JPH04217650A - Production of acid addition salt of delta-amino-levulinic acid - Google Patents

Abstract

PURPOSE:To produce an acid addition salt of delta-aminolevulinic acid from an easily available inexpensive raw material on an industrial scale in high yield. CONSTITUTION:Tetrahydrofurfurylamine (VI) is made to react with phthalic anhydride to introduce a phthalyl group for protecting the amino group of the compound (VI) and obtain N-tetrahydro-furfurylphthalimide (III). The 1- and 4-carbon atoms of the compound (III) are oxidized to form 5- phthalimidolevulinic acid (II) and 5-phthalimidopentan-4-olide (V). The compound (V) is converted to the compound (II) by oxidation reaction. The compounds (II) produced by the above two reactions are joined and the protecting group is eliminated with an acid to obtain the objective acid addition salt of delta- aminolevulinic acid, which can easily be converted to delta-aminolevulinic acid by neutralizing with an alkali.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a method for producing acid addition salts of δ-aminolevulinic acid. Acid addition salts of δ-aminolevulinic acid are easily converted to δ-aminolevulinic acid by neutralization. δ-Aminolevulinic acid is chemically unstable and is usually stored and distributed in the form of an acid addition salt.

0002

[Prior art] δ-aminolevulinic acid is a vitamin B1
2. Known as a precursor of heme and chlorophyll. Furthermore, it has been reported that δ-aminolevulinic acid has a selective herbicidal effect by Rivaiz et al. of the University of Illinois in the United States. (Enzyme Microb. Techno
l. , Vol. 6, P390 (1984))
Several methods are conventionally known for producing acid addition salts of δ-aminolevulinic acid, which is a synthetic intermediate of -aminolevulinic acid. For example, Pisha et al. have reported a method for converting δ-chlorolevulinic acid ester or δ-levulinic acid ester into a δ-phthalimide derivative to convert it into an acid addition salt of δ-aminolevulinic acid (Bull.
Soc. Chim. Fr. , 1750 (1956)
).

[0003] Also, Bielen et al. used 4,5-dioxovaleric acid obtained from δ-bromolevulinic acid,
reported a method for synthesizing acid addition salts of δ-aminolevulinic acid by performing a non-enzymatic transamination reaction (Phytochemistry, Vol. 18, 4).
41 (1979)).

Furthermore, Palatinate et al. reported a method for synthesizing an acid addition salt of δ-aminolevulinic acid by reducing a ketonitrile compound with zinc and acetic acid (Tetrahe et al.
doron Lett. , Vol. 25, No. 28
, 2977 (1984)).

[0005]

[Problems to be Solved by the Invention] However, none of the conventional methods for producing acid addition salts of δ-aminolevulinic acid is capable of industrially producing δ-aminolevulinic acid efficiently. In addition, conventional manufacturing methods have problems such as high manufacturing costs due to expensive raw materials, complicated manufacturing processes, and generation of hazardous waste.

The present invention has been made in view of the above points, and is an acid addition method of δ-aminolevulinic acid that can industrially produce acid addition salts of δ-aminolevulinic acid in good yield from readily available and inexpensive raw materials. A method for producing salt is provided.

[0007]

[Problems to be Solved by the Invention] As a result of intensive research to achieve the above object, the present inventors have devised a method for producing δ-aminolevulin by a simple process using easily available and inexpensive tetrahydrofurfurylamine as a starting material. It has been found that acid addition salts of acids can be obtained.

That is, the present invention is based on the reaction formula shown in Chemical formula 2.
As shown in (1), a protecting group for protecting the amino group is introduced into the amino group of tetrahydrofurfurylamine (IV) shown by the general formula (IV), and the general formula (III) is obtained.
A step of obtaining a compound (III) represented by the formula (III), a step of obtaining a compound (II) represented by the general formula (II) by oxidizing the carbons at the 1st and 4th positions of the obtained compound (III), A method for producing an acid addition salt of δ-aminolevulinic acid represented by the general formula (I), comprising the step of deprotecting the protecting group of the compound (II) obtained by using an acid.

[0009]

[Chemical 2]

(In the formula, R and R' are a general amino group-protecting group or a hydrogen atom, and at least one is a general amino group-protecting group. Also, both R and R' are In the case of the above-mentioned protecting group, R and R' may be bonded to each other to form a ring. In the formula, X is a monovalent organic acid group or an inorganic acid group.) Hereinafter, δ of the present invention - The method for producing an acid addition salt of aminolevulinic acid will be explained in more detail.

In the present invention, tetrahydrofurfurylamine (IV), which is inexpensive and easily available, is used as a starting material.

The protecting group for the amino group in step (a) is not particularly limited as long as it can generally be used as a protecting group for the amino group. For example, an acyl group,
A silyl group or the like can be used. Protecting group R for amino group
, R' are both protecting groups as described above,
One may be the protecting group and the other may be a hydrogen atom. It may also be a protecting group in which R and R' are bonded to each other to form a cyclic structure, such as phthalimide.

