JP2618713B2 - Method for producing β-hydroxyamino compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial application] The β-hydroxyamino compound produced by the present invention is an industrially important compound, for example, 1-aminopropanediol or 1- (methylamino) -Propanediol has received attention as a raw material for X-ray contrast agents, which have been growing in demand in recent years.

[Prior Art] Methods for producing β-hydroxyamino compounds have been well known.

For example, as shown in the following reaction formula, as a method for producing 1-aminopropanediol, there is a method of reacting glycidol with ammonia (for example, L. Knorr et al.,
“Ber.deutsch.Chem.Ges.”, Vol. 32, 750, 1899, K. Baum
"J. Org. Chem.", Vol. 27, 2231, 1962, "Publication Patent Publications" Sho 56-161357, Sho 56-161355, Sho 56-16
1356).

The reaction mechanism is considered to be a ring-opening addition reaction to the electron-deficient carbon atom of the epoxy ring of glycidol by nucleophilic attack of ammonia.

[Problems to be Solved by the Invention] However, in these prior arts, in addition to the main reaction represented by the above reaction formula, there are many side reactions represented by the following reaction formula, and therefore, the yield of the target product is low and sufficient. Was not.

Further, as a technique related to the present invention, glycerin-α
A method for producing 1-aminopropanediol from monochlorohydrin and aqueous ammonia is known (K.
Baum et al., "J. Org. Chem." Vol. 27.2231, 1962).

This method is basically different from the present invention in that an epoxy compound is not used as a raw material and a halohydrin compound is used instead.

However, it may be via an epoxy compound as an intermediate.

The amount of by-produced hydrogen chloride is at most only an equimolar amount to glycerin-α-monochlorohydrin as the raw material charged.

With such an amount, the yield of 1-aminopropanediol is not improved.

Therefore, this method is used for producing a β-hydroxyamino compound from an epoxy compound and an amine.
There is no indication that the presence of HCl increases the yield.

This method also has a disadvantage that the reaction rate is lower than that of the present invention.

This is shown in << Reference Example 1 >><< Reference Example 2 >><< Reference Example 3 >> after the Examples and Comparative Examples.

[Object of the Invention] An object of the present invention is to develop a technique capable of producing a β-hydroxyamino compound from an epoxy compound and an amine in good yield.

In view of the above situation, the present inventors have conducted intensive studies and as a result, when reacting an epoxy compound with an amine, if the reaction is carried out in the presence of a certain amount or more of hydrogen halide or its ammonium salt, β- The inventors have found that the yield of the hydroxyamino compound is improved, and completed the present invention.

[Constitution of the Invention] That is, the present invention relates to an epoxy compound represented by the following general formula A-1 or general formula A-2 [However, in the general formulas A-1 and A-2, R ₁ ,
R ₂ , R ₃ , and R _{4 each} represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, or a substituent that can take any combination of the same or different selected from aryloxy groups; And an alkylene group having 3 or 4 carbon atoms in the chain]. [Wherein, in the general formula B, R ₅ represents a substituent selected from a hydrogen atom, an alkyl group or an aryl group], and is represented by the following general formula C-1 or C-2 Hydroxyamino compounds Wherein the reaction is carried out in the presence of an excess amount of hydrogen halide or an ammonium salt thereof on a molar basis with respect to the epoxy compound, the production method of a β-hydroxyamino compound.

Hereinafter, the method for producing the β-hydroxyamino compound of the present invention will be described in detail.

<< Epoxy Compound >> The raw material epoxy compound used in the present invention is an epoxy compound represented by the following general formula A-1 or general formula A-2. [However, in the general formulas A-1 and A-2, R ₁ ,
R ₂ , R ₃ , and R _{4 each} represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, or a substituent that can take any combination of the same or different selected from aryloxy groups; Represents an alkylene group having 3 or 4 carbon atoms in the chain].

Examples of specific epoxy compounds include glycidol,
Ethylene oxide, propylene oxide, epoxidized soybean oil, epoxidized linseed oil, allyl glycidyl ether, butyl glycidyl ether, phenyl glycidyl ether, 2-ethylhexyl glycidyl ether, trimethylolpropane polyglycidyl ether, glycerol polyglycidyl ether, ethylene glycol polyglycidyl ether , Cyclohexene monoepoxide,
Vinylcyclohexene monoepoxide, etc.,
These epoxy compounds may further have a substituent within a range that does not hinder the reaction.

<< Amine >> The amine used in the present invention is an amine represented by the following general formula B [Wherein, in the general formula B, R ₅ represents a substituent selected from a hydrogen atom, an alkyl group and an aryl group].

Specific examples of amines include ammonia, methylamine, ethylamine, ethanolamine, benzylamine, cyclohexylamine, and the like, and these amines may further have a substituent within a range that does not hinder the reaction. .

It is considered that some or most of these are present as salts (ammonium salts) with an amine as a raw material and / or a β-hydroxyamino compound as a product in the reaction system. The salt form is also effective for improving the yield of the β-hydroxyamino compound.

