JP3257371B2 - Method for producing 5-phthalimido-4-oxopentenoic acid or its pyridine salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 5-phthalimido-4-oxopentenoic acid or a pyridine salt thereof useful as a raw material for various chemicals.

[0002]

2. Description of the Related Art 5-Phthalimido-4-oxopentenoic acid is a substance useful as a raw material for synthesizing 5-aminolevulinic acid, which can be used as a highly selective herbicide and an intermediate for the production of various chemicals. There is a method for producing N-furfurylphthalimide by oxidizing it with bromine in methanol and then re-oxidizing it with chromium (VI) oxide (L. Pichat, J. Bull. So.
c. Chim. France, 1966, 3564).

On the other hand, as an example of the production of 5-phthalimido-4-oxopentenoic acid in the course of the synthesis of 5-aminolevulinic acid, there is a photosensitized singlet oxygen oxidation reaction of N-furfurylphthalimide in a pyridine solvent, In this case, depending on conditions such as a treatment method after the reaction, 5-phthalimide-4
Applicant has reported that -oxopentenoic acid or its tautomer, 5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, or a mixture of these isomers, is obtained. Have previously discovered and disclosed (JP-A-6-271519).

[0004] When the purpose is to produce a chemical such as 5-aminolevulinic acid, the latter oxidation is advantageous as a low-cost production method that does not consume a chemical oxidizing agent and is easy to carry out, but is inexpensive. When an easily available dye sensitizer is used, the dye sensitizer decomposes with the progress of the reaction (fading of the reaction solution is observed), and the progress of the reaction gradually slows down, requiring a long reaction time. There was a problem of doing.
Even if the amount of the dye sensitizer used is increased to solve this problem, the decomposition and fading become more severe, and the reaction time cannot be reduced, and the amount of reaction by-products derived from the dye sensitizer is also increased. Increase, decrease in product purity and coloring,
A new problem arises.

[0005] The decomposition of the dye sensitizer is more remarkable under the reaction conditions in which the raw materials are used at a high concentration, and in such a case, the reaction is often not completed. In order to avoid this, it is necessary to use a large amount of a solvent of 3 to 30 liters per 1 mol of N-furfurylphthalimide, which is a substrate, and a large reactor is required for industrial implementation. Another disadvantage is that the equipment costs are high.

Under these circumstances, as a result of intensive studies, the present inventors have found that the use of pyridine, which is a solvent, containing an appropriate amount of water as a reaction medium significantly decomposes the dye sensitizer. It has been found that the reaction is suppressed and the reaction is completed in a short reaction time, and the effect that the dye sensitizer is hardly decomposed makes it possible to carry out the reaction without disadvantage even when the raw material is used at a high concentration.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to make use of the above-mentioned new knowledge and to obtain N
In a method for producing 5-phthalimido-4-oxopentenoic acid or a pyridine salt thereof by photosensitized singlet oxygen oxidation reaction of furfurylphthalimide, decomposition of a dye sensitizer and the above-mentioned problems derived therefrom are considered in principle. To resolve
It is an object of the present invention to provide a production method which can be carried out at a high concentration and can complete the reaction in a short time and is excellent in economic efficiency.

The process for producing 5-phthalimido-4-oxopentenoic acid or a pyridine salt thereof according to the present invention comprises the step of reacting N-furfurylphthalimide with pyridine or pyridine.
A mixture with another organic solvent containing at least 5% by volume is used as a reaction medium, and in the presence of a dye sensitizer, molecular oxygen acts while irradiating with light to oxidize the reaction medium. It is characterized in that 0.5 to 15% by volume of water of pyridine coexists and the oxidation reaction proceeds in a homogeneous phase.

[0009]

According to the method of the present invention, molecular oxygen is allowed to act on N-furfurylphthalimide while irradiating it with light in the presence of a dye sensitizer. The reaction is presumed to proceed as shown in the following equation. Is done.

