JPH0759568B2 - Method for producing hexahydro-2H-1,3-diazepin-2-ones - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention has the formula (I) R—NH—R′—NH—R (I) (wherein R is a hydrogen atom or a lower alkyl group, and R ′ is A tetramethylene group or a tetramethylene group substituted with a lower alkyl group) and phosgene are used to prepare a compound of formula (II) (Wherein R and R'are the same as R and R'in formula (I)) The present invention relates to a method for producing hexahydro-2H-1,3-diazepin-2-ones.

Hexahydro-2H-1,3-diazepin-2-ones represented by the above formula (II) are aprotic polar solvents and pharmaceuticals.
It is a useful substance as an intermediate for agricultural chemicals. In particular, it is an excellent solvent for high molecular compounds such as polyamides, polyvinyl chloride, polyvinyl alcohol, polystyrene, polyurethane, and phenol resins, and it forms complex salts with many inorganic salts and dissolves, It is a useful substance that is also used as a solvent for the reaction.

(Prior Art) Many methods for producing hexahydro-2H-1,3-diazepin-2-ones have been proposed.

For example, a method of reacting 1,4-butanediamine with carbonyl sulfide and cyclizing with concentrated hydrochloric acid. A method of reacting 1,4-butanediamine with carbon monoxide and sulfur. A method of isomerizing 2-piperidinone oxime with polyphosphoric acid. A method of treating hexahydro-2H-1,3-diazepine-2-thione with an aqueous alkaline solution. A method of reacting hexahydro-2H-1,3-diazepin-2-one with an alkyl halide. A method of reacting hexahydro-2H-1,3-diazepine with an alkyl halide in an aqueous alkaline solution has been proposed.

In addition, the diamines represented by the formula (I) are directly reacted with phosgene to produce hexahydro-2H-1,3-diazepine-
A method for obtaining 2-ones is not known, but as an indirect method, N, N'-bis (trimethylsilyl) -1,4-butanediamine and phosgene are reacted to obtain hexahydro-1,3- A method is known in which bis (trimethylsilyl) -2H-1,3-diazepin-2-one is then hydrolyzed [Chem. Ber., Chem. Ber., Vol. 93, page 2813 (1960)].

However, it is necessary to obtain a silylated product of 1,4-butanediamine in advance using an expensive silylating agent, and the yield of the phosgenation reaction is as low as 60%, which is not industrially satisfactory.

(Problems to be Solved by the Invention) A method for obtaining hexahydro-2H-1,3-diazepin-2-ones using the diamines represented by the formula (I) and phosgene is known as described above. However, it was not a direct and still unsatisfactory industrial process.

INDUSTRIAL APPLICABILITY The present invention is an industrial method in which a diamine represented by the above formula (I) and phosgene are directly reacted in one step, and hexahydro-2H-1,3-diazepin-2-ones can be obtained at a good yield and at a low cost. It provides a manufacturing method.

(Means for Solving the Problems) The present inventors have used hexahydro-2H-1,3-diazepine-containing diamines represented by the formula (I) and phosgene.
The inventors have earnestly studied the industrial production method of 2-ones and obtained the following findings.

Usually, the reaction using phosgene is carried out in the absence of water as much as possible, and it is known that phosgene is easily hydrolyzed in an alkaline aqueous solution, which requires a large excess of phosgene. It was expected.

Surprisingly, however, in the reaction of the diamines of formula (I) according to the invention with phosgene, it was found that 1.0 to 1.5 times the stoichiometric amount of phosgene is sufficient, and By allowing the presence of a dehydrochlorinating agent, the desired product hexahydro-2H-1, represented by the above formula (II),
It was found that the yield of 3-diazepin-2-ones is dramatically improved as compared with the conventional method. Further, at that time, the pH is kept in a certain range during the reaction by the dehydrochlorinating agent in the presence of water, that is, 3.
It was found that the yield can be dramatically improved by maintaining it at 0 to 10.0, and the present invention has been achieved.

