JPH0276841A - Production of aminolevulinic acids - Google Patents

Abstract

PURPOSE:To readily obtain the subject compounds in high yield by electrolytically oxidizing a readily available inexpensive N-acylfurfurylamine as a raw material in a solution thereof in methanol, reducing the resultant compound, opening the ring with dilute sulfuric acid and simultaneously oxidizing the reduction product with KMnO4. CONSTITUTION:An N-acylfurfurylamine, such as N-acetylfurfurylamine or N- benzoylfurfurylamine, expressed by the formula (R1 is acyl) is electrolytically oxidized in a solution thereof in methanol or oxidized in a bromine-methanol solution, then reduced with Raney nickel catalyst, etc., subjected to simultaneous ring opening with dilute sulfuric acid in 1-10% concentration and oxidation using KMnO4 to afford a delta-acylaminolevulinic acid useful as a raw material for delta-aminolevulinic acid having selective herbicidal action, vitamin B12, porphyrin derivatives, such as coproporphyrin, specifically acting on cancerous cells in simple operation with hardly any formation of toxic wastes. The resultant delta-acylaminolevulinic acid is then hydrolyzed to afford the delta-aminolevulinic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing amylpuric acids. More specifically, we will discuss not only δ-aminolevulinic acid, which has a selective herbicidal effect, but also δ-acylaminolevulinic acid, which can be suitably used as a raw material for vitamin B12 and porphyrin derivatives such as cobrovorphyrin, which specifically acts on cancer cells. Regarding manufacturing methods.

[Prior Art] It has been known that δ-aminolevulinic acid (hereinafter referred to as ALA) is an intermediate for tetrapyrrole biosynthesis in living animals.

In addition, ALA acts on weeds but not on grains.
Since it is harmless to humans and livestock, Levites et al. have reported that it can be used as a selective herbicide (Enzyme Microbiological Technology).
Enzy+*.

(Former Crob, Technol), Vol. 6, p. 390 (1984)).

Several methods have been reported for the production of ALA. For example, Plchat et al. replaced δ-chloro or δ-bromo-levulinic acid ester with a δ-phthalimide derivative to add an amino group. To report on the method of inducing levulinic acid, the Société Simique de France (Bull, Soc., C.
hlm, Fr., p. 1750 (1956)) and Beale et al.
A by non-enzymatic transamination using OVA)
reported an interesting method for synthesizing LA (see Phytochemistry, vol. 18, p. 441 (1979)), Buffalz (Pf'
reported a method for synthesizing ALA by reducing a ketonitrile compound with zinc and acetic acid (Tetrahedron Lett, et al.
), 1984.25I:B, 2977).

However, depending on these manufacturing methods, it is not possible to industrially produce ALA efficiently, and the raw materials are expensive, the manufacturing process is complicated, and hazardous waste is generated. There are problems such as ALA becoming expensive. Another problem is that ALA itself is unstable and usually needs to be stored as a hydrochloride in a cool, dark place.

[Problems to be Solved by the Invention] Therefore, the present inventors solved the problem by solving δ-acylaminolevulinic acid (
Focusing on the fact that δ-acyl-ALA (hereinafter referred to as δ-acyl-ALA) is stable and can be stored for a long time at room temperature, and can be easily converted to ^LA hydrochloride if necessary, and in view of the above-mentioned conventional technology, we developed a method that is easy to obtain. As a result of intensive research to find a method for industrially producing δ-acyl ALA and ALA with high yield using inexpensive raw materials, we have discovered, for the first time, a method for producing δ-acyl ALA and ALA that satisfies all of these requirements. This finding led to the completion of the present invention.

[Means for Solving the Problems] That is, the present invention electrolytically oxidizes N-acylfurfurylamine in its methanol solution, then reduces it, and then
A method for producing δ-acyl ALA characterized by ring opening using dilute sulfuric acid and simultaneous oxidation with KMnO4, and a method for oxidizing N-acylfurfurylamine in a bromine-methanol solution, followed by reduction, and then using dilute sulfuric acid. K at the same time as ring opening
δ-acyl AL characterized by oxidation with MnOa
The present invention relates to a method for producing ALA and a method for producing ALA, which is characterized by hydrolyzing the δ-acyl ALA.

[Operations and Examples] According to the production method of the present invention, δ-acylALA is produced by electrolytically oxidizing N-acylfurfurylamine in methanol, followed by reduction, and then ring-opening using dilute sulfuric acid.
Obtained by oxidation with MnO4.

