JPH0372450A - Production of 5-aminolevulinic acid and its intermediate - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the title compound useful as herbicide, agricultural chemical or synthetic raw material by reducing 1,5- dihydroxy-2-pyridone and hydrolyzing prepared 2,5-piperidinedione. CONSTITUTION:1,5-Dihydroxy-2-pyridone shown by formula I is reduced with hydrogen in the presence of a catalyst such as palladium carrying carbon having preferably about 5-10wt.% palladium content or Raney nickel under 1-3atm. hydrogen pressure to give 2,5-piperidinedione shown by formula II. Then this compound is hydrolyzed by a well-known method to give the objective compound shown by formula III and the intermediate from industrially readily obtainable raw materials in higher yield, in a larger amount and simpler than a conventional procedure. The compound shown by formula I can be readily synthesized from a compound shown by formula IV supplied in an industrially large amount through a compound shown by formula V to formula VI.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing 5-aminolevulinic acid and its synthetic intermediate, 2,5-piperidinedione.

[Conventional technology]

5-Aminolevulinic acid is known as a biosynthetic intermediate for heme, vitamin B12, cytochrome, etc., and is also a compound useful as a raw material for agricultural chemicals and chemicals.
It has been reported by Noribaila et al., University of Illinois, USA, that it has selective herbicidal activity.

Conventionally, methods for producing 5-aminolevulinic acid include a method using photosynthetic bacteria and a method of chemically synthesizing it. Among the latter methods, A method of introducing a carbon-nitrogen unit and further reducing it. ■ Using levulinic acid as a raw material, oxidize it to protect the 2nd and 3rd carbons as double bonds, then aminate the 5th carbon, and then How to give back, and■
A known method is to oxidize 2-hydroxypyridine to form 2,5-dihydroxypyridine, then reduce this to form 2,5-piperidinedione, and further hydrolyze this.

However, method (2) requires protection of one carboxyl group of succinic acid, and requires highly toxic cyanide compounds such as copper cyanide and silver cyanide to introduce a carbon-nitrogen unit. There was also the drawback that toxic substances such as zinc had to be handled at times. Furthermore, when introducing an amino group, method (2) does not have a method for selectively introducing the amino group, so the above-mentioned troublesome procedure of changing and restoring a part that does not need to be structurally changed is required. do. Furthermore, although the process (2) is relatively short, the raw material 2-hydroxypyridine is expensive and difficult to obtain, and the total yield is low at about 8-10%.

[Problem to be solved by the invention]

Therefore, it has been desired to provide a method for producing 5-aminolevulinic acid in high yield with simple operations using inexpensive and easily handled raw materials.

[Means to solve the problem]

Under these circumstances, the present inventor conducted extensive research and found that the yield could be improved by reducing 1,5-dihydroxy-2-pyridone, which can be easily synthesized from 2-furaldehyde, which is supplied in large quantities industrially. (The present invention was completed by discovering that 2°5-piperidinedione, which is a synthesis product of 5-aminolevulinic acid, can be obtained.

The present invention is illustrated by the following reaction formula.

(III) That is, the present invention reduces 1,5-dihydroxy-2-pyridone (1) to produce 2,5-piperidinedione (n)
This is a method for producing 5-aminolevulinic acid (III) by preparing 5-aminolevulinic acid (III) and then hydrolyzing it.

1,5-dihydroxy-2-pyridone (I), which is a raw material for the method of the present invention, is produced by 0RGANIC according to the following reaction formula.
5YNTHE! SES, Ca1l, Vol TV,
489;0RGANIC:5YNT)IBSBS,
Co11. Vol V, 403; ^cta.

Chem. (Diacetylmethyl)-5-hydro-2,5-dimethoxyfuran (VI), which is further deacetylated and then reacted with hydroxylamine hydrochloride.

(I) 2 which is a diacetyl form from 2-furaldehyde (IV)
- For the synthesis of furaldehyde diacetate (v), a small amount of concentrated sulfuric acid is added as a catalyst to acetic anhydride having an acetyl group, and the mixture is kept at about 0 to 30°C, preferably about 10 to 20°C. About 0.5 to 2 equivalents, preferably about 1.
Add 0 to 1.5 equivalents of 2-furaldehyde (IV) and stir at room temperature for about 15 to 450 minutes to react. Thereafter, vacuum distillation is performed in a nitrogen stream and a fraction of about 107 to b 11I1 mHg is collected to obtain 2-furaldehyde diacetate (V) in a yield of about 70 to 80%.