In the method of the present invention, since water is substantially present, that is, the reaction is carried out in an aqueous medium, the diamine hydrochloride successively produced by hydrochloric acid by-produced by the phosgenation reaction is Since it is dissolved in water without being precipitated outside the system, the reaction can be carried out in a homogeneous state. Therefore, the pH of the reaction can be controlled very easily.

In addition, since a dehydrochlorinating agent is also used during the reaction, the dehydrochlorinating agent not only acts efficiently on catching byproduct hydrochloric acid, but also
When the reaction is carried out while maintaining the pH in the range of 3.0 to 10.0, the target product is obtained in a high yield which cannot be predicted by the conventional techniques.

The reason is that when the monocarbamyl chloride of the diamine, which is first formed by the phosgenation of the diamine, undergoes intramolecular cyclization, the pH is controlled so that the by-product due to the intermolecular reaction and the dicarbamide of the diamine are generated. This is probably because byproducts such as milk loride can be suppressed.

In the present invention, the starting diamines represented by the formula (I) are, for example, 1,4-butanediamine, N, N′-dimethyl-1,4-butanediamine, N, N′-diethyl-1,4. -Butanediamine, N, N'-dipropyl-1,4-butanediamine, N, N'-dibutyl-1,4-butanediamine, N, N'-
It is dimethyl-2,5-hexanediamine, and these diamines can be easily obtained by reacting a corresponding dihaloalkane with ammonia or a corresponding monoalkylamine.

In the method of the present invention, these diamines are used as raw materials and the corresponding hexahydro-2H-1,3 represented by the above formula (II) is used.
-Diazepin-2-one, hexahydro-1,3-dimethyl-2H-1,3-diazepin-2-one, 1,3-diethylhexahydro-2H-1,3-diazepin-2-one, hexahydro-1 , 3-Dipropyl-2H-1,3-diazepine-2-
Hexahydro-, such as one, 1,3-dibutylhexahydro-2H-1,3-diazepin-2-one, hexahydro-4,4,7,7-tetramethyl-2H-1,3-diazepin-2-one 2H-1,3-diazepin-2-ones are obtained.

In the present invention, the diamines are either directly phosgenated or made into the hydrochloride salt and combined with the reaction with phosgene.

However, in the method in which the reaction is carried out while maintaining the pH at 3.0 to 10.0, it is advantageous to charge it as the hydrochloride from the beginning of the reaction.

When using it as the diamine hydrochloride, if hydrochloric acid is used as the diamine dihydrochloride in an equivalent amount, the
The pH is about 3, and the reaction rate is extremely slow even if the obtained dihydrochloride is subjected to a phosgenation reaction.

Therefore, when used as the hydrochloride, it is preferable to react in the vicinity of the monohydrochloride which has been reacted with hydrochloric acid in an equivalent amount or less. When the dihydrochloride is charged from the beginning, dehydrochlorination is performed in advance with a dehydrochlorinating agent to adjust the pH to 3 or more. Then, the phosgenation reaction is preferably performed.

When the diamines are charged as they are for the reaction, the pH at the beginning of the reaction is 11 or higher, and hydrochloric acid is preferably added before the phosgenation reaction so that the pH is 10 or lower.

The water used in the present invention needs to be substantially present, and may be placed in the reactor in advance, or may be added dropwise together with the dehydrochlorinating agent, for example, as an aqueous solution of an alkali metal compound. May be. The amount of water used is not particularly limited, but is preferably an amount sufficient to maintain a uniform reaction, and is 0.5 to 50 times by weight, preferably 3 to 3 times the weight of the diamine.
0 weight times is good.

The dehydrochlorinating agent used in the present invention is an alkali metal compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or trimethylamine,
Aliphatic tertiary amines such as triethylamine, aromatic tertiary amines such as dimethylaniline, diethylaniline, tertiary amines such as pyridine, methylpyridine, heterocyclic tertiary amines such as pyrazine, etc. Is preferred. If a dehydrochlorinating agent is not used, the raw material itself becomes a catching agent for by-produced hydrochloric acid, and it becomes difficult to proceed the reaction any further.