[0013] The oxidation of carbons at the 1st and 4th positions in step (b) can be carried out by an oxidation reaction using ruthenium oxide or an oxidation reaction using a chromic acid-based oxidizing agent.

The oxidation reaction using ruthenium oxide can be carried out, for example, by using ruthenium tetroxide, ruthenium dioxide or It is carried out using a ruthenium trichloride catalyst and stirring overnight. This suitable solvent is, for example, a mixed solvent of carbon tetrachloride, acetonitrile, water, etc., but is not particularly limited.

On the other hand, the oxidation reaction using a chromic acid-based oxidizing agent is carried out in an appropriate solvent, for example, an organic solvent such as acetone.
This is carried out using chromium trioxide, t-butyl chromate, etc.

[0016] Such an oxidation reaction proceeds via a reaction intermediate (V) such as the general formula (V) shown in Chemical Formula 3. The reaction intermediate (V) can actually be isolated during the reaction. In addition, step (b) using the reaction intermediate (V)
Compound (II) can be obtained by carrying out an oxidation reaction similar to the above.

[0017]

[Chemical formula 3]

The deprotection reaction of the protecting group for the amino group in step (c) is carried out using an acid in a suitable solvent. The acid used in this deprotection reaction is an organic or inorganic acid that forms an acid addition salt with the amino group of δ-aminolevulinic acid. Examples of such organic acids include acetic acid, trifluoroacetic acid, para-toluenesulfonic acid, and the like. Also,
Examples of inorganic acids include hydrochloric acid, sulfuric acid, and nitric acid.

[0019] Suitable solvents include, for example, water and dioxane, but are not particularly limited.

The acid addition salt (I) of δ-aminolevulinic acid thus obtained is disclosed in, for example, JP-A-2-7684.
As disclosed in Publication No. 1, δ-aminolevulinic acid can be obtained by neutralizing the acid addition salt (I) of δ-aminolevulinic acid with an alkali such as sodium hydroxide.

[0021]

[Examples] Examples of the present invention will be described in detail below.

Example 1 (A) Preparation of N-tetrahydrofurfuryl phthalimide 19.8 g (134 mmol) of phthalic anhydride is dissolved in 500 ml of chloroform. 10 g (99 mmol) of tetrahydrofurfurylamine was added to this solution with stirring. Next, the mixed solution was heated under reflux overnight, and the water produced was distilled off. After cooling, the reaction solution was poured into 300 ml of saturated sodium bicarbonate solution to separate the organic solvent layer. After the aqueous layer was extracted twice with chloroform, the extract was combined with the previously separated organic solvent layer.

Next, the organic solvent layer was washed with aqueous sodium bicarbonate and water, and then dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained crude product was recrystallized from a hexane:methylene chloride mixed solvent to obtain N-tetrahydrofurfuryl phthalimide.

N-tetrahydrofurfuryl phthalimide yield: 2
1.8g (Yield 95.2%) Melting point: 86.5~
87.5°C 1H-NMR (CDCL3): δ7.9-7.8
(m, aromatic-H), 7.75-7.65 (
m, aromatic-H), 4.3-4.2 (1H
, m), 4.0-3.6 (4H, m), 2.1-1.8
(3H, m), 1.75-1.6 (1H, m).

(B) 5-phthalimidopentane-4-olide and 5-
5.0 g (22 mmol) of N-tetrahydrofurfuryl phthalimide obtained in step (A) for producing phthalimide levulinic acid and 25 m of carbon tetrachloride.
19 g of powdered sodium periodate (87 m
mol), Ruthenium chloride hydrate 0.10g (2.2
mol%) and stirred vigorously at ambient temperature overnight. After the reaction was completed, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform/1N aqueous hydrochloric acid solution and extracted with chloroform. This organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to column chromatography on silica gel using chloroform:methanol=95:5v/v as an eluent to obtain 5-phthalimidopentane-4-
I got Orid. Furthermore, column chromatography was performed using chloroform:methanol:formic acid=95:4:1v/v to obtain 5-phthalimide revulinic acid.

5-phthalimidopentane-4-olide yield: 1.
5 g (Yield 28%) Melting point: 170-171
°C 1H-NMR (CDCL3): δ7.91-7.8
3 (2H, m, aromatic-H), 7.78-7
．． 72 (2H, m, aromatic-H), 4.
87 (1H, dq, J = 5.3 & 7.1Hz, H-4)
, 4.02 (1H, dd, J=14.2, 7.7Hz,
H-5), 3.84 (1H, dd, J=14.2, 5.
2Hz, H-5), 2.71 - 2.49 (2H, m
, H-2), 2.46-2.34 (1H, m, H-3)
, 2.13-2.03 (1H, m, H-3).

