent that is immiscible with water is added in approximately the same amount as water. After the reaction is completed, the inert solvent layer is separated and optionally dried to easily obtain an inert solvent solution of the N-substituted amine halide. In this reaction, 1 to 1.5 mol of hypohalite is used per 1 mol of N-substituted amine hydrohalide. Hypohalites used in the production method of the present invention include sodium hypochlorite, calcium hypochlorite, and sodium hypochlorite, and alkali metal hydroxides such as caustic soda in the reaction system. It can also be carried out by a method in which hypohalite is generated on the spot by blowing halogen such as chlorine in the presence of chlorine. Thus, in the method for producing N,N'-disubstituted carbodiimides of the present invention, the N-substituted amine hydrohalide produced as a by-product can be easily and quantitatively converted into N-substituted amine halide and reused. Therefore, the production cost of N,N'-disubstituted carbodiimide can be dramatically reduced compared to conventional methods. The N,N'-disubstituted carbodiimide obtained by the production method of the present invention is generally obtained as a solution in an inert solvent, but according to the production method of the present invention, almost no side reactions occur, so it is free from impurities. It exists in small quantities and can be used as is in the next organic synthesis reaction, or if necessary, purified by conventional methods. The present invention will be explained in more detail below using Examples. Examples 1-18 In a flask with a stirrer and a dropping funnel, the first
As shown in the table, N,N'-dicyclohexylthiourea, N,
N'-di-i-propylthiourea, N-cyclohexyl N'-n-butylthiourea, N,N'-diphenylthiourea, N,N'-di-t-butylthiourea, N-t-butyl N'-methylthio urea or N-benzyl-N'-t-butylthiourea, respectively.
1.0 mol, and carbon tetrachloride, i-octane, toluene, as shown in the column as dry organic solvents.
Alternatively, add 400 ml of n-hexane to each, and suspend the di-substituted thiourea in the organic solvent while stirring while maintaining the reaction temperature shown in the column. Next, an organic solvent solution of the aliphatic amine halide solution shown in column 1, i.e., diethylamine chloride, dimethylamine chloride, di-i-propylamine chloride, monoethylamine chloride, or di-t-butylamine chloride (1.2 as the amine halide) mol) was gradually added dropwise from the dropping funnel over 30 minutes while maintaining the reaction temperature in the column. Further, the reaction is allowed to proceed for 30 minutes at the above reaction temperature with stirring to complete the reaction. After the reaction is completed, the precipitated crystals (hereinafter referred to as crystals (A)) are removed by filtration to obtain an organic solvent solution of carbodiimide shown in column 1. The carbodiimide organic solvent solution thus obtained is washed with 400 ml of water, separated, dried over potassium carbonate, the organic solvent is distilled off, and further distilled under reduced pressure to obtain the corresponding carbodiimide. The yield, melting point, and boiling point of these carbodiimides are shown in the column. The aliphatic amine chloride used in the reaction is recovered and reused as shown below. The separated crystals (A) are added to the washing water used previously and dissolved under stirring. Separate the insoluble matter (mainly sulfur) and prepare an aqueous solution of aliphatic amine hydrochloride. 200ml of the organic solvent shown in the column and a sodium hypochlorite aqueous solution (12% aqueous solution: effective chlorine concentration)
1.6 mmole/g) in a bilayer solution consisting of 750 ml,
The above-prepared aqueous aliphatic amine hydrochloride solution is added dropwise with vigorous stirring. At this time, the reaction temperature is 15
Adjust so that the temperature is below ℃. Continue vigorous stirring for an additional 30 minutes after addition. The mixture is left to stand, the organic solvent layer is separated, and 5 g of anhydrous calcium chloride is added and dried to obtain a non-aqueous organic solvent solution of aliphatic amine halide. The recovery rate of the aliphatic amine halide thus obtained and the available chlorine content of the solution are shown in the column. Comparative Example 1 Experiments were conducted in the same manner as in Examples 1 to 18 under the conditions shown in Table 1, using 400 ml of a mixed solvent of CCl ₄ :water in a ratio of 9:1 as a solvent for disubstituted thiourea. The results are shown in Table 1. Comparative Example 2 The method using hypohalite acids described in Liebig Annalen, 612, 11-22 (1958) was repeated. The results are shown in Table 1. Comparative Example 3 The method using quinones described in Nikka Shi, 92, 357-360 was repeated. The results are shown in Table 1.

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Claims (1)

[Claims] 1 N,N'-disubstituted thiourea is reacted with an N-substituted amine halide in the presence of an inert solvent, and if necessary, the by-produced N-substituted amine hydrohalide is reacted with hypohalous acid. A method for producing an N,N'-disubstituted carbodiimide, which is reacted with a salt and reused as an N-substituted amine halide. 2 N,N'-disubstituted thiourea has the formula Here, R ₁ or R ₂ may be the same or different,
A compound representing an alkyl group that may have a substituent, a cycloalkyl group that may have a substituent, an aryl group that may have a substituent, and an aralkyl group that may have a substituent, respectively. A manufacturing method according to claim 1. 3 N-substituted amine halide has the formula Here, R ₃ and R ₄ may be the same or different,
Each represents hydrogen or an alkyl group having 1 to 8 carbon atoms, or R ₃ and R ₄ can be taken together to form a 5- to 6-membered alicyclic group which may be interrupted by O, and X is Represents C1 or Br, provided that R ₃ and R ₄
3. The method according to claim 1 or 2, which is a compound of: and which do not both represent hydrogen at the same time. 4. React N,N'-disubstituted thiourea with N-substituted amine halide in the presence of an inert solvent, and react the by-produced N-substituted amine halide with hypohydrohalite to form N-substituted amine halide. N recited in claim 1, to be reused as
Method for producing N'-disubstituted carbodiimides.