The reaction temperature in the present invention is not particularly limited, but is preferably 0 to 70 ° C.

The amount of the dehydrochlorinating agent used in the present invention varies depending on the pH range during the reaction, but, for example, when the reaction is performed in the neutral region, it is appropriately determined according to the hydrochloric acid produced as a by-product and the amount of hydrochloric acid consumed during the charging. , And the amount of phosgene is 1.0 to 1.5 times the stoichiometric amount for diamines, that is, 1.
0 to 1.5 times mol is sufficient.

The usual preferred embodiments of the method of the invention are as follows.

Water and the diamine represented by the above formula (I) are added to a reactor equipped with a phosgene blowing tube, a dropping funnel, a pH measuring electrode, a thermometer, a reflux condenser and a stirrer. The reaction may be started as it is, but preferably, hydrochloric acid is added to adjust the pH of the charged solution to about 3 to 10. While stirring this solution at an appropriate temperature, phosgene is introduced from a phosgene blowing tube, and at the same time, a dehydrochlorinating agent is dropped from a dropping funnel. This maintains the pH of the reaction solution at 3.0 to 10.0, preferably 5.0 to 8.0. After completion of blowing and dropping, unreacted phosgene is purged with nitrogen, and a target product is taken out by a usual method such as extraction and / or distillation.

(Effects of the Invention) The present invention has the following effects as compared with the conventional technique for obtaining hexahydro-2H-1,3-diazepin-2-ones using the diamines represented by the formula (I) and phosgene. Have.

(1) Since the diamines represented by the above formula (I) are directly reacted with phosgene, the operation is simple.

(2) The amount of toxic and highly corrosive phosgene used may be 1.0 to 1.5 times the molar amount of the diamines represented by the formula (I), and hexahydro-2H-1,3-diazepine-2- can be inexpensively used. The ons are obtained in high yield.

(Example) An example and a comparative example are shown below.

Example-1 A 300 ml glass flask equipped with a phosgene blowing tube, a dropping funnel, a thermometer, a reflux condenser and a stirrer was charged with 100 m of water.
l, N, N'-dimethyl-1,4-butanediamine 23.2 g (0.20
Mol), while 84.0 g (0.40 mol) of 20% aqueous sodium hydroxide solution was prepared in the dropping funnel.

The temperature inside the flask was maintained at 20 ° C., and phosgene was blown through the phosgene blowing tube at 10 g / hr for 2 hours while stirring. At the same time, a 20% aqueous sodium hydroxide solution was added dropwise from the dropping funnel over 2 hours. After blowing and dropping,
Further, it was aged at 20 ° C. for 1 hour.

The reaction mass was sampled and hexahydro-1,3-dimethyl-2H-1,3-diazepin-2-one was quantified by gas chromatography. Production yield is 78.9%
Met.

Example-2 Instead of N, N'-dimethyl-1,4-butanediamine, 1,
The reaction was performed and analyzed in the same manner as in Example 1 except that 17.6 g (0.20 mol) of 4-butanediamine was used. as a result,
The production yield of hexahydro-2H-1,3-diazepin-2-one was 80.1%.

Example-3 Instead of N, N'-dimethyl-1,4-butanediamine, N,
An analysis was carried out by reacting in the same manner as in Example-1 except that 28.9 g (0.20 mol) of N'-diethyl-1,4-butanediamine was used. As a result, 1,3-diethyl-hexahydro-2
The production yield of H-1,3-diazepin-2-one-is 75.7%.
Met.

Example 4 Instead of N, N'-dimethyl-1,4-butanediamine, N,
An analysis was carried out by reacting in the same manner as in Example-1 except that 31.7 g (0.20 mol) of N'-dipropyl-1,4-butanediamine was used. As a result, the yield of hexahydro-1,3-dipropyl-2H-1,3-diazepin-2-one was 72.7%.
Met.