The starting materials used in the present invention have the general formula (I): (wherein,
R+ represents an acyl group), which is easily available and inexpensive. In general formula (1), specific examples of the acyl group include an acetyl group and a benzoyl group.

The starting material represented by the general formula (1) is first dissolved in methanol, a supporting salt such as ammonium bromide is appropriately added, and then oxidized by electrolysis, and the starting material is oxidized by the general formula (I): is the same as above), and such a dimethoxy compound is replaced by a dimethoxy compound represented by the general formula (n
a>: A mixture of a cis-dimethoxy compound represented by the formula (in which R1 is the same as above) and a trans-dimethoxy compound represented by the general formula (n b): (wherein R1 is the same as above).

There is no particular limitation on the amount of the starting material dissolved in the methanol, but usually 100 ml of methanol is used.
5 to 30 g of the above starting materials per 5 to 8 to 12 g of
g: Preferably.

The conditions for electrolyzing the methanol solution in which the starting materials are dissolved are as follows: the temperature of the methanol solution is 0°C or less, and the temperature is below -
10-0°C, voltage 15-20V.

<16~18V, and current 0.5~2. O.A.

Nakanzu<0.8~1. It is OA. When the temperature of the methanol solution is higher than 0° C., the reaction solution tends to be colored reddish brown and the yield tends to decrease. Further, if the current and voltage are each smaller than the lower limit, it will take a long time to complete the reaction or the production efficiency of the dimethoxy compound will be low, and if it is larger than the upper limit, the starting material N
-Depending on the concentration of acylfurylamine, the exothermic reaction tends to become intense, making it difficult to control the temperature of the reaction solution. The electrolysis time cannot be determined unconditionally because it varies depending on the amount of methanol solvent and supporting salt used, but it is usually 2 to 8 hours, especially 3 to 5 hours.

Note that for the electrodes during electrolysis, a platinum plate is usually used as an anode and a nickel plate as a cathode.

After electrolysis, the solution is neutralized with a methanolic sodium hydroxide solution, the inorganic salt is filtered, and the filtrate is concentrated under reduced pressure to recover the dimethoxy compound as crystals accompanied by a viscous substance. When this is extracted with ethyl acetate while hot, a trans-dimethoxy compound is converted, and a dimethoxy compound with a large cis form is recovered from the mother liquor. Cis and trans here refer to the general formula (II)
In the compound represented by , it means cis or trans regarding the methoxy group.

In addition, as a method for obtaining the dimethoxy compound represented by the general formula (1), there is a method in which the starting material is oxidized with a brominated methanol solution in the presence of sodium carbonate. Compared to the above-mentioned electrolytic oxidation method, this method has the characteristics that it generates less heat, does not require neutralization after the reaction, is easy to handle, and produces a large amount of trans isomer, but the yield is slightly lower.

The blending amount of the sodium carbonate is 0.0% based on the starting material.
It is preferable to set it as 5-2 molar equivalents, and <0.8-1.2 molar equivalents. The bromine-methanol solution is one in which 1 molar equivalent of bromine is added dropwise to methanol in an amount approximately 5 times that of the starting material at 0 to 10°C. The amount of bromine-methanol liquid to be blended is 40 to 80 ml per 10 g of starting material.
It is preferable that the number of particles <50 to 55 m1. In addition, when adding, the liquid temperature after reaction is adjusted to be 0°C or less, preferably -5 to 0°C. The liquid temperature is 0
If the temperature is higher than ℃, the yield of the dimethoxy compound tends to decrease.

Next, the dimethoxy compound is dissolved in methanol, reduced at normal pressure using Raney nickel as a catalyst, and then the product is distilled under reduced pressure to obtain the general formula (II). A dimethoxytetrahydro compound represented by the formula (wherein R1 is the same as above) can be used. This is the general formula (Ha)
: A mixture of a cis-compound represented by the formula (wherein R+ is the same as above) and a trans-compound represented by the general formula (I[[b): (wherein R1 is the same as above).

There is no particular limitation on the amount of the dimethoxy compound represented by the general formula (It) dissolved in methanol, but usually 5 to 3 ml of the above mixture per 100 ml of methanol.
It is preferable to set it as 8-15i in particular 0g1.

The amount of Raney nickel added to the methanol solution of the mixture is 100 methanol solution.

0.5 to 5.0 g per ml, nakadzu <1.0 to 2
．． It is preferable to set it to 0g.

The product thus reduced by the Raney nickel catalyst is distilled under reduced pressure, but there are no particular limitations on the conditions for such vacuum distillation. Normal conditions, i.e. temperature 120-160℃,
The pressure is 1 to 10 Torr, and when R1 is a benzoyl group, the temperature is 170 to 200°C and the pressure is 0.
This is carried out under conditions of 1 to 5 Torr.