[0010]

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The reaction is carried out by dissolving N-furfurylphthalimide, a dye sensitizer and water in a solvent and passing molecular oxygen under light irradiation. As the solvent, pyridine is preferably used alone, but a solvent containing pyridine, that is, a mixed solvent of pyridine and another organic solvent can also be used. Examples of such a solvent include a mixture of pyridine and an organic solvent such as acetone, methyl ethyl ketone, toluene, benzene, chloroform, dichloromethane, ethyl acetate, methanol, ethanol, etc., which contains pyridine at 25% by volume or more. Can be mentioned.

The amount of the solvent used is required to be 2 ml or more per 1 mmol of N-furfurylphthalimide, but the effect of coexistence of water is remarkably observed up to about 20 ml, and the reaction is carried out using a larger amount of the solvent. In such cases, the reaction proceeds advantageously without the addition of water. However, the use of large amounts of reaction medium is disadvantageous, as described above with respect to the prior art. The method of the present invention is significant in the aspect of using a reaction medium in the range of 2 to 20 ml per 1 mmol of the starting N-furfurylphthalimide, in which the effect of adding water is remarkable, and Advantageously, it is in the range from 2 to 10 ml.

The concentration of water coexisting in the reaction medium is 0.1.
Select from the range of 5% or more and 15% or less (% by volume). The preferred range is 1 to 10%. If it is less than 0.5%, the effect is not sufficient. On the other hand, the coexistence of a large amount of water not only does not improve the effect any more, but also disadvantageously dissolves N-furfurylphthalimide in the solvent. Some commercially available pyridines contain a small amount of water. In that case, the water content is adjusted so as to be within the above range in consideration of the amount of water already contained.

Known dye sensitizers can be used, but organic dyes such as rose bengal, erythrosine, and phloxine are particularly effective. The amount of solvent used is 1
Respect liter, 10 ^-4 to 1 mol / liter, preferably suitably 10 ^-3 ~10 ^-4 mol / liter.

As molecular oxygen as an oxidizing agent, oxygen in the atmosphere can be used, and of course, commercially available pure oxygen gas can be used. The ventilation rate may be determined as appropriate depending on the gas composition (O ₂ partial pressure), the reaction temperature, and the raw material concentration, but it is necessary to supply the gas at a rate higher than the amount of oxygen consumed by the reaction.
As a measure of the supply amount, the raw material (N-furfurylphthalimide) 100 mmol / liter, Rose Bengal 10 ^-4 mo
For example, when oxygen gas (O ₂ 100%) is passed under the conditions of l / liter and 0 ° C., 5 to 50 per 100 ml of solvent is used.
A ventilation range of ml / min is preferred.

The light source for the light irradiation is not particularly limited, and includes sunlight, fluorescent lamps, tungsten-halogen lamps, high-pressure mercury lamps,
A high-pressure sodium lamp, a metal halide lamp and the like can be used arbitrarily, and preferred are a fluorescent lamp, a tungsten-halogen lamp, a high-pressure mercury lamp and the like having high visible light energy efficiency.

The reaction can be carried out in a wide temperature range from -40 ° C to 40 ° C, but preferably from 0 ° C to 25 ° C from the viewpoint of reaction efficiency and safety.

After completion of the reaction, the solvent is distilled off to obtain a product mainly composed of pyridine 5-phthalimido-4-oxopentenoate. This product includes 5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, which is a tautomer of 5-phthalimido-4-oxopentenoic acid described above, and a dye sensitizer. Although a small amount of the decomposition products and the like is contained, when the process proceeds to the next reaction step for the purpose of synthesizing 5-aminolevulinic acid, the process can proceed to the next step as it is or after decolorization with activated carbon.

When isolating 5-phthalimido-4-oxopentenoic acid, water is added to the crude product after distilling off the solvent to dissolve it, and after removing insoluble matters by filtration, dichloromethane, chloroform and the like are removed. After washing with a halogenated hydrocarbon-based organic solvent and removing water, 5-phthalimide-4
Pyridine salt of oxopentenoic acid is obtained. When the temperature at which water is removed is 25 ° C. or higher, the compound may be obtained as an oil instead of crystals,
By adding a small amount of pyridine to the oil and allowing it to stand,
It can be crystallized.

