JPS63107965A - Production of tetrahydro-2(1h)-pyrimidinones - Google Patents

Abstract

PURPOSE:To directly readily obtain the titled compound which is an intermediate of medicine, agricultural chemicals, etc., in low price and one stage in high yield, by reacting diamines with phosgene substantially in the presence of water and dehydrochloric acid agent, when the diamine is reacted with the phosgene each as a raw material. CONSTITUTION:Diamines expressed by formula I (R is H or lower alkyl; R' is trimethylene or trimethylene substituted by lower alkyl) is reacted with phosgene substantially in the presence of water and dehydrochloric acid agent, preferably at 0-70 deg.C, more preferably while maintaining pH within the range of 3.0-10.0 to provide a compound expressed by formula II. Water used in above-mentioned reaction is used preferably in an amount enough to maintain an uniform reaction, namely 0.5-50wt. times, preferably 3-30wt. times based on the diamine. The dehydrochloric acid agent is sodium hydroxide, pyridine, etc., and preferably used in a range of 1.0-1.5 times of stoichiometric amount based on diamines of raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to the formula (I) +1-o-Ro-o-1! (1) (In the formula, R is a hydrogen atom or a lower alkyl group, and Ro is a trimethylene group or a trimethylene group substituted with a lower alkyl group.) Using diamines represented by the formula (n) ( The present invention relates to an improvement in a method for producing tetrahydro-2(IH)-pyrimidinones represented by the formula (where R and R' are the same as R and R' in formula (1)).

Tetrahydro-2(II)- represented by the above formula (II)
Pyrimidinones are useful substances as aprotic polar solvents and intermediates for pharmaceuticals and agricultural chemicals. Especially polyamides,
It is an excellent solvent for polymeric compounds such as polyvinyl chloride, polyvinyl alcohol, polystyrene, polyurethane, and phenolic resins. It forms complex salts with many inorganic salts and dissolves them, and is also a solvent for many organic reactions. It is a useful substance that is also used as

(Prior Art) Many methods for producing tetrahydro-2(LH)-pyrimidinones have been proposed.

For example, a method of reacting diamines represented by formula (1) with urea, a method of reacting diamines represented by formula (I) with carbon monoxide, a method of isomerizing 2-pyrrolidinone oxime, 2- A method of hydrogenation by reacting propenal with urea, tetrahydro-2(LH)-
A method of reacting a pyrimidinone with an alkyl halide,
A method of reacting tetrahydro-2(IH)-pyrimidinethione with an alkyl halide has been proposed.

In addition, a method using diamines represented by the above formula (+) and phosgene is also known, and N, N'-dimethyl-1
, Method of Reacting 3-Propanediamine and Phosgene in Toluene C Journal of the Chemical Society (J, Chem, Soc,), 1947, 31
page 5], and N,N'-bis(trimethylsilyl)-1
, 3-propanediamine and phosgene, and then hydrolyzing the obtained tetrahydro-1,3-bis(trimethylsilyl)-2(1)1)-pyrimidinone [Hemische Berichte (Chem.

Her, ), vol. 93, p. 2813 (1960)
〕It has been known.

However, the method of reacting N,N'-diamino-1,3-propanediamine and phosgene in toluene is
When the present inventors conducted additional experiments, the yield was less than 20%. Mana, N, N'-bis(trimethylsilyl)-
Although the method of reacting 1,3-propanediamine and phosgene has a yield of i%, it is necessary to obtain a silylated product in advance, and this method cannot be carried out by directly reacting phosgene, and requires expensive silylation. agent must be used.

(Problems to be Solved by the Invention) Using diamines represented by the above formula N) and phosgene,
Methods for obtaining tetrahydro-2(II()-pyrimidinones) are known as mentioned above, but none of them are satisfactory as industrial production methods.Therefore, these production methods were improved to obtain the formula ( There has been a desire for an industrial production method in which diamines represented by (2) and phosgene are directly reacted in one step, and tetrahydro-2(Ill)-pyrimidinones can be obtained at low cost and in good yields.

