JPS5950663B2 - Method for producing γ-amino-β-hydroxybutyric acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing γ-amino-β-hydroxybutyric acid, particularly industrially excellent epichlorohydrin, carbon monoxide,
A basic substance and an alcohol are reacted with a cobalt carbonyl catalyst to form a γ-hydroxybutyric acid ester, which is reacted with ammonia to form 4-hydroxy-2-pyrrolidone, which is then hydrolyzed to form a γ-hydroxybutyric acid ester. When monoamino-β-hydroxybutyrate is purified and γ-amino-β-hydroxybutyric acid is obtained,
The present invention relates to a method for producing γ-amino-β-hydroxybutyric acid by collecting cobalt separated during the above steps and carbonylating it into a cobalt carbonyl catalyst.

γ-Amino-β-hydroxybutyric acid is a useful pharmaceutical agent as a brain function and metabolism regulator.

Various methods have been proposed for producing this, but for example, by reacting epichlorohydrin with sodium cyanide and an aminating agent such as ammonia, ammonium carbonate, phthalimide, etc., γ-amino (or phthalimino)-β- A method of producing hydroxybutyronitrile and then hydrolyzing it with a mineral acid (Japanese Patent Publication No. 33-J-Mo V2)
No. 37-17577, No. 12664-1973), and also by reacting epichlorohydrin and hydrocyanic acid, γ
-Chloro-β-hydroxybutyronitrile, which was then treated with hydrogen peroxide and an alkali to produce γ-chloro-β-hydroxybutyronitrile.
-hydroxybutyric acid amide, and further adding ammonia to this to form γ-amino-β-hydroxybutyric acid amide,
A method of hydrolyzing this (Special Publication No. 13611/1989)
These are all highly poisonous and expensive cyanide,
Also, as a method that does not use hydrocyanic acid or sodium cyanide, it is a method of converting vinyl acetic acid or vinyl acetate amide into γ-amino-β-hydroxybutyric acid and hydrolyzing this (Japanese Patent Publication No. 53
-13610, JP-A-49-218, JP-A-49-7
No. 6820, No. 80017 (Sho 49-80017), etc. However, none of these methods is preferable from the viewpoint of raw material availability, stability, and yield.

The present invention aims to solve these drawbacks, and uses epichlorohydrin, carbon monoxide, a basic substance, and alcohol as raw materials, and a cobalt carbonyl catalyst. This is reacted with ammonia to give 4-hydroxy-2-pyrrolidone, which is then hydrolyzed to give γ-amino-β-hydroxybutyrate. and the γ-chloro-β-human. Provided is an industrially advantageous method for producing γ-amino-β-hydroxybutyric acid with a high yield, which enables the reuse of the catalyst by recovering and regenerating the cobalt contained in the roxybutyric acid ester production liquid. This is what I am trying to do. That is, the present invention comprises: (1) a carbonylation step in which epichlorohydrin, carbon monoxide, a basic substance, and alcohol are reacted in the presence of a cobalt carbonyl catalyst to produce γ-chloro-β-hydroxybutyric acid ester; Catalytic decomposition step in which a mineral acid or a mineral acid and oxygen are supplied to the liquid produced in the carbonylation step to decompose the cobalt carbonyl catalyst; (3) an alcohol removal step in which alcohol in the catalyst decomposition liquid in the catalyst decomposition step is removed by distillation; , (4) Supplying water or a mixture of water and an extraction solvent to the alcohol removal solution in the alcohol removal step, allowing the γ-chloro-β-hydroxybutyric acid ester to be contained in the organic layer and the cobalt compound in the aqueous layer, and then , a separation step of separating an organic layer and an aqueous layer, (5) a purification step of distilling the organic layer to separate γ-chloro-β-hydroxybutyric acid ester, and (6) a γ-chloro purified in the purification step. −β
- Reacting hydroxybutyric acid ester and ammonia,
Amination reaction step to produce 4-hydroxy-2-pyrrolidone, (7) Supplying a base to the reaction solution produced in the amination reaction step and hydrolyzing it to produce γ-amino-β-hydroxybutyrate. Hydrolysis step, (8) Purification step of purifying γ-amino-β-hydroxybutyric acid from the reaction solution of the hydrolysis step, (9) On the other hand, it is separated in the separation step of (4) organic layer and aqueous layer. a cobalt recovery step in which an alkali metal carbonate or hydroxide is supplied to the aqueous layer and recovered as a cobalt compound, and (10) a catalyst production step in which the cobalt compound recovered in the cobalt recovery step is carbonylated to produce cobalt carbonyl. It is characterized by being combined.

