JPS6312467B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing α-bromoisovalerylurea.

More specifically, using isovaleric acid as a raw material, it is reacted with bromine in the presence of isovaleric acid halide or α-bromoisovaleric acid halide to form α-bromination, and further reacted with thionyl chloride and urea to form α-
The present invention relates to a method for producing bromoisovalerylurea.

α-Bromoisovalerylurea is an industrially useful compound as an intermediate for pharmaceuticals or organic drugs.
It has also been widely used as a hypnotic sedative since ancient times.

Conventionally, the method for producing α-bromoisovaleryl urea involves α-brominating the α-carbon of isovaleric acid to obtain α-bromoisovaleric acid, which is then chlorinated with a chlorinating agent to form α-bromoisovaleryl urea. A method is known in which valeric acid chloride is obtained, purified, and then reacted with urea.

The α-bromination method is usually carried out by reacting isovaleric acid with bromine using red phosphorus or halogenated phosphorus as a catalyst.

However, in this method, the phosphorus-containing compounds left over from the catalyst cannot be reused, so appropriate treatment such as removing them from the system after the reaction is required, and consideration must be given to waste disposal or effective use of phosphorus. This has become a major industrial problem.

The present inventors previously conducted a detailed study on the behavior of the reaction, regarding problems when using a phosphorus-based catalyst for α-bromination of fatty acids, and found that fatty acid halide or α-brominated fatty acid halide is I applied for a patent after learning that it had the same effect as a system catalyst. (Japanese Patent Application No. 55-100923) In the present invention, this method is employed in the α-bromination step (a) of isovaleric acid. That is, when isovaleric acid and bromine are reacted, isovaleric acid halide or α-bromoisovaleric acid halide is used as a catalyst. This is advantageous in that it does not require post-treatment problems like those when using a phosphorus-based catalyst, and since α-bromoisovaleric acid halide is a reaction product of the subsequent step (b), no purification is required.

The isovaleric acid halide or α-bromoisovaleric acid halide used as a catalyst in the present invention is at least one of isovaleric acid chloride, isovaleric acid bromide, or an α-bromine derivative thereof.

The amount of isovaleric acid halide or α-bromoisovaleric acid halide is determined based on the raw material isovaleric acid.
A range of 0.0005 to 1 mole is appropriate. If the amount added is less than this, the effect as a catalyst will not increase, and if it is more than 1 mole, the necessary amount of α-bromoisovaleric acid halide will be converted to α-bromo fatty acid by appropriate treatment such as hydrolysis. This increases the number of steps and is not economical. Therefore, the amount is preferably 1 mole or less relative to the isovaleric acid used.

As an embodiment of the α-bromination step (a), a halogenating agent is added to the raw material isovaleric acid to convert a part of it into isovaleric acid halide, and bromine is added thereto to form the target product α- Produce bromoisovaleric acid or separately produce and add isovaleric acid halide,
It is preferable to react isovaleric acid and bromine in the presence of this catalyst.

In this case, the proportion of bromine to be reacted with isovaleric acid is 1.0 to 1.5 times the mole of bromine, preferably 1.02 to 1.1 times the mole of bromine to isovaleric acid.

If the amount of bromine added is small, the unreacted rate will increase, and if it is too large, the amount of bromine recovery equipment will increase, making it uneconomical. Further, the reaction temperature in the α-bromination step is suitably in the range of 60 to 90°C; if the temperature is too low, the reaction rate will be slow, and if the temperature is too high, the loss of bromine will be large.

In the present invention, α obtained in the α-bromination step (a)
-React the reaction solution containing bromoisovaleric acid with thionyl chloride.

In the step (b) of reacting the reaction solution containing α-bromoisovaleric acid with thionyl chloride, thionyl chloride is reacted dropwise into the reaction solution, and the amount is preferably 1 to 1.5 times the mole of raw material isovaleric acid. is 1.05 ~
It is 1.1 times the mole. If the amount added is too small, the amount of unreacted α-bromoisovaleric acid will increase, and if it is too large, not only will the yield not increase, but separation will be laborious.
The reaction temperature in this step is preferably kept in the range of 30 to 90°C, preferably 60 to 80°C.

In this step (b), the presence of N,N-dimethylformamide, N,N-dimethylacetamide or pyridine as a catalyst is effective in improving the yield. The amount is 0.05 to 15% by weight based on the raw material isovaleric acid, preferably 0.1
~5% by weight is suitable.

To recover unreacted thionyl chloride from the reaction solution in step (b), it is sufficient to obtain thionyl chloride as the first distillate by distillation, and the remaining liquid can be fed to the next step (c) for efficient reaction. can be done.

