Process for preparing 5-aminolevulinic acid

A process for preparing 5-aminolevulinic acid or a salt thereof, which comprises reacting furfurylamine, of which the amino group has been protected, with oxygen molecule under irradiation by light in the presence of a sensitizer; hydrogenating the resulting compound in the presence of a metallic catalyst; and hydrolyzing the hydrogenated compound. 5-Aminolevulinic acid, useful as a raw material for various chemicals and as an agricultural chemical, can be prepared at a high yield by a simple procedure from a raw material which is inexpensive and readily available.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a process for preparing 5-aminolevulinic 
acid or a salt thereof which is useful as a raw material for various 
chemicals and is an agricultural chemical. The process can be applied to 
the industrial manufacture of 5-aminolevulinic acid with advantage. 
2. Description of the Background Art 
5-Aminolevulinic acid is an intermediate for biosynthesis of haem, vitamin 
B.sub.12, and cytochrome. It is known to be a useful compound as a raw 
material for various chemicals and also as an agricultural chemical. This 
compound has been reported to exhibit a selective herbicidal action by 
Revitz et al. at Illinois University. 
The 5-aminolevulinic acid can be prepared either by using photosynthetic 
microorganisms or by chemical synthetic methods. Included in typical known 
methods of chemical synthesis of 5-aminolevulinic acid are, (1) a method 
of converting succinic acid into a monoester and introducing a 
carbon-nitrogen unit into the monoester, followed by reduction; (2) a 
method of oxidizing levulinic acid to protect the 2- and 3-positions as a 
double bond, aminating the 5-position carbon atom of the protected 
compound, and reducing the amino compound; and (3) a method of oxidizing 
2-hydroxypyridine to 2,5-dihydroxypyridine, reducing the 
2,5-dihydroxypyridine into 2,5-pyperidinedione, and hydrolyzing the 
2,5-pyperidinedione. 
Problems encountered in the above-mentioned method (1) are the necessity of 
protecting one carboxyl group of succinic acid, the requirement of using a 
deadly toxic cyano compound, such as silver cyanide or copper cyanide, for 
introducing the carbon-nitrogen unit, and also the need