If it is desired to remove the pyridine base from the resulting salt to obtain free 5-phthalimido-4-oxopentenoic acid, use a strong acid in an organic solvent such as chloroform, ethyl acetate, dichloromethane, ethanol or methanol. The pyridine salt may be treated with an ion exchange resin.

Example 1 An experimental apparatus shown in FIG. 1 was assembled. That is, a glass tube (1) with a glass ball filter was fixed to a test tube (2) with a side tube having a capacity of 20 ml using a thermometer holder, and a water tank (3) with a water cooling jacket (4) and a 100 W tungsten halogen lamp (3) was used. 5) Set inside. The water tank has a facility for supplying cooling water (6).

682 mg of N-furfurylphthalimide
(3.0 mmol) in a test tube, and Rose Bengal 4.5
The solution was dissolved in 15 ml of water-containing (1.0% by volume) pyridine to which mg (4.5 μmol) was added. Under light irradiation, oxygen gas (7) was supplied through a glass ball filter.

The supply rate was 25 ml / min, and excess gas was discharged from the exhaust gas outlet. During the reaction, the water temperature was kept at 5 ° C.

The reaction solution (8) was sampled 5 times, 1 ml at a time, every 30 minutes from the start of the reaction.
The progress of the reaction and the residual amount of the dye sensitizer rose bengal were confirmed by analysis, and the time until the end of the reaction, that is, the time until N-furfurylphthalimide was completely consumed, was taken as the reaction time. FIG. 2 is a graph showing how the conversion ratio of the raw materials and the residual ratio of the dye sensitizer change with time.

After completion of the reaction, pyridine was distilled off under reduced pressure at room temperature, the obtained solid was dissolved in water, and the insoluble matter was filtered off. Then, the filtrate was washed with chloroform, and the water was removed by evaporation under reduced pressure.

The pyridine salt of 5-phthalimido-4-oxopentenoic acid was obtained as a pale yellow solid. Yield 4
81 mg. The reaction yield, calculated assuming that 5 ml of sampling loss was present in the reaction solution, was calculated to be 71%. The reaction time was 1.5 hours, and the residual ratio of the sensitizer at the end of the reaction was 45% at the start of the reaction.

The pyridine salt of 5-phthalimido-4-oxopentenoic acid is subjected to depyridine using a strongly acidic ion exchange resin "Amberlyst 15E" to give 5-phthalimido-4-oxopentenoic acid. Was.

The spectrum data are shown below: ¹ H-NMR (CDCl ₃ ) δ 4.80 (2H, s); 6.84 (1H, d, J = 16 Hz); 7.13 (1H, d, J) = 16Hz); 7.79-7.82 (2H, m); 7.87-7.90 (2H, m) 13 C-NMR (CDCl 3) δ 45.7; 123.5; 131.9; 136.3; 135.6; 166.5; 167.4; 191.4 IR (Nujol) νmax / cm 1780; 1730; 1690;

Example 2 The operation of Example 1 was repeated under the same conditions except that the water content of pyridine was changed to 0.5% by volume. The reaction time was extended to 2.0 hours, at which time the residual ratio of the sensitizer was 34%. The yield is 501 mg. The reaction yield calculated after excluding the sampling loss of 5 ml was 74%. A graph corresponding to FIG. 2 is shown in FIG.

Example 3 The operation of Example 1 was repeated under the same conditions except that the water content of pyridine was increased to 10% by volume. The reaction time was 1.5 hours, the sensitizer residual rate at that time was 33%, the yield was 467 mg, and the sampling loss was 5%.
The reaction yield calculated without the ml was 67%. FIG.
Is shown in FIG.