Therefore, the form to be added to the reaction system is not only the form of hydrogen halide described above, but also the form of an ammonium salt with an amine as a raw material or an ammonium salt with another amine (including ammonia). May be.

Hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide and the like used in the present invention may be used alone or in combination of several kinds.

Considering the price, hydrochloric acid, hydrobromic acid and hydroiodic acid are preferred, and hydrochloric acid is more preferred.

Any of these may be used either in the anhydrous or aqueous state.

<< Concentration Ratio >> The above-mentioned concentration ratio of the epoxy compound, the amine, and the hydrogen halide or its ammonium salt needs to be in the following order in a molar ratio.

Epoxy compound <hydrogen halide or ammonium salt thereof <amine When the concentration of the epoxy compound is equal to or greater than the concentration of hydrogen halide or its ammonium salt, there is almost no yield improving effect as shown in Reference Example. .

Therefore, the required amount of hydrogen halide or its ammonium salt is 1.1 mole times or more, preferably 2 times or more of the epoxy compound (all in a molar ratio).

It is easily understood from the reaction formula that the amine is required to be at least equimolar to the epoxy compound. However, if the amine is not excessive with respect to the hydrogen halide or its ammonium salt present in the system, 1) the reaction is complete. Does not progress to
2) There are inconveniences such as an increase in side reactions caused by the acidic bias in the system.

Thus, the amine should be used in excess of the hydrogen halide or its ammonium salt.

Although the specific concentration ratio of each component cannot be generally limited, the molar ratio of hydrogen halide or its ammonium salt / epoxy compound is 1.1 times or more, preferably 2 times or more.

It is not preferable to use 100 mole times or more, since the purification cost is increased (neutralization, amine recovery). The amine / epoxy compound molar ratio is at least twice, preferably 5
More than double.

The larger the ratio, the higher the yield of the β-hydroxyamino compound tends to be. However, the use of 100 mol times or more is disadvantageous because the purification cost (recovery of amine) also increases.

<< Solvent >> In the method for producing a β-hydroxyamino compound of the present invention, a solvent may or may not be used.

If a solvent is used, it must, of course, be inert to the reaction.

Examples of preferred solvents are water, alcohols, ethers, hydrocarbons and the like.

<< Reaction temperature >> The reaction temperature in the case of carrying out the method for producing a β-hydroxyamino compound of the present invention is not particularly limited, but is usually -50 to 150 ° C, preferably 0 to 100 ° C. Done in

<< Pressure >> The reaction pressure when carrying out the method for producing a β-hydroxyamino compound of the present invention is not particularly limited, but is usually 50 mmHg to 200 atm, preferably normal pressure to 50 atm.
It is performed in the range.

<< Reaction Form >> The reaction in the production method of the present invention is carried out by a liquid phase reaction, but the form is not particularly limited. Any of a continuous flow system, a batch system, and a semi-batch system may be used.

The following can be considered as specific embodiments when the method for producing a β-hydroxyamino compound of the present invention is carried out.

The method according to claim 1, wherein (a) the amount of hydrogen halide or its ammonium salt is 1.1 mole times or more of the epoxy compound as one of the raw materials.

(B) The method according to claim 1, wherein the amount of the hydrogen halide or its ammonium salt is at least 2 mol times the amount of the epoxy compound as one of the raw materials.

(C) The method according to claim, wherein the amine is ammonia or methylamine.

(D) The method according to the claim, wherein the epoxy compound is glycidol.

Hereinafter, the effects of the present invention will be described with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[Example 1] 150 ml volume equipped with a stirrer, a condenser, and a thermometer
26.4 g (493 mmol, 5 mol times based on glycidol) of ammonium chloride [NH ₄ Cl] were added to a jacketed glass reactor of the formula (1), and then aqueous ammonia (28%), which is a specific example of the compound of formula B, was added. 90.0 g (including 1,480 mmol as NH ₃ ) was added.

While stirring the reaction solution, the temperature of the hot water circulating in the jacket was adjusted to raise the temperature of the reaction solution to 28 ° C.

Glycidol which is a specific example of the compound of the formula A-1
7.3 g (98.6 mmol) was charged to the reactor.

The reaction solution temperature rises at the same time as glycidol is charged,
Thereafter, the reaction temperature was maintained at 33 ° C., and the reaction was continued for 3 hours (ammonia was used at 15.0 mol times with respect to glycidol). After the reaction was completed, ammonia was distilled off from the reaction solution under reduced pressure.

 The remaining liquid after the ammonia was distilled off was neutralized with an aqueous NaOH solution.

As a result of analyzing the liquid after neutralization by gas chromatography, it was found that 1-aminopropanediol as a target product was produced in a yield of 82.0 mol%.

This example is compared with Comparative Example 1, and shows the effect of improving the yield of 1-aminopropanediol by adding ammonium chloride.

[Example 2] Instead of ammonium chloride, ammonium bromide [NH ₄ B
r] 48.3 g (493 mmol, 5 mol times glycidol) was added to the reactor except that the experiment of Example 1 was repeated.

As a result, 1-aminopropanediol was produced in a yield of 81.8 mol%.