The obtained dimethoxytetrahydro compound represented by the general formula (110) is easily ring-opened by dissolving it in dilute sulfuric acid with a concentration of about 1 to 15%, for example, to form the general formula N: (wherein R1 is the same as above) N-acyl ALA can be obtained by producing an unstable compound represented by and immediately oxidizing it with potassium permanganate.The amount of sulfuric acid blended per 1 mole of the dimethoxytetrahydro compound represented by the general formula It is preferable to blend the sulfuric acid in an amount of .5 to 2.0 mol, especially 0.8 to 1.2 mol.If the amount of sulfuric acid blended is less than 0.5 mol, unreacted substances may be mixed in. Moreover, if it exceeds 2.0 mol, a product that is difficult to crystallize is produced, and the yield tends to decrease.

In addition, when adding a dilute sulfuric acid solution of the compound represented by general 2fl1D to an aqueous potassium permanganate solution, 5
Since a viscous substance may be formed at temperatures above 0.degree. C., it is desirable to stir the mixture under water cooling.

There is no particular limitation on the concentration of the potassium permanganate aqueous solution, but the concentration of potassium permanganate is usually 0.
0.6 to 0.38 mol/g, and preferably <0.2 to 0.3 mol/g.

The blending amount of potassium permanganate is 0.5 to 2.0 mol per mol of the compound represented by the general formula (Ill),
It is preferable that the content is <0.8 to 1.2 mol. If the amount is less than 0.5 mol, unreacted substances will be recovered, and if it exceeds 2.0 mol, a viscous product will be produced and the yield will tend to decrease.

In the compound represented by the general formula (1N), when R1 is an acetyl group, a black precipitate is formed after dropping the potassium permanganate aqueous solution, but this is filtered off and the filtrate is oxidized, for example. Adjust the pH to 3.0 to 3.5 using an aqueous sodium solution, concentrate under reduced pressure,
If the residue is extracted with ethyl acetate, a highly pure general formula (
V):1102cmCII2C)h -COCH2Nl
δ-acyl ALA represented by lRI (V) (wherein R1 is the same as above) is recovered.

The δ-acyl ALA thus recovered can be easily converted into a salt such as ALA hydrochloride by heating with dilute hydrochloric acid, and ALA can also be obtained by neutralizing with an alkali such as sodium hydroxide. These δ-acyl ALA and ALA can be used for various purposes.

Next, the method for producing δ-acyl^LA and ALA of the present invention will be explained based on Examples, but the present invention is not limited to the Examples.

Production example 1 Anode! - and platinum plate (2C1lX 5c+aXt
O, 2+a+s), -1-7 Kel plate (2CI
Pour 75 ml of methanol into a cylindrical container equipped with a cylindrical container (IX 5 cm ,
Electrolysis was carried out for 4.8 hours while applying a current of 0.87 A and maintaining the liquid temperature at 110 to 0°C.

The reaction solution was neutralized with a methanol solution containing 1 g of sodium hydroxide, the precipitated inorganic substances were separated, and the mixture was concentrated under reduced pressure to recover crystals accompanied by a viscous substance.

Hot extraction with ethyl acetate and recrystallization of the obtained crystals from benzene yielded colorless crystals with a melting point of 106-107°C (
trans form) changed. In addition, when the viscous material obtained from the mother liquor is distilled under reduced pressure, the boiling point is 128-135℃, 2-5℃.
The viscous substance distilled at Torr was changed. Elemental analysis and gas chromatography (CC) analysis revealed that the obtained viscous substance was composed of a compound represented by the general formula (Ila) and a general formula (II).
It was found to be a mixture of compounds represented by b) (in the formula, R+ represents an acetyl group).

The NMR measurement results are shown in Table 1.

The yield of the mixture of cis-dimethoxy compound and trans-dimethoxy compound was 88.3%, and as a result of analysis by gas chromatography, the ratio of cis-dimethoxy compound to nidoran-dimethoxy compound (weight ratio) was 88:
It was 34.

Production example 2 N-acetylfurfurylamine log to methanol 40
A mixture of 15.5 g of sodium carbonate and 15.5 g of sodium carbonate was stirred, and a bromine-methanol solution (bromine concentration: 1 g, 7%, 81.5 g) was added dropwise at -10 to θ°C to oxidize the mixture. , the same dimethoxy compound as that obtained in Production Example 1 was obtained.