5-phthalimide revulinic acid yield: 2.1 g (yield 37%) melting point: 16
0-162°C 1H-NMR (CDCL3-DMSO-d6):
δ7.88-7.83 (m, aromatic-H)
, 7.78-7.73 (m, aromatic-H),
4.57 (s, H-5), 2.85 (t, J=6.6
Hz, H-3), 2.64 (t, J=6.6Hz, H
-2).

(C) 5-phthalimidopentane-4-olide obtained in step (B) 0.30 g (1.2 mmol) of carbon tetrachloride 2
．． Add powdered sodium periodate to a two-phase mixed solution of 0 ml, acetonitrile 10 ml, and water 3.0 ml.
5g (12mmol), Ruthenium chloride hydrate 90
mg (30 mol%) and stirred vigorously at 50°C for 24 hours. After the reaction was completed, the solvent was distilled off under reduced pressure.

Next, the obtained residue was diluted with chloroform.
It was dissolved in an aqueous N hydrochloric acid solution and extracted with chloroform. The organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (chloroform: methanol: formic acid = 95:4:
1v/v) to obtain 5-phthalimide revulinic acid.

5-phthalimide revulinic acid yield: 32 mg (yield 10%) Melting point: 160-162°C 1H-NMR (CDCL3-DMSO-d6):
δ7.88-7.83 (m, aromatic-H)
, 7.78-7.73 (m, aromatic-H),
4.57 (s, H-5), 2.85 (t, J=6.6H
z, H-3), 2.64 (t, J=6.6 Hz, H-
2).

(D) 5-aminolevulinic acid hydrochloride production step (B),
2.1 g of 5-phthalimide levulinic acid obtained in (C)
(8.0 mmol) was suspended in 100 ml of 6N aqueous hydrochloric acid solution and heated under reflux for 8 hours. After the reaction was completed, the reaction solution was cooled to ambient temperature. Next, the crystals that had crystallized were filtered off, and the solvent was then distilled off under reduced pressure. Furthermore, the obtained residue was recrystallized from ethanol-water to obtain 5-aminolevulinic acid hydrochloride.

5-Aminolevulinic acid hydrochloride Yield: 0.861 g (yield 63.8%)
Point: 142 to 145°C (Literature value 149 to 151°C) 1H-NMR (D2O): δ4.07 (s, H-5
), 2.84 (t, J=6.3Hz, H-3), 2.6
6 (t, J=6.2Hz, H-2).

Example 2 0.30 g (1.3 mmol) of N-tetrahydrofurfuryl phthalimide obtained in step (A) of Example 1, 2 ml of carbon tetrachloride, 10 ml of acetonitrile, and 3 m of water
Add 1 part of powdered sodium periodate to 1 part of the two-phase mixed solution.
．． 7 g (7.8 mmol) and 8.0 mg (2.2 mol%) of ruthenium chloride hydrate were added, and the mixture was vigorously stirred at 80° C. overnight. After the reaction was completed, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform/1N aqueous hydrochloric acid solution, extracted with chloroform, the organic solvent layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol:formic acid = 95:4:1v/v), and as in Example 1, 5-phthalimidopropane-4-olide was not produced. Phthalimide levulinic acid was obtained.

5-phthalimide levulinic acid yield: 0.20 g (yield 59%) melting point: 1
60-162°C 1H-NMR (CDCL3-DMSO-d6):
δ7.88-7.83 (m, aromatic-H)
, 7.78-7.73 (m, aromatic-H),
4.57 (s, H-5), 2.85 (t, J=6.6H
z, H-3), 2.64 (t, J=6.6Hz, H-2
).

The obtained 5-phthalimide revulinic acid,
Deprotection was performed in the same manner as in step (D) of Example 1 to obtain 5-aminolevulinic acid hydrochloride.

Example 3 (A) Preparation of N-benzoyltetrahydrofurfurylamide Tetrahydrofurfurylamine 10ml (97mmol)
), and 15 ml of triethylamine (107 mm
11 ml (97 mmol) of benzoyl chloride was slowly added dropwise to the benzene solution of ol) at 0°C under anhydrous conditions. After the addition was complete, the solution was stirred at ambient temperature overnight, and after the reaction was complete, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solution of n-hexane and ethyl acetate to obtain N-benzoyltetrahydrofurfurylamide.

N-benzoyltetrahydrofurfurylamide Yield: 16 g (yield 77%) Melting point: 93-94°C 1H-NMR (CDCl3): δ7.80-7.8
6 (2H, m, aromatic-H), 7.52-
7.38 (2H, m, aromatic-H), 6.
61 (1H, br, NH), 4.07 (1H, dq
, J=7.1, 3.3Hz, H-4), 3.93-3
．． 72 (3H, m, H-1, H-5), 3.35 (1H
, ddd, J=13.4, 7.7, 5.3Hz, H-5
), 2.09-1.86 (3H, m, H-2, H-3)
, 1.68-1.54 (1H, m, H-3).