This example is compared with Comparative Example 1 and shows the effect of improving the yield of 1-aminopropanediol by adding ammonium bromide.

Example 3 35% by weight instead of 26.4 g of ammonium chloride [NH ₄ Cl]
Example 1 was repeated except that 38.5 g of an aqueous hydrogen chloride solution (including 13.5 g of HCl, 370 mmol, 5 mol times of glycidol) was charged into the reactor, and 5.48 g (74.0 mmol) of glycidol was charged into the reactor. The experiment was repeated.

As a result of analysis by gas chromatography, 1-aminopropanediol was produced in a yield of 82.7 mol%.

This example is compared with Comparative Example 2 and shows the effect of improving the yield of 1-aminopropanediol by adding hydrochloric acid.

Example 4 The reactor was replaced with a reactor having a volume of 300 ml, and 38.5 g of a 35% by weight aqueous hydrogen chloride solution (including 13.5 g of HCl, 370 mmol, 5 mol times of glycidol) was added to the reactor, Formula B
An aqueous methylamine solution (40
%), And then 5.48 g (74.0 mmol) of glycidol was charged to the reactor.

As a result of analysis by gas chromatography after neutralization, 1- (methylamino) -propanediol was produced in a yield of 84.1 mol%.

This example is compared with Comparative Example 3, and shows the effect of improving the yield of 1- (methylamino) -propanediol by adding hydrochloric acid.

Comparative Example 1 The same experiment as in Example 1 was repeated, except that ammonium chloride was used, and the remaining solution after ammonia distillation was neutralized with an aqueous NaOH solution.

 The residual liquid was analyzed by gas chromatography.

As a result, 6.7 g (74.0 mmol) of 1-aminopropanediol was produced.

That is, the yield based on the raw material glycidol was 75.0 mol%.

[Comparative Example 2] The same experiment as in Comparative Example 1 was repeated except that the amount of glycidol charged was reduced to 5.48 g (74.0 mmol) (ammonia was used at 20.0 mol times with respect to glycidol).

As a result, 1-aminopropanediol was produced in a yield of 79.0 mol%.

[Comparative Example 3] The reactor was replaced with a reactor having a capacity of 300 ml, and instead of ammonia water, 184 g of a 25% by weight aqueous methylamine solution (including CH ₃ NH ₂
The experiment of Comparative Example 2 was repeated except that 73.6 g (1480 mmol) of the glycidol was used (methylamine was used at 20.0 mol times relative to glycidol).

As a result, 1- (methylamino) -propanediol was produced at a yield of 81.0 mol%.

Reference Example 1 The following experiment was performed according to the method of K. Baum et al., "J. Org. Chem." Vol. 27.2231, 1962.

Experiment of Comparative Example 1 except that 10.9 g of glycerin-α-monochlorohydrin (98.6 mmol, 15 mol times with respect to NH ₃ ) was charged instead of glycidol, neutralized, and analyzed by gas chromatography. Was repeated.

As a result, 1-aminopropanediol was produced in a yield of 66.7%.

This reference example is compared with Comparative Example 1, and shows that when the raw material is glycerin-α-monochlorohydrin, the yield is low in the same reaction time (3 hours).

Reference Example 2 The experiment of Reference Example 1 was repeated, except that the reaction time was changed to 24 hours.

As a result, 1-aminopropanediol was produced in a yield of 75.5%.

This Reference Example is contrasted with Comparative Example 1 and Reference Example 1, in which glycerin-α-monochlorohydrin has a lower reaction rate than glycidol, and the yield of 1-aminopropanediol can be increased even when reacted for a long time. Indicates that it is comparable to that of glycidol. The amount of hydrogen chloride produced as a by-product in this reference example was glycerin-α-
It is an equimolar amount to monochlorohydrin.

<< Reference Example 3 >> Before filling in aqueous ammonia, 10.3 g of a 35% by weight aqueous hydrogen chloride solution (including 3.60 g of HCl, 98.6 mmol, 1 mol times of glycidol) was added to the reactor to neutralize it. Then, the experiment of Comparative Example 1 was repeated, except that the analysis was performed by gas chromatography.

As a result, 1-aminopropanediol was produced in a yield of 75.1 mol%.

This reference example is compared with Comparative Example 1, and shows that adding only about equimolar hydrogen chloride to glycidol has little effect on improving the yield of 1-aminopropanediol.

Claims (1)

(57) [Claims] An epoxy compound represented by the following general formula A-1 or general formula A-2 [However, in the general formulas A-1 and A-2, R ₁ ,
R ₂ , R ₃ , and R _{4 each} represent a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkoxy group, or a substituent that can take any combination of the same or different selected from aryloxy groups; And an alkylene group having 3 or 4 carbon atoms in the chain]. [Wherein, in the general formula B, R ₅ represents a substituent selected from a hydrogen atom, an alkyl group or an aryl group], and is represented by the following general formula C-1 or C-2 Hydroxyamino compounds Wherein the reaction is carried out in the presence of an excess amount of hydrogen halide or an ammonium salt thereof on a molar basis with respect to the epoxy compound.