The present invention will be explained in more detail below.

First, the step (l) of carbonylating epichlorohydrin involves reacting epichlorohydrin, carbon monoxide, alcohol, and a basic substance in the presence of cobalt carbonyl;
In this step, a reaction solution containing γ-chloro-β-hydroxybutyric acid ester is obtained. The epichlorohydrin used in this step is preferably of high purity, but is not limited to these.

Although carbon monoxide may be a mixed gas of hydrogen, inert gas, etc., it is preferable to use a highly pure carbon monoxide. Also,
The aliphatic alcohol serving as the ester moiety is preferably selected from methanol, ethanol, isopropanol, and n-butanol, but is not limited thereto.

Moreover, aliphatic hydrocarbons, aromatic hydrocarbons, acetone, water, etc. can also be made to coexist with these. The amount of aliphatic alcohol used is 1 to 20 per mole of epichlorohydrin.
It is twice the molar amount, preferably 5 to 10 times the molar amount. The cobalt carbonyl used as a catalyst can be selected from dicobalt octacarbonyl, hydrocobalt tetracarbonyl and its sodium salt, and an aliphatic alcohol or acetone solution of cobalt tetracarbonyl anion.

The amount of cobalt carbonyl used is 1 part of epichlorohydrin.
0.005 to 1 mol, preferably 0.0 to mol
It is 1 to 0.25 mol.

As the base, alkali metal compounds or alkaline earth metal compounds and amines that exhibit basicity in the reaction system are used, and these may be used in combination.

Specifically, alkali metal or alkaline earth metal oxides, hydroxides, carbonates, bicarbonates, phosphates, organic acid salts,
Examples include aliphatic and aromatic alcoholades, and preferred examples include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium acetate, sodium alcoholade, sodium hydroxide, and potassium hydroxide. Examples of the amine include trimethylamine and triethylamine. These bases are 0.01 to 1 mol, preferably 0.0 mol, per 1 mol of epichlorohydrin.
It is used in an amount of 3 to 0.1 mol to control inhibition in the reaction system, maintain catalyst activity, and allow the reaction to proceed with high selectivity.

Note that even if these bases are not completely dissolved and are partially undissolved, they do not impede the reaction in any way. The reaction temperature is 0 to 100°C, preferably 10 to 60°C.

The reaction pressure is from normal pressure to 200 atm, usually from normal pressure to 100 atm, particularly preferably from 5 to 30 atm.

Next, the step (2) of decomposing cobalt carbonyl in the product liquid is performed with a mineral acid alone or in the coexistence of a mineral acid and oxygen. The mineral acid used is preferably sulfuric acid or hydrochloric acid.

The mineral acid used is usually an aqueous solution or an alcohol solution, but hydrogen chloride gas or pure sulfuric acid can also be used. The amount of mineral acid used is 1.
The amount is 0 to 20 times by mole, preferably 2 to 10 times by mole.

Further, when decomposing the catalyst, the decomposition can be promoted by allowing oxygen to coexist.

Although pure oxygen may be used as oxygen, air is preferably used.

Oxygen is preferably bubbled into the reaction solution, and the amount used is at least equimolar to cobalt carbonyl.
The catalytic decomposition step can be carried out at a temperature of 0 to 80°C, preferably 10 to 70°C.

Next, in the alcohol removal step (3), excess alcohol is distilled off to obtain a concentrated liquid.

The step (4) of separating the organic layer and the aqueous layer involves adding water or water and an extractant to the concentrated liquid obtained in step (3) above, and adding γ-
an organic layer containing chloro-β-hydroxybutyric acid ester;
It separates into an aqueous layer containing cobalt compounds, but in this case,
Preferably, an extractant is used in addition to water. There are no particular restrictions on the extractant, but halogenated hydrocarbons,
Esters, ketones, ethers, etc. are preferred.