Example 4 The charge of N-furfurylphthalimide was increased to 1.36 g (6.0 mmol) (that is, the concentration of the raw material was doubled with respect to the solvent and the dye sensitizer). The operation of Example 1 was repeated under the same conditions except for ()). The reaction time required 4 hours, and the sensitizer residual ratio at that time was 14%. The yield is 704 mg. The reaction yield calculated after excluding the sampling loss of 7 ml was 65%. FIG. 5 shows a graph corresponding to FIG.

Comparative Example 1 The operation of Example 1 was repeated under the same conditions except that the water content of pyridine was changed to 30% by volume. The reaction time required 2 hours, at which time the residual ratio of the sensitizer was only 4%. Yield 432 mg. The reaction yield calculated after excluding the sampling loss of 5 ml was 64%. FIG. 6 shows a graph corresponding to FIG.

[Comparative Example 2] Molecular sieve "MS-
The operation of Example 1 was repeated under the same conditions except that anhydrous pyridine dried using "4A" (manufactured by Wako Pure Chemical Industries) was used as a solvent. The reaction time was 2 hours, at which time the residual ratio of the sensitizer was 0%. The yield is 447 mg. The reaction yield calculated after excluding the sampling loss of 5 ml was 66%.
FIG. 7 shows a graph corresponding to FIG.

Comparative Example 3 The procedure of Example 4 was repeated under the same conditions except that anhydrous pyridine (described above) was used as a solvent. The reaction time was 6 hours, and the sensitizer residual ratio at that time was 3%. The yield is 521 mg. Sampling loss 8
The reaction yield calculated without ml was 55%. FIG.
8 is shown in FIG.

[0035]

According to the production method of the present invention, 5-phthalimido-4-oxopentenoic acid or a pyridine salt thereof useful as a synthetic intermediate such as 5-aminolevulinic acid is converted to N-
In the production of furfurylphthalimide by photosensitized singlet oxygen oxidation reaction, the starting materials can be used in a high concentration, the reaction can be completed in a short time, and the desired product can be obtained in high yield. In this way, economical production becomes possible.

[Brief description of the drawings]

FIG. 1 is a diagram showing a configuration of an experimental apparatus used in an example of the present invention.

FIG. 2 is a graph showing data of Example 1 of the present invention and showing changes in the raw material conversion rate and the sensitizer residual rate with the passage of reaction time.

FIG. 3 is data similar to FIG. 2, showing data of Example 2 of the present invention.

FIG. 4 is a graph similar to FIG. 2, showing data of Example 3 of the present invention.

FIG. 5 is a graph similar to FIG. 2, showing data of Example 4 of the present invention.

FIG. 6 is a graph similar to FIG. 2, showing data of Comparative Example 1 of the present invention.

FIG. 7 is a graph similar to FIG. 2, showing data of Comparative Example 2 of the present invention.

FIG. 8 is a graph similar to FIG. 2, showing data of Comparative Example 3 of the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Glass tube with glass ball filter 2 Test tube with side tube 3 Tungsten halogen lamp 4 Water-cooled jacket 5 Water tank 6 Cooling water 7 Oxygen gas 8 Reaction liquid

────────────────────────────────────────────────── ─── Continuation of front page (56) References JP-A-7-233095 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 209/48

Claims (2)

(57) [Claims] 1. A reaction medium comprising N-furfurylphthalimide and a mixture of pyridine or another organic solvent containing pyridine in an amount of 25% by volume or more is irradiated with light in the presence of a dye sensitizer. A method for producing 5-phthalimido-4-oxopentenoic acid or a pyridine salt thereof, which comprises oxidizing by the action of oxygen in the form of oxygen, wherein 0.5 to 15% by volume of water of pyridine coexists in the reaction medium, A production method, wherein the oxidation reaction proceeds in a phase. 2. 1 mmol of raw material N-furfurylphthalimide
2. The method according to claim 1, wherein the reaction is carried out using 2 to 10 ml of the reaction medium.