JPH04273850A - Production of symmetric type 1,3-disubstituted urea - Google Patents

Abstract

PURPOSE:To obtain a 1,3-disubstituted urea in high yield at normal temperature by reacting a primary amine of lower substitution with phosgene in a water solvent while adding an inorganic base and maintaining pH of the reaction solution in an alkali range. CONSTITUTION:A primary amine (e.g. methylamine or ethylamine) shown by the formula RNH2 (R is 1-4C alkyl) is reacted with phosgene by advancing the reaction while adding an organic base such as sodium hydroxide and maintaining the reaction solution at pH 8-14 to give a symmetric type 1,3- disubstituted urea (e.g. 1,3-diethylurea). By this method, advantageously the symmetric type 1,3-disubstituted urea can be produced under a mild condition, readily and in high yield.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing symmetrical 1,3-disubstituted ureas useful as raw material compounds for pharmaceuticals, agricultural chemicals, etc. from primary amines.

0002

[Prior art] Symmetrical 1,3- by lower alkyl group
The following methods are known as methods for producing di-substituted ureas. (1) A method for producing by an exchange reaction between urea and a primary amine (Japanese Patent Publication No. 2-7945) (2) A method for producing by an exchange reaction between a carbonate ester and a primary amine (Japanese Patent Publication No. 17572/1982) ) (3) A method of manufacturing by reacting carbon dioxide and a primary amine under high temperature and high pressure (Japanese Patent Publication No. 1987-9107) (4) Reacting a primary amine with carbon monoxide in the presence of a platinum catalyst. A method for producing symmetrical 1,3-disubstituted urea by reacting a primary amine with phosgene in the presence of an inorganic base (Chemical
al Reviews, 73, No. 1, 75
(1973) )

0003

[Problems to be Solved by the Invention] However, the above methods (1) to (4) all carry out the reaction at a high temperature of around 200° C. and under a high pressure of 15 to 50 bar. Furthermore, since primary amines are used in large excess in many cases, it is necessary to separate and recover them. moreover,
For the above reasons, the manufacturing equipment becomes large and complicated, which is not preferable for industrial manufacturing.

[0004] Furthermore, there has been no report on a method for producing 1,3-disubstituted urea by applying the method (5) above to a primary amine substituted with a lower alkyl group. This is because when lower monoalkylamines are used, impurities such as biuret and guanidine are likely to be produced under normal conditions, making it difficult to obtain high-yield, high-purity 1,3-disubstituted urea. This is thought to be for a reason.

In view of the above circumstances, the present inventors conducted intensive studies on a method for producing symmetrical 1,3-disubstituted urea by reacting a lower alkyl group-substituted primary amine with phosgene. discovered that 1,3-disubstituted urea could be produced in high yield at room temperature by reacting phosgene while maintaining the pH of the reaction solution at 9 to 14 while adding an inorganic base, and completed the present invention. I ended up letting it happen.

[0006]

Means for Solving the Problems The present invention is represented by the general formula RNH2, where R represents an unbranched or branched alkyl group of 1 to 4 carbon atoms. RNHCONHR (in the formula, R
is the same as above).

Examples of the primary amine used in the present invention include methylamine, ethylamine, n-propylamine, isopropylamine, cyclopropylamine, n-propylamine, and n-propylamine.
-butylamine, isobutylamine, secondary butylamine, tertiary butylamine, cyclobutylamine and the like.

Although this reaction is carried out in the presence of water, it can also be carried out in a mixed solvent system of water and an organic solvent. Such organic solvents include hydrocarbons such as hexane, heptane, and cyclohexane, aromatic hydrocarbons such as benzene, toluene, and chlorobenzene, diethyl ether, dibutyl ether,
Ethers such as tetrahydrofuran, esters such as ethyl acetate and butyl acetate, methylene chloride, chloroform,
Lower halogenated hydrocarbons such as 1,2-dichloroethane are used.

The amount of phosgene used may be about 0.3 to 0.6 mol, preferably about 0.4 to 0.5 mol, per mol of primary amine. If the amount of phosgene used is small, a large amount of primary amine remains and the yield decreases. Furthermore, if the amount of phosgene used is too large, it is also undesirable because by-products such as biuret will increase.