According to the conventional method, it was necessary to separate the insoluble tar from the reaction solution obtained in step (b) and then purify and isolate it by simple distillation. Grass acid halide or α
- Since bromoisovaleric acid halide is used, there is no need for a distillation operation, which is advantageous because it can be transferred to the next step.

The reaction solution obtained in step (b) can be reacted with urea in the presence of a chlorinated hydrocarbon solvent to obtain α-bromoisovalerylurea, which is the final target product, in step (c).

The chlorinated hydrocarbon solvent used in step (c) is
1.2-dichloroethane, trichlorethylene, perchlorethylene, etc. can be used as long as the boiling point is above room temperature, but good results are obtained when 1.2-dichloroethane or trichlorethylene is used.

When reacting urea and α-bromoisovaleric acid chloride, the proportion thereof is 100 to 500 mol%, preferably
It is sufficient to add 150 to 300 mol% of urea. In this case, urea may be dehydrated and dried.

Also, the reaction temperature is 10℃~150℃, preferably 40℃
It may be carried out at a temperature of ~90°C.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but is not limited thereto.

Example 1 46 g (0.45 mol) of isovaleric acid was charged into a 300 ml round bottom flask equipped with a reflux condenser, a thermometer, and a stirrer, and 8 g of α-bromoisovaleric acid chloride was added thereto as a catalyst. The temperature was raised to .degree. C., and 90.4 g (0.565 mol) of bromine was added dropwise over 4 hours while maintaining this temperature. After dropping, the mixture was aged at the same temperature for 4 hours with stirring, and then kept at 100°C for 2 hours.

After cooling the reaction solution, 0.25 ml of N,N-dimethylformamide was added as a chlorination catalyst, and 56.5 g (0.475 mol) of thionyl chloride was added dropwise at 50° C. over 2 hours. After dropping, aging was carried out at the same temperature for 2 hours.

90 g (1.5 mol) of urea and 220 ml of ethylene dichloride were placed in a 500 ml round bottom flask equipped with a thermometer, reflux condenser, and stirrer, and heated to 80° C. with stirring to distill out 63 g of ethylene dichloride.

Next, at 60°C, α-bromoisovaleric acid chloride 106 obtained above was added, and the mixture was aged at the same temperature for 4 hours. After aging, 200 ml of water was added, washed, and overdried.

2-Bromo-3-methylbutyryl urea 104g
(0.466 mol) was obtained.

The yield was 95.0% based on the raw material isovaleric acid.

When this is recrystallized with ethanol water, the melting point is 155 ~
White crystals at 156°C were obtained with a yield of 94%.

Example 2 α-bromoisovaleric acid chloride obtained in the same manner as in Example 1 was distilled to have a bp30 of 68 to 70°C.
The residual liquid obtained by distilling off the following fractions was reacted with urea in the same manner as in Example 1 to obtain 2-bromo-3-methylbutyryl urea.

The yield was 92.5% based on the raw material isovaleric acid.

The fraction with a bp30 of 68 to 70°C or less can be used as a catalyst in the synthesis of α-bromoisovaleric acid.

Example 3 2-Bromo-3-methylbutyryl urea was obtained in the same manner as in Example 1, except that perchloroethylene was used as a solvent during the reaction with urea.

The yield was 90.0% based on the starting material isovaleric acid.

Claims (1)

[Claims] 1. Isovaleric acid and bromine are combined in the presence of isovaleric acid halide or α-bromoisovaleric acid halide.
- Step (a) of brominating, step (b) of reacting the reaction solution obtained in step (a) with thionyl chloride to produce α-bromoisovaleric acid chloride, and step (b) of reacting the reaction solution obtained in step (b) with thionyl chloride. A method for producing α-bromoisovalerylurea, which comprises a step (c) of reacting with urea in the presence of a chlorinated hydrocarbon solvent. 2. The method according to claim 1, wherein 1.0 to 1.5 times the mole of bromine is added to isovaleric acid. 3. The method according to claim 1, wherein 0.0005 to 1 mole of isovaleric acid halide or α-bromoisovaleric acid halide is added to isovaleric acid. 4 1.0 to 1.5 of thionyl chloride to isovaleric acid
The method according to claim 1, wherein twice the molar amount is added. 5. The method according to claim 1, wherein the residual liquid from which unreacted thionyl chloride is recovered from the reaction solution in step (b) is supplied to step (c) and reacted with urea. 6. The method according to claim 1, wherein urea is added 1 to 5 times the mole of α-bromoisovaleric acid halide. 7. The method according to claim 1, wherein the chlorinated hydrocarbon solvent is 1,2-dichloroethane. 8. The method according to claim 1, wherein the chlorinated hydrocarbon solvent is trichlorethylene.