Specifically, they include dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, acetate, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, and the like. The amount of water used depends on the amount of by-product salt, e.g.
If Na2cO3 is used as a base substance, NaCl will be produced as a by-product, but it is preferable for operations to add more than the solubility of the salt because it can be handled as a homogeneous solution (5).
In the step of purifying γ-chloro-β-hydroxybutyric acid ester from the organic layer separated in the above step, first, the extraction solvent and low-boiling substances are distilled off, and then the γ-chloro-β-hydroxybutyric acid ester is distilled off. to recover.

The higher the purity of the recovered γ-chloro-β-hydroxybutyric acid ester, the better, but if it is 85% or higher, it can be used in the next step without any adverse effects.

(6) In the amination step of reacting the γ-chloro-β-hydroxybutyric acid ester recovered in the above step with ammonia to produce 4-hydroxy-2-pyrrolidone, use an excess of ammonia and the reaction temperature range described below. By carrying out this method, 4-hydroxy-2-pyrrolidone can be obtained in good yield. The ammonia to be used is not particularly limited, but aqueous ammonia or liquid ammonia is preferable.
The amount of ammonia to be used is 5 to 60 times the mole of γ-chloro-β-hydroxybutyrate, preferably 10
~30 times the molar amount. The reaction temperature is 65-130°C, preferably 70-100°C.

Under these conditions, the normally considered amide, ie, γ-amino-β-hydroxybutyric acid amide, is hardly produced;
4-hydroxy-2-pyrrolidone is obtained in good yield.

(7) In the hydrolysis step of hydrolyzing the reaction solution containing 4-hydroxy-2-pyrrolidone to obtain a salt of γ-amino-β-hydroxybutyric acid, the amination reaction solution can be used as it is, but preferably, Hydrolysis is carried out after distilling off excess ammonia.

Hydrolysis is carried out with an acid or a base, but it is preferable to carry out the hydrolysis with a base in terms of the production of by-products and the reaction rate.There are no particular restrictions on the base used, but it is preferable to carry out the hydrolysis with an acid or a base. Hydroxides are preferred.

Specific (= is potassium hydroxide, sodium hydroxide, calcium hydroxide, etc.) The concentration of the base in the reaction system is not particularly limited, but is usually 50% or less, preferably about 5 to 30%. , 1 to 30 times mole relative to 4-hydroxy-2-pyrrolidone, preferably 5 to 15
It is sufficient to use twice the molar amount. Reaction temperature is 20-160℃
℃, preferably 30 to 100℃.

(8) In the step of purifying γ-amino-β-hydroxybutyric acid from the hydrolysis reaction solution, there is no particular restriction on the method, and any generally known method may be used.

For example, a reaction solution is treated with an ion exchange resin (acidic resin and strong acidic resin, or strong acidic resin), concentrated, added with alcohol, crystallized, centrifuged, and dried to obtain highly pure γ. -Amino-β-hydroxybutyric acid is obtained. The cobalt recovery step (9) is a step of converting cobalt into water-insoluble cobalt carbonate and cobalt hydroxide by adding an alkali metal carbonate or hydroxide to the aqueous layer obtained in step (4). and its messenger. The alkali metal carbonate to be used is preferably potassium carbonate or sodium carbonate, and the hydroxide is preferably potassium hydroxide or sodium hydroxide.

Regarding the concentration used, it may be used as a solid, or an aqueous solution may be used. The amount used is 7 or more, preferably 9 or more when carbonating, and 9 or more when hydroxylating.
By adding the above preferably up to 12 or more,
Precipitate cobalt carbonate and cobalt hydroxide.

At this time, by blowing air, a product with even better sedimentation properties can be obtained. The slurry containing the carbonated and hydroxylated cobalt compound is filtered and washed with water to obtain a cake containing 50 wt% or more of water.

The resulting cobalt compound cake containing water can be dehydrated by various conventionally known methods.

For example, air drying, vacuum drying, and azeotropic dehydration.
I By the above method, cobalt is recovered as cobalt carbonate or cobalt hydroxide.