[0010] Examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, and the like. Sodium hydroxide is preferably used because it has a high solubility in water and because an inorganic salt formed as a by-product in the reaction with phosgene has a high solubility in water.

[0011] The inorganic base is used during the reaction when the pH of the reaction solution is about 8.
-14, preferably about 9-13. If the pH is about 8 or less, the urea production reaction is inhibited or impurities such as guanidine are produced, which is not preferable. Furthermore, if the reaction is carried out under conditions of a high alkaline concentration with a pH exceeding 14, it is not preferable because phosgene decomposition increases and impurities such as biuret are produced.

The reaction is generally carried out at a temperature of about 0°C to 70°C, preferably about 10°C to 50°C. At this temperature the reaction proceeds sufficiently fast. The reaction is carried out while maintaining this temperature range while removing the reaction heat. When the reaction temperature exceeds about 70°C, hydrolysis of phosgene becomes significant, and when the reaction temperature falls below about 0°C, the reaction slows down, which is not preferable.

The reaction pressure may be either increased or reduced pressure, but the reaction is usually carried out at normal pressure. The reaction method can be carried out continuously, semi-continuously, or batchwise. The reaction is usually carried out by introducing an aqueous solution of phosgene and an inorganic base into a premixed solution of primary amines and water, or in some cases an organic solvent, such that the pH of the reaction solution is maintained at 8 to 14. be exposed.

The 1,3-disubstituted urea produced in the above reaction is already precipitated as crystals in the reaction solution, or is precipitated as crystals by cooling the reaction solution. The desired product is isolated by filtering and drying in a conventional manner. This product is further purified by means such as recrystallization, if necessary.

[0015]

Effect of the invention: By the method of the present invention, symmetrical 1,3-
Disubstituted urea can be easily produced under mild conditions with good yield.

[0016]

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited to these Examples.

Example 1 64.4 g (1.00 mol) of a 70% aqueous solution of ethylamine and water were placed in a glass reactor equipped with a gas inlet tube, reflux condenser, thermometer, stirrer, dropping funnel, and pH electrode. 26.0
44.5 g (0.45 mol) of phosgene and 191 g (1.10 mol) of a 23% caustic soda aqueous solution were introduced over 3 hours while adjusting the temperature to 10-20° C. and pH 10-13 while stirring.

After the introduction, when the reaction solution was cooled to 5° C., crystals of the product were precipitated to form a slurry, which was filtered, washed with 15 g of cold water, and dried under reduced pressure. 93.6 g of 3-diethylurea was obtained. Yield is 81%
The purity was 97%. Also, the melting point is 108~
The temperature was 109°C.

Example 2 The same procedure as in Example 1 was carried out except that 77.7 g (1.00 mol) of a 40% aqueous solution of methylamine was used instead of ethylamine. The product 1,3-dimethylurea is
4.1g was obtained. The yield was 73% and the purity was 98%. Moreover, the melting point was 102-104°C.

Example 3 Isopropylamine was used instead of ethylamine at 59.1
The same procedure as in Example 1 was conducted except that 45 g (1.00 mol) and 45 g of water were added. 123.8 g of the product 1,3-diisopropylurea was obtained. The yield was 86% and the purity was 97%. Also, the melting point is 188-190℃
Met.

Example 4 73.1 g of secondary butylamine instead of ethylamine
The same procedure as in Example 1 was conducted except that 45 g of water (1.00 mol) and 45 g of water were added. The product 1,3-di-second
159.5 g of grade butyl urea was obtained. The yield was 93% and the purity was 96%. Also, the melting point is 133-135℃
Met.

Claims (1)

[Claims] Claim 1: A primary amine represented by the general formula RNH2 (wherein R represents an unbranched or branched alkyl group having 1 to 4 carbon atoms) and phosgene are combined into an inorganic A general formula, RNHCO, characterized in that the reaction is carried out while maintaining the pH of the reaction solution in the range of 8 to 14 while adding a base.
Symmetrical 1 represented by NHR (wherein R is the same as above)
, 3-disubstituted urea production method.