For example, methanol is added to the obtained 2-furaldehyde diacetate (V) under a nitrogen atmosphere, bromine oxidation or electrooxidation is performed in the methanol, then methanol is distilled off, and then methylene chloride, chloroform or acetic acid is added. 2(Diacetylmethyl)-5-hydro-2,5-
Dimethoxyfuran (VI) is obtained with a yield of about 75-85%.

Furthermore, 2 (diacetylmethyl)-5-hydro-2,5
- Dimethoxyfuran (Vl) is treated with sodium methylate in methanol, for example, to remove the acetyl group to form a formyl group, and then hydroxylamine hydrochloride is added to cause condensation with the formyl group, The resulting sodium chloride is removed and then placed under an acidic aqueous solution to convert the five-membered ring to a six-membered ring, yielding 1,5-dihydroxy-2-pyridone (I). The yield at this time is about 70-75%.

The method of the present invention is carried out as follows.

The reduction of 1,5-dihydroxy-2-pyridone (I) is preferably carried out by hydrogenation in the presence of a catalyst.

Preferably, the hydrogen pressure is about 1 to 3 atmospheres. Examples of the catalyst include palladium-supported carbon or Raney nickel having a palladium content of about 5 to 10% by weight. The amount of catalyst used is 1.5
- about 5 to 1 for dihydroxy-2-pyridone (I)
0% by weight is preferred. Examples of the solvent include alcohols such as methanol, ethanol, propanol, and butanol.

When palladium-supported carbon is used as a catalyst, the generated amide may exhibit some degree of catalyst toxicity, so to prevent this, acetic acid or glacial acetic acid should be added in an amount of about 5 to 20% by weight based on the reaction solvent. It is preferable.

This reaction is carried out at a reaction temperature of about 50 to 120°C, preferably about 6
About 5-10 hours at 5-110°C, preferably 10-2
Complete by refluxing for 5 hours. After the reaction is complete, the reaction solution is filtered to remove the catalyst, and then the solvent is distilled off, followed by silica gel column chromatography (developing solvent: chloroform, dichloromethane with approximately 10% addition of an alcohol such as methanol or ethanol to adjust the polarity. )
By drying the eluate obtained under reduced pressure, 2°5-piperidinedione (II) is obtained in a yield of about 30 to 70%.

Furthermore, 5-aminolevulinic acid (I[I) can be obtained by hydrolyzing 2,5-piperidinedione (n). The reaction is ^rch, Pharm, (Weinheim)
317+304 (1984) can be used, for example, 2,5-piperidinedione (n
) and add mineral acids such as hydrochloric acid and sulfuric acid to the reaction temperature of about 50-10
This is carried out by heating under reflux at 0°C, preferably about 80 to 100°C, for about 30 minutes to 7 hours, preferably about 2 to 5 hours. After the reaction was completed, it was concentrated under reduced pressure, then methanol,
If alcohols such as ethanol and propanol are added, the yield of crystals of 5-aminolevulinic acid (Iff) is approximately 50%.
~75%.

When using 5-aminolevulinic acid (III) as a herbicide, 5-aminolevulinic acid (III) is extracted from the reaction solution obtained by hydrolyzing 2,5-piperidinedione (n) according to the method of the present invention.
Even if aminolevulinic acid (III) is not isolated, the reaction solution can be neutralized with hydroxide, sodium carbonate, sodium bicarbonate, etc. and used as a herbicide as it is. When 5-aminolevulinic acid is used as a herbicide, it is approximately 5 to 30 mmoj
! /j! .

Preferably about 15-25 mmoj! / j! The concentration should be approximately 30 to 5 per square meter.
〇 - Spraying is preferred.

〔Effect of the invention〕

As described above, the method of the present invention allows 5-7 milbric acid and its intermediate, 2,5-piperidinedione, which are useful as herbicides, agricultural chemicals, synthetic raw materials, etc., to be obtained from industrially available 2-furaldehyde. Using the obtained 1,5-dihydroxy-2-pyridone, it can be produced easily and in large quantities with a higher yield than conventional methods, and is of high industrial value.

〔Example〕

The present invention will be further explained below with reference to Examples.

Reference Example 1 (i) Add 0.05% of concentrated sulfuric acid to 51g of acetic anhydride as a catalyst.
Add 48g of 2-
Furaldehyde (IV) was added dropwise, then at room temperature for about 20 minutes.
The mixture was stirred for a minute.

After that, 0.2 g of anhydrous sodium acetate for pt+ adjustment.
was added and distilled under reduced pressure in a nitrogen stream to obtain 74 Jg of 107-b hydrodiacetate (V). The yield from 2-furaldehyde (IV) was 75%.