(Means for Solving the Problems) The present inventors have made efforts to develop an industrial method for producing tetrahydro-2'(1)1)-pyrimidinones using diamines represented by the above formula (1) and phosgene. We investigated and obtained the following findings.

Usually, reactions using phosgene are carried out in the absence of water as much as possible, and it is known that phosgene is easily hydrolyzed in alkaline aqueous solutions. of phosgene would be required.

However, it has surprisingly been found that in the reaction of the diamine represented by the formula (I) and phosgene according to the present invention, 1.0 to 1.5 times the stoichiometric amount of phosgene is sufficient. In addition, by allowing water and a dehydrochlorination agent to exist, the tetrahydro-
It was found that the yield of 2(IH)-pyrimidinones was dramatically improved compared to the conventional method. Furthermore, in the presence of water, the pH during the reaction is maintained within a certain range using a dehydrochlorination agent, that is,
It was found that the yield was further improved dramatically by maintaining the ratio between 3.0 and 10.0, which led to the present invention.

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

In addition, since a dehydrochlorination agent is used in conjunction with the reaction, the dehydrochlorination agent not only efficiently catches by-product hydrochloric acid, but also works particularly well when the reaction is carried out while maintaining the pH in the range of 3.0 to 10.0. , the desired product can be obtained in a higher yield than could be expected using conventional techniques.

The reason for this is that when monocarbamyl chloride of amines, which is first produced by phosgenation of diamines, undergoes intramolecular cyclization, by controlling the pH, byproducts due to intermolecular reactions and dicarbamyl chloride of diamines are produced. This is thought to be because it became possible to suppress by-products such as milk chloride.

In the present invention, the raw material diamines represented by the formula (1) are, for example, 1,3-propanediamine, N,N'-
Dimethyl-1,3-propanediamine, N.

N'-diethyl-1,3-propanediamine, N,N'
-dipropyl-1,3-propanediamine, N,N'-
Bis(1-methylethyl)-1,3-propanediamine, N,N'-dibutyl-1,3-propanediamine, 2
．． 2-dimethyl-1,3-propanediamine, N, N'
, 2,2-tetramethyl-1,3-propanediamine. These diamines can be easily obtained by reacting a corresponding dihaloalkane with ammonia or a corresponding monoalkylamine.

In the method of the present invention, using these compounds of formula (1), the corresponding tetrahydro-2(1)1)-pyrimidinone, tetrahydro-1,3-dimethyl-2(lH)-pyrimidinone, 1,3-diethyltetrahydro -2(I)l)
-pyrimidinone, tetrahydro-1,3-dipropyl-
2(1)1)-pyrimidinone, tetrahydro-1,3-
Bis(1-methylethyl)-2(1)1)-pyrimidinone, 1,3-dibutyltetrahydro-2(IH)-pyrimidinone, tetrahydro-5,5-dimethyl-2(I
H)-pyrimidinone, tetrahydro-1,3°5.5-
Formulas such as tetramethyl-2(IH)-pyrimidinone (U
) Compounds of tetrahydro-2(LH)-pyrimidinones can be obtained.

In the method of the present invention, diamines are directly phosgenated or converted into hydrochlorides and subjected to reaction with phosgene.

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

When using diamines as hydrochlorides, if an equivalent amount of hydrochloric acid is used to prepare the diamines as dihydrochlorides, p)I at the beginning of the reaction will be about 3, and even if the dihydrochlorides obtained are subjected to a phosgenation reaction, The reaction rate is extremely slow.

Therefore, when using the hydrochloride, it is preferable to react around the monohydrochloride with an equivalent amount or less of hydrochloric acid reacted, and when preparing the dihydrochloride from the beginning, dehydrochloride it in advance with a dehydrochloric agent to bring the pH to 3 or more. After that, it is preferable to carry out a phosgenation reaction.