(B) Preparation of 5-benzoylamide pentan-4-olide and 5-benzoylamide levulinic acid N-benzoyltetrahydrofurfurylamide 0.3 g (1.4
6 mmol) carbon tetrachloride 2 ml acetonitrile 1
In a two-phase mixed solution of 0 ml and 3 ml of water, 1.9 g (8.8 mmol) of powdered sodium periodate and 8 mg (2.2 mol%) of ruthenium chloride hydrate were added.
was added and stirred vigorously at ambient temperature overnight. After the reaction was completed, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform/1N hydrochloric acid aqueous solution,
Extracted with chloroform. This extract was dried over anhydrous magnesium sulfate, and chloroform was distilled off under reduced pressure. The obtained residue was subjected to column chromatography using silica gel. By using a mixed solution of chloroform and methanol at a ratio of 30:1 V/V as an eluent, 5-benzoylamide pentane-4
Olide was eluted. Furthermore, 5-benzoylamide levulinic acid was eluted with a mixture of chloroform, methanol, and formic acid in a ratio of 18:1:1 V/V.

5-benzoylamide pentane-4-olide yield:
0.076 g (yield 24.0%) Melting point: 12
9-130°C 1H-NMR (CDCl3): δ7.83-7.7
7 (2H, m, aromatic-H), 7.54-
7.37 (3H, m, aromatic-H), 7.
02 (1H, br, NH), 4.73 (1H, dq
, J=7.3, 3.4Hz, H-4), 3.90 (1H
, ddd, J=14.5, 6.6, 3.2Hz, H-5
), 3.54 (1H, ddd, J=14.5, 7.0,
5.6Hz, H-5) 2.59-2.51(2H, m
, H-2), 2.41-2.28 (1H, m, H-3)
, 2.09-1.94 (1H, m, H-3).

5-benzoylamide levulinic acid yield: 0.075 g (yield 21.8%)
Point: 120 to 122°C 1H-NMR (CD3 OD): δ7.85 (2H
, d, J=7.1Hz, aromatic-H), 7.
55 (1H, t, J=7.2Hz, aromatic-
H) ,7.46(2H,t,J=7.3Hz,aro
matic-H), 4.26 (2H,s,H-5)
,2.80(3H,t,J=6.3Hz,H-3),2
．． 61 (2H, t, J=6.4Hz, H-2).

The 5-benzoylamide pentane-4-olide obtained here was further oxidized in the same manner as in step (C) of Example 1, thereby converting it into 5-benzoylamide levulinic acid.

(C) Production of 5-aminolevulinic acid hydrochloride 5-benzoylamide levulinic acid 0.874 g (3.72 mmo
1) was suspended in 10 ml of 6N aqueous hydrochloric acid solution and heated under reflux for 7 hours. After the reaction was completed, it was cooled to ambient temperature and the precipitated crystals were filtered off. Then, the solvent in this filtrate was distilled off under reduced pressure. The obtained residue was recrystallized from 10% by weight aqueous ethanol to obtain 5-aminolevulinic acid hydrochloride.

5-aminolevulinic acid hydrochloride yield: 0.390 g (yield 62.5%) 1
H-NMR (D2O): δ4.07 (s, H-5),
2.84(t, J=6.3Hz, H-3), 2.66(
t, J=6.2Hz, H-2).

[0044]

Effects of the Invention According to the method for producing acid addition salts of δ-aminolevulinic acid of the present invention, the method uses readily available and inexpensive tetrahydrofurfurylamine as a raw material, generates almost no hazardous waste, and the production process is complicated. Instead, the acid addition salt of δ-aminolevulinic acid can be obtained in high yield. As a result, the acid addition salt of δ-aminolevulinic acid can be industrially produced at low cost.

Claims (1)

[Claims] Claim 1: As shown in reaction formula (1) shown in Chemical Formula 1, a protecting group for protecting the amino group is introduced into the amino group of tetrahydrofurfurylamine (IV) shown by general formula (IV). A process for obtaining a compound (III) represented by general formula (III) and the obtained compound (III)
The general formula (
δ- represented by general formula (I), which comprises a step of obtaining compound (II) represented by II) and a step of deprotecting the protecting group of the obtained compound (II) with an acid. A method for producing an acid addition salt of aminolevulinic acid. [Formula 1] (wherein, R and R' are a general amino group-protecting group or a hydrogen atom, and at least one is a general amino group-protecting group. Also, both R and R' is the above-mentioned protecting group, R and R' may be bonded to each other to form a ring. In the formula, X is a monovalent organic acid group or an inorganic acid group.)