(Cage) In a nitrogen atmosphere, add 2-furaldehyde diacetate (V) to 60.0 g of methanol as a reaction solvent.
40-1 To remove acidic substances generated by the reaction, 17.4 g of anhydrous sodium carbonate was added, and dry ice was added.
While cooling with carbon tetrachloride and maintaining the temperature at about -15 to -10°C, add 15. Oml and methanol 200m! A mixed solution of was added dropwise. After completion of the dropwise addition, methanol was distilled off under reduced pressure, further dissolved in methylene chloride, washed with water, dehydrated using anhydrous sodium sulfate, and then methylene chloride was distilled off under reduced pressure to obtain 2(diacetylmethyl)-5. 62.4 g of -hydro-2,5-dimethoxyfuran (VI) was obtained. 2-
The yield of synthesis of 2 (diacetylmethyl)-5-hydro-2,5-dimethoxyfuran (Vl) from furaldehyde diacetate (V) was 79%.

(iii) 50.0 g of 2 (diacetylmethyl)-5-hydro-2゜5-dimethoxyfuran (VI) and 200 ml of methanol! This was added dropwise to sodium methylate consisting of 0.41 g of sodium and 100 methanol, followed by stirring at room temperature for 15 minutes.

Next, add 16.0 g of hydroxylamine hydrochloride and 5.1 g of anhydrous sodium acetate to 200 mj! After stirring at room temperature for about 20 minutes, the resulting sodium chloride was removed by filtration, and the filtrate was heated to reflux for about 10 minutes, and then heated to 100 mj! under reduced pressure. It was concentrated to Distilled water 100- and I
250 mj of N hydrochloric acid! was added and allowed to stand at room temperature for 10 minutes, and the resulting crystals were filtered off, washed with water, and dried to obtain 17.6 g of 1,5-dihydroxy-2-pyridone (1).

2 (Diacetylmethyl)-5-hydro-2,5-dimethoxyfuran (VI) to 1,5-dihydroxy-2-
The yield of synthesis of pyridone (I) was 72%, and the overall yield of 1,5-dihydroxy-2-pyridone (1) from 2-furaldehyde (IV) by the above route was 43%.

Example 1 (i) 1,5-dihydrobix 2- obtained in reference number of layers
2.0 g of pyridone (I) was mixed with 200 mt' of ethanol, and the mixture was heated under reflux at 1.2 atm in a hydrogen atmosphere for 20 hours in the presence of 0.2 g of 5% palladium on carbon.

After heating to reflux, the catalyst was removed by filtration, and the solid obtained by drying under reduced pressure was subjected to column chromatography using silica gel and mixed with chloroform and methanol (volume ratio 9:1).
), 2,5-piperidinedione (
If) 0.694 g was obtained.

The obtained product was confirmed to be 2,5-piperidinedione (II) from the results of 'II-NMR and infrared absorption spectrum (Nujol method), and was synthesized from 1,5-dihydroxy-2-pyridone (1). The yield was 39%.

'H-NMR (90 MHz, COCl s) δ (pp
[11) 7.35(no:1)1), 3.97(d:
J=3Hz, 28).

2,70 (s: 48) Infrared absorption spectrum (Nujol method) 322081-
'(NH), 1720cm-'(C=0)1640c
m″″′ (lactam C=0) (■) IN-salt in 98 g of 2.5-piperidinedione (II) OJ! 20+nl was added to dissolve and heated at 90°C for 5 hours. After concentrating under reduced pressure, 2-propanol was added to perform crystallization, filtered, and recrystallized again from ethanol and 2-propanol to obtain 0.326 g of white crystals.

The structure of the obtained product was determined from the results of 'H-NMR and infrared absorption spectrum as 5-aminolevulinic acid (I[I)
It was confirmed that it was a hydrochloride.

The yield of 5-aminolevulinic acid (III) from 2.5-piperidinedione (n) was 55%, and the overall yield from 2-furaldehyde (IV) was 9%.

'H-NMR (90M) Iz, D20) δ (ppm)
2.81(01:4)1), 4.15(s:28
) Infrared absorption spectrum (Nugizil method) 3200-2
950cm-'(NH-), 1720CII+-'(
C=0) Example 2 (i) 1,5-dihydroxy-2- obtained in Reference Example 1
2.0 g of pyridone (1) was mixed with 150 g of ethanol and 35 g of acetic acid, and the mixture was heated under reflux at 1 atm in a hydrogen atmosphere for 15 hours in the presence of 0.2 g of 5% palladium on carbon.

After heating under reflux, the same treatment as in Example 1 was carried out,
1.26 g of 2,5-piperidinedione (n) was obtained. ' From the results of H-NMR and infrared absorption spectra 2
, 5-piperidinedione (II), and the yield from 1,5-dihydroxy-2-pyridone (I) was 70%.