Example-5 Instead of N, N'-dimethyl-1,4-butanediamine, N,
An analysis was conducted by reacting in the same manner as in Example-1 except that 34.5 g (0.20 mol) of N'-dibutyl-1,4-butanediamine was used. As a result, 1,3-dibutylhexahydro-2H
The production yield of -1,3-diazepin-2-one was 72.3%.

Example-6 Instead of N, N'-dimethyl-1,4-butanediamine, 2,
The reaction and analysis were carried out in the same manner as in Example-1 except that 28.9 g (0.20 mol) of 5-dimethyl-2,5-hexanediamine was used. As a result, hexahydro-2H-4,4,7,7-
The production yield of tetramethyl-2H-1,3-diazepin-2-one was 75.2%.

Example-7 The reaction and analysis were carried out in the same manner as in Example-1 except that 40.5 g (0.40 mol) of triethylamine was used instead of the 20% aqueous sodium hydroxide solution. As a result, the hexahydro-1,3-dimethyl-2H-1,3-diazepin-2-one production yield was 71.4%.

Example-8 In a 500 ml glass flask equipped with a phosgene blowing tube, a dropping funnel, an electrode for pH measurement, a thermometer, a reflux condenser and a stirrer, 100 ml of water, N, N'-dimethyl-1,4-butanediamine 23.2 g (0.20 mol) and 36% hydrochloric acid 30.4 (0.30 mol)
Charged.

On the other hand, 168.
0 g (0.80 mol) was prepared.

While cooling, the reaction temperature was maintained at 20 ° C., and phosgene was bubbled under stirring at 10 g / hr for 2 hours. At the same time, an aqueous sodium hydroxide solution was added dropwise over 2 hours while controlling the pH of the reaction solution at 7.0 ± 0.3. After the completion of blowing and dropping, the inside of the system was purged with 20 l / min of nitrogen for 20 minutes.

The reaction mass was sampled, and hexahydro-1,3-dimethyl-2H-1,3-diazepin-2-one was quantified by gas chromatography. The production yield was 91.2%.

After adding 49% aqueous sodium hydroxide to the reaction-terminated liquid to adjust the pH to around 12, the mixture was extracted twice with 150 g of 1,2-dichloroethane, and the oil layer was separated and distilled to obtain hexahydro-1,3-dimethyl. -2H-1,3-diazepin-2-one (boiling point 94-95 ° C /
A fraction of 4 torr) was obtained.

(Comparative Example 1) To a 300 ml glass flask equipped with a phosgene blowing tube, a thermometer, a reflux condenser and a stirrer, 100 ml of toluene, N, N '.
23.2 g (0.20 mol) of dimethyl-1,4-butanediamine were charged. The temperature inside the flask was maintained at 20 ° C., and phosgene was blown through the phosgene blowing tube at 10 g / hr for 2 hours while stirring.

The reaction mass was sampled and hexahydro-1,3-dimethyl-2H-1,3-diazepin-2-one was quantified by gas chromatography. Production yield is 15.3%
Met.

Claims (6)

[Claims] 1. A compound represented by the formula (I) R-NH-R'-NH-R (I) (wherein R is a hydrogen atom or a lower alkyl group, and R'is a tetramethylene group or a lower alkyl group-substituted tetramethyl group. A diamine represented by the formula (II) (Wherein R and R'are the same as R and R'in the formula (I)), when the hexahydro-2H-1,3-diazepin-2-ones are obtained, substantially water and a dehydrochlorinating agent are used. A method for producing hexahydro-2H-1,3-diazepin-2-ones, which comprises reacting in the presence of 2. The method according to claim 1, wherein the pH is maintained at 3.0 to 10.0. 3. The method according to claim 1, wherein the pH is maintained at 5.0 to 8.0. 4. The method according to claim 1, wherein phosgene is used in an amount of 1.0 to 1.5 times the molar amount of the diamine represented by the formula (I). 5. The method according to claim 1, wherein the dehydrochlorination agent is an alkali metal compound. 6. The method according to claim 1, wherein the dehydrochlorinating agent is a tertiary amine.