Further, when the diamines are directly charged and reacted, the pH at the beginning of the reaction is 11 or more, and it is preferable to add hydrochloric acid in advance to the phosgenation reaction to adjust the pH to 10 or less.

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

The dehydrochlorination agent used in the present invention is an alkali metal compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, or an aliphatic tertiary amine such as trimethylamine or triethylamine, dimethylaniline, or diethylaniline. aromatic tertiary amines, such as
Tertiary amines such as heterocyclic tertiary amines such as pyridine, methylpyridine, pyrazine and the like are preferred.

If a dehydrochlorination agent is not used, the raw material itself becomes a catch agent for by-product hydrochloric acid, making it difficult to proceed with the reaction any further.

Furthermore, the reaction temperature in the present invention is not particularly limited, but
Preferably it is carried out at 0 to 70°C.

The amounts of phosgene and dehydrochlorination agent used in the method of the present invention are:
Although not particularly limited, 1.0 to 1.5 times the stoichiometric amount of the raw material diamine is sufficient.

Further, the amount of dehydrochlorination agent relative to phosgene may be around the stoichiometric amount.

A typical preferred embodiment of the method of the invention is as follows.

Water and the diamines represented by formula (1) above 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. Although the reaction may be started as it is, it is preferable to add hydrochloric acid to adjust the pH of the charging solution to about 3 to 10. While stirring this liquid at an appropriate temperature, phosgene is introduced from the phosgene blowing tube, and at the same time, a dehydrochloric agent is added dropwise from the dropping funnel. Thereby, the pH of the reaction solution is maintained at 3.0 to 10.0, preferably 5.0 to 8.0. After blowing and dropping,
Unreacted phosgene is purged with nitrogen, and the desired product is taken out by a conventional method such as extraction and/or distillation.

(Effects of the Invention) The present invention has the following effects compared to the conventional technique for obtaining tetrahydro-2(Ill)-pyrimidinones using the diamine represented by the formula (1) and phosgene.

(1) Tetrahydro-2(IH)-pyrimidinones can be obtained in high yield and at low cost.

(2) Since the diamines shown in formula (1) and phosgene are directly reacted, the operation is simple.

(Example) Examples and comparative examples are shown below.

Example-1 Into a 300 d glass flask equipped with a phosgene blowing tube, a dropping funnel, a thermometer, a reflux condenser, and a stirrer, 100 adSN of water, 20.5 g of N'-dimethyl-1,3-propanediamine (0 , 20 mol), and on the other hand, 84.0 g of 20% aqueous sodium hydroxide solution was placed in the dropping funnel.
(0.4 mol) was prepared.

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

After completing the blowing and dropping, the mixture was further aged at 20''C for 1 hour.

This reaction mass was sampled and subjected to gas chromatography to obtain tetrahydro-1,3-dimethyl-2(18
)-pyrimidinone was quantified. Production yield is 77.1
%Met.

Example-2 14.8 g of 1,3-propanediamine (0,2
The reaction was carried out in the same manner as in Example-1 except that 0 mol) was used,
Analysis was carried out. As a result, tetrahydro-2(IH)-
The production yield of pyrimidinone was 76.8%.

Example 3 Example except that 26.0 g (0.20 mol) of N,N'-diethyl-1,3-propanediamine was used instead of N,N"-dimethyl-1,3-propanediamine. 1
The reaction and analysis were performed in the same manner as above. As a result, 1.3-
The production yield of diethyltetrahydro-2(Ill)-pyrimidinone was 73.3%.

Example 4 Example except that 37.2 g (0.20 mol) of N, N'-dibutyl-1,3-propanediamine was used instead of N, N'-dimethyl-1,3-propanediamine. The reaction and analysis were conducted in the same manner as in 1. As a result, 1.
The production yield of 3-dibutyltetrahydro-2(IH)-pyrimidinone was 71.9%.