(if) 2,5-piperidinedione (II) 0.40
3 g was treated in the same manner as in Example 1 to obtain 5-7 milbric acid (
0.331 g of the hydrochloride of III) was obtained as white crystals.

'H-NMR and infrared absorption spectrum results confirmed that it was a hydrochloride of 5-aminolevulinic acid (III), and the yield from 2,5-piperidinedione (II) was 5.
5%, and the total rate from 2-furaldehyde (TV) was 17%.

In this example, when performing the reduction reaction of 2,5-piperidinedione (II) from 1,5-dihydroxy-2-pyridone (1), 5% palladium-supported carbon was used as a catalyst, and acetic acid was allowed to coexist. This shows an example of a reaction carried out using the following method.

Example 3 (i) 1,5-dihydroxy-2- obtained in Reference Example 1
2.0 g of pyridone (1) was mixed with methanol 1501R1, and heated under reflux at 1.5 atm in a hydrogen atmosphere for 15 hours in the presence of 0.2 g of Raney nickel.

After heating to reflux, the same treatment as in Example 1 yielded 2
, 0.568 g of 5-piperidinedione (II) was obtained. l l(-It was confirmed to be 2.5-piperidinedione (n) from the results of NMR and infrared absorption spectrum, and the yield from 1.5-dihydroxy-2-pyrrolidone (I) was 32%. .

(u) 2,5-piperidinedione (II) 0.401
By treating g in the same manner as in Example 1, 5-aminolevulin i! (I[[) hydrochloride as white crystals 0
, 335g was obtained. 'H-NMR and infrared absorption spectrum results confirmed that it was 5-aminolevulinic acid (III), the yield from 2,5-piperidinedione (If) was 56%, and 2-furaldehyde (IV )
The rate of racema from 2000 to 2000 was 8%.

This example shows an example in which Raney nickel was used as a catalyst in the reduction reaction of 2,5-piperidinedione (n) from 1,5-dihydroxy-2-pyridone (I).

Example 4 (i) 1,5-dihydroxy-2- obtained in Reference Example 1
Pyridone (1) 2.0g 2-propanol 150rn
1 and 35 ml of acetic acid, and heated under reflux for 14 hours at 1 atm in a hydrogen atmosphere in the presence of 0.2 g of 5% palladium on carbon. After heating under reflux, 2,5-piperidinedione (n) was converted into 1.
23g was obtained. From the results of H-NMR and infrared absorption spectrum, it was confirmed that it was 2,5-piperidinedione (n), and the yield from 1115-dihydroxy-2-pyridone (I) was 69%.

(ii) 2,5-piperidinedione (If) 0.29
IN-hydrochloric acid 10mj for 8g! was added, dissolved, and heated at 90°C for 5 hours. A 20% aqueous sodium hydroxide solution was added to this to adjust the pH to 7. This was further diluted with distilled water to make 1000-, and the amount of 5-aminolevulinic acid (I [I) present in this aqueous solution was determined by colorimetric assay using Ehrlich's reagent, and the concentration was 1.9 mm.
It was o 1/1. 2.5-piperidinedione (
The yield from n) was 72%, and the yield from 2-furaldehyde (
The raceway rate from 1) was 21%.

In this example, the final product, 5-aminolevulinic acid (
This shows an example in which Ill) was not crystallized.

Test Example 1 5-aminolevulinic acid (III) obtained in Example 1 was dissolved in distilled water to give 25 mmoj! / l, Table 1
The herbicidal activity of the obtained 5-aminolevrin!! (III) was evaluated after 2 days after spraying at 50-/m'' on the plants shown in Table 1. It is particularly effective as a highly selective herbicide as it does not show any activity against large, monocotyledonous cereals.

Also, the 5-7 milbrin obtained in Example 2 and Example 3!
! (II) also showed similar activity.

Test Example 2 5-Aminolevulinic acid (III) obtained in Example 4 was diluted with distilled water to 25 mmol/l, and Test Example 1 was prepared.
When the same evaluation as above was conducted, it was confirmed that the activity was exactly the same as the result of Test Example 1.

As shown in the above test examples, 5-
Aminolevrin i! (III) is extremely useful as a highly selective herbicide.

that's all

Claims (1)

[Claims] 1,1,5-dihydroxy-2-pyridone is reduced to produce 2
, 5-piperidinedione, and then hydrolyzing this. A method for producing 2,5-piperidinedione, which comprises reducing 2,1,5-dihydroxy-2-pyridone.