In the catalyst production step (10), the cobalt carbonate and cobalt hydroxide recovered in the step (9) are reacted with carbon monoxide and hydrogen to produce cobalt carbonyl. Here, cobalt carbonyl includes dicobalt octacarbonyl, hydrocobalt tetracarbonyl, cobalt tetracarbonyl anion, and the like.

As a solvent, hydrocarbons such as toluene and benzene, monoalcohols such as methanol, ethanol and isopropanol, polyhydric alcohols such as ethylene glycol and glycerin, monomethyl ether of ethylene glycol,
Ethers such as dimethyl ether, ketones such as acetone, methyl ethyl ketone, etc. can be used as suitable solvents.

The reaction was carried out at high temperature and high pressure (150 to 20
Although it can be produced at a temperature of 0° C. and a pressure of 150 atm or higher, the reaction rate and reaction conditions can be improved by coexisting cobalt carbonyl itself.

For example, by allowing dicobalt octacarbonyl to coexist in a toluene solvent and reacting, the reaction rate is improved and dicobalt octacarbonyl can be produced.

Further, as a preferred production method, the reaction of recovered cobalt hydroxide with carbon monoxide and hydrogen in acetone or alcohol solvent is carried out in the presence of dicobalt octacarbonyl, cobalt tetracarbonyl anion, or a mixture thereof. As a result, the catalyst can be produced under conditions that are more relaxed than the conventional conditions of high temperature and high pressure, and the produced catalyst is a solution of cobalt tetracarbonyl anion, which has great operational advantages when carried out industrially.

As for the conditions for production by this method, the amount of acetone and alcohol used as a solvent may be greater than the amount that dissolves the cobalt tetracarbonyl anion to be produced. The solubility of cobalt tetracarbonyl anion is, for example, 15 wt/v% in acetone, 20 wt/v% in methanol, and 10 W in ethanol.
t/V%, 5wt/v% for isopropyl alcohol
That's about it. The amount of cobalt tetracarbonyl anion or dicobalt octacarbonyl used as a seed catalyst is 0.005 or more in atomic ratio to cobalt carbonate or cobalt hydroxide. If the atomic ratio is 0.005 or more, the pressure is 150 kg/Cm2 or less, and if the atomic ratio is 0.01 or more, the pressure is 50 kg/CIn2 or less, and the atomic ratio is 0.0.
If it is 2 or more, the reaction will proceed at a pressure of 30 kg/CIIl2 or less. The molar ratio of carbon monoxide and hydrogen is 1:1 to 1:1:
A range of 0.1 is sufficient, and the reaction pressure is 150 kg/
CIn2 or less, preferably 5 to 100 kg/Cn for operational reasons
It is l. The reaction temperature is 50-150°C. A solution of cobalt tetracarbonyl anion prepared by the above method is used as a catalyst for carbonylation, and a portion can be used with the next seed catalyst.

As explained above, the method of the present invention has various advantages over previously proposed methods, but its major characteristics are (1) it can be produced with high yield from epichlorohydrin, which is inexpensive and easily available; (2) It is easy to operate as it does not use highly toxic hydrocyanic acid or sodium cyanide; (3) It is easy to purify and has high purity γ-amino-β-hydroxy because no aminocrotonic acid is produced as a by-product. Butyric acid can be produced, and the industrial merits are very large.

EXAMPLES The present invention will be explained in more detail with reference to Examples below.

Example In a stainless steel autoclave with an internal volume of 51 cm, 5.0 mol of picchlorohydrin, 26.5 g of sodium carbonate, and cobalt tetracarbonyl anion (4). 2 mol) methanol solution 250ml 1. Prepare 34 moles of methanol,
45 at carbon monoxide pressure 10 kg/ClIl2 and temperature 25°C
A time reaction was performed.

The conversion rate of epichlorohydrin was 96.3%, and the selectivity of methyl γ-chloro-β-hydroxybutyrate was 78%. After the reaction, the reaction solution was cooled and transferred to a glass reactor No. 31, and 50 g of concentrated sulfuric acid (97 wt % product) was added dropwise over 30 minutes while bubbling air at a rate of 251/Hr.