Example 5 Example except that 20.4 g (0.20 mol) of 2,2-dimethyl-1,3-propanediamine was used instead of N,N'-dimethyl-1,3-propanediamine.
The reaction and analysis were conducted in the same manner as in 1. As a result, the production yield of tetrahydro-5,5-dimethyl-2(IH)-pyrimidinone was 75.5%.

Example-6 26.0 g (0.20 mol) of N, N', 2,2-tetramethyl-1,3-propanediamine was used instead of N, N'-dimethyl-1,3-propanediamine. The reaction and analysis were conducted in the same manner as in Example-1 except for the following. As a result, tetrahydro-1,3,5,5-tetramethyl-
The production yield of 2(1)-birimidinone was 73.9%.

Example-7 The reaction and analysis were conducted 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. the result,
The production yield of tetrahydro-1,3-dimethyl-2(Ill)-pyrimidinone was 70.4%.

Example-8 Into a 500 d 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 d of water, N,N''-dimethyl-1
, 20.4 g (0.20 mol) of 3-propanediamine and 30.4 g (0.30 mol) of 36% hydrochloric acid were charged.

Meanwhile, in the dropping funnel, add 1 liter of 20% sodium hydroxide aqueous solution.
68°0 g (0.80 mol) was prepared.

The reaction temperature was maintained at 20° C. with cooling, and phosgene was bubbled in at Log/hr for 2 hours while stirring. At the same time, aqueous sodium hydroxide solution was added for 2 hours to reduce p)l of the reaction solution to 7.
It was added dropwise while controlling the amount to be 0±0.3. After the blowing and dropping were completed, the inside of the system was purged with nitrogen at 201/min for 20 minutes.

This reaction mass was sampled and analyzed by gas chromatography to obtain tetrahydro-1,3-dimethyl-2(18).
- Pyrimidinone was quantified. Production yield is 90.7%
Met.

After the reaction was completed, 49% aqueous sodium hydroxide was added to adjust the pH to around 12, and then 150 g/1,2-dichloroethane was added.
The oil layer was extracted twice and the oil layer was separated and distilled to obtain 21.8 g of tetrahydro-1,3-dimethyl-2(IH)-pyrimidinone (boiling point 93-94° (15 Lorr fraction)).

(Comparative Example 1) Toluene 100% was added to a 300 m glass flask equipped with a phosgene blow tube, a thermometer, a reflux condenser, and a stirrer.
20.4 g (0.20 mol) of d,,N,N'-dimethyl-1,3-propanediamine were charged. The internal temperature of the flask was maintained at 20° C., and phosgene was blown into the flask at Log/hr for 2 hours through the phosgene blowing tube while stirring.

This reaction mass was sampled and analyzed by gas chromatography.
)-pyrimidinone was quantified. Production yield is 17.6
%Met.

Claims (5)

[Claims] (1) Formula (I) R-NH-R'-NH-R (I) (wherein, R is a hydrogen atom or a lower alkyl group, and R' is a trimethylene group or a trimethylene group substituted with a lower alkyl group) .) The reaction between diamines and phosgene results in formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (In the formula, R and R' are the same as R and R' in formula (I). ) A method for producing tetrahydro-2(1H)-pyrimidinones, which is characterized in that the reaction is carried out substantially in the presence of water and a dehydrochlorination agent. (2) Formula (I) R-NH-R'-NH-R(I) (wherein, R is a hydrogen atom or a lower alkyl group, and R' is a trimethylene group or a trimethylene group substituted with a lower alkyl group) ) and/or its hydrochloride and phosgene, the formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (where R and R' are the formula (I )) When obtaining the tetrahydro-2(1H)-pyrimidinones represented by
．． 1. A method for producing tetrahydro-2(1H)-pyrimidinones, the method comprising carrying out the reaction while maintaining the temperature at 0. (3) The method according to claim (2), wherein the pH is maintained at 5.0 to 8.0. (4) The method according to claim (1) or (2), wherein the dehydrochlorination agent is an alkali metal compound. (5) The method according to claim (1) or (2), wherein the dehydrochlorination agent is a tertiary amine.