The yield was 82.3%, and the ratio of cis-dimethoxy compound to nidoran-dimethoxy compound (weight ratio) was 48:5.
It was 4.

Example 1 The dimethoxy compound log obtained in Production Example 1 was dissolved in 50 ml of methanol, 1 g of Raney nickel was added thereto as a catalyst, the solution was reduced at normal pressure, and the product was distilled under reduced pressure to obtain a viscous substance. Note that the yield was about 90%.

Next, 10 g of the viscous material obtained was mixed with 100 m of 10% sulfuric acid.
1 molar equivalent of potassium permanganate aqueous solution was added dropwise to the solution under water cooling and stirring, the black precipitate was filtered off, and the filtrate was diluted with 10% sodium hydroxide aqueous solution.
When the residue was extracted with ethyl acetate, crystals of 6-acetyl ALA with a melting point of 94 to 95°C were obtained. This crystal was mixed with δ-acetyl ALA obtained from commercially available ALA hydrochloride, but no decrease in the melting point was observed. Yield was 30-40%.

1 g of δ-acetyl ALA was heated under reflux in 10 ml of 1O% hydrochloric acid for 2 hours, concentrated under reduced pressure, and about twice the amount of methanol was added to the residue and dissolved by heating. After cooling to room temperature, ethyl acetate was added. When added dropwise, ALA hydrochloride precipitated as crystals. The melting point was 145-147°C, and the yield was about 70% when the filtrate was concentrated.

Furthermore, when ALA hydrochloride was neutralized using an alkali, ALA was converted.

Example 2 N-benzoylfurfurylamine log methanol 5
0 ml and added LQg of sodium carbonate, the mixture was stirred and oxidized by adding dropwise a bromine-methanol solution (8 g of bromine to 50 ml of methanol) at -10 to θ°C. After stirring for 2 hours, the precipitate was filtered and washed with methanol, and the filtrate and washing liquid were combined and transferred to a reduction vessel, and 1 g of Raney nickel was added thereto and reduced at normal pressure. 1
After absorbing a molar equivalent of hydrogen, the catalyst was filtered and the filtrate was concentrated under reduced pressure. Dissolve the residue in about 3 times the volume of acetone,
This solution was added to 100 ml of 10% sulfuric acid, and an aqueous potassium permanganate solution (calculated from N-benzoylfurfurylamine, 1 molar equivalent) was added dropwise at 5° C. or below while stirring to oxidize.

When the reaction solution was filtered after its dark purple color disappeared, a black precipitate mixed with white crystals was obtained. This black precipitate was extracted with acetone while hot, and the extract was concentrated, resulting in a melting point of 120-122°C.
δ-benzoyl AL^ was changed. When the filtrate of the black precipitate was concentrated under reduced pressure, similar crystals were obtained, with a yield of about 60% calculated from N-benzoylfurfurylamine.
%Met.

Next, δ-benzoyl ALA was hydrolyzed and further neutralized to obtain ALA.

[Effects of the Invention] The production method of the present invention uses readily available and inexpensive N-acylfurfurylamine as a raw material, generates almost no hazardous waste, has a simple production process, and produces δ − in high yield. Acyl ALA can be obtained. Furthermore, δ −
Since acyl-ALA is stable and can withstand long-term storage, and can be easily converted to ALA by hydrolysis if necessary, the present invention is also an excellent method for producing ALA at low cost and industrially.

Claims (1)

[Claims] 1 δ-acylaminolevulinic acid, characterized in that N-acylfurfurylamine is electrolytically oxidized in its methanol solution, then reduced, and then ring-opened using dilute sulfuric acid and simultaneously oxidized with KMnO_4. manufacturing method. 2. A method for producing δ-acylaminolevulinic acid, which comprises oxidizing N-acylfurfurylamine in a bromine-methanol solution, then reducing it, ring-opening it using dilute sulfuric acid, and simultaneously oxidizing it with KMnO_4. 3. The method for producing δ-acylaminolevulinic acid according to claim 1 or 2, wherein the N-acylfurfurylamine is N-acetylfurfurylamine or N-benzoylfurfurylamine. 4. The method for producing δ-aminolevulinic acid according to claim 1, which comprises hydrolyzing δ-acylaminolevulinic acid. 5. The method for producing δ-aminolevulinic acid according to claim 2, characterized in that δ-acylaminolevulinic acid is hydrolyzed. 6. The method for producing δ-aminolevulinic acid according to claim 4 or 4, wherein the δ-acylaminolevulinic acid is δ-acetylaminolevulinic acid or δ-benzoylaminolevulinic acid.