After 1 hour, the concentration of carbon monoxide in the purge gas is 10pp.
The decomposition of the catalyst is terminated when the temperature decreases to about n.

Next, excess methanol was distilled off, 180 g of water and 700 g of chloroform were added, and the organic layer was separated into an organic layer and an aqueous layer. After chloroform was distilled off, methyl γ-talolo-β-hydroxybutyrate was removed from the organic layer by distillation. 544g (3.
56M) is recovered with a purity of 97%.

The recovered methyl γ-chloro-β-hydroxybutyrate was
1 reactor, 25% by weight ammonia water 370
0g (54.4 mol) was added, heated at an external temperature of 80°C, and reacted for 3 hours.

After the reaction, excess ammonia was distilled off and analysis by high performance liquid chromatography revealed that 2.80 moles of 4-hydroxy-2-pyrrolidone (yield 78%) had been produced.

Furthermore, an amino acid analyzer revealed that γ-aminoβ-hydroxybutyric acid amide was produced at a yield of 0.2%. In this reaction solution,
560 g of caustic soda was added and reacted at a temperature of 50° C. for 6 hours.

After the reaction, the reaction solution was analyzed and found that 4-hydroxy-2
-The reaction rate of pyrrolidone was 98%, and 2.62 mol of γ-amino-β-hydroxybutyric acid (yield 93.5
%) was generated. This reaction solution was treated with an acidic resin to remove most of the sodium, and then treated with a strong acidic resin.
By adsorbing amyl-amino-β-hydroxybutyric acid and the remaining sodium, washing with water, and eluting with 2N aqueous ammonia, γ-amino-β-hydroxybutyric acid (2.
A 5 wt % aqueous solution of 55 mol) was recovered.

After recovery, ammonia is recovered and then concentrated to reduce the concentration of γ-amino-β-hydroxybutyric acid to 30 wt%.
I made it. Next, methanol 21 was added and the mixture was left at a temperature of 5° C. for a day and night, filtered through a centrifuge, and then dried overnight in a vacuum dryer. After drying, it was taken out as completely white crystals, and Alcolade titration showed that γ-amino-
2.10 mol of β-hydroxybutyric acid were obtained. Furthermore, the mother liquor contains 0.45 mol of γ-amino-β-hydroxybutyric acid, and can be recycled to the next reaction without any problem.

Claims (1)

[Claims] 1 (1) Epichlorohydrin, carbon monoxide, a basic substance and alcohol in the presence of a cobalt carbonyl catalyst,
a carbonylation step of reacting to produce γ-chloro-β-hydroxybutyric acid ester; (2) a catalytic decomposition step of supplying a mineral acid or a mineral acid and oxygen to the product liquid of the carbonylation step to decompose the cobalt carbonyl catalyst; , (3) an alcohol removal step in which the alcohol in the catalyst decomposition solution in the catalyst decomposition step is removed by distillation; (4) water or a mixed solution of water and an extraction solvent is supplied to the alcohol removal solution in the alcohol removal step; - Separation step of organic layer and aqueous layer in which chloro-β-hydroxybutyric acid ester is contained in the organic layer and a cobalt compound is contained in the aqueous layer, and then this is separated; (5) the organic layer is distilled and γ-chloro-β - Purification step to separate hydroxybutyric acid ester, (6) γ-chloro- purified in the purification step
An amination reaction step in which β-hydroxybutyric acid ester and ammonia are reacted to form 4-hydroxy-2-pyrrolidone; (7) a basic substance is added to the reaction solution produced in the amination reaction step, and this is hydrolyzed; and (8) a purification step of purifying γ-amino-β-hydroxybutyric acid from the reaction solution of the hydrolysis step. A cobalt recovery step in which an alkali metal carbonate or hydroxide is supplied to the aqueous layer separated in the organic layer and aqueous layer separation step and recovered as a cobalt compound, (10) cobalt compound recovered in the cobalt recovery step. 1. A method for producing γ-amino-β-hydroxybutyric acid, which comprises combining a catalyst production step of carbonylating γ-amino-β-hydroxybutyric acid to produce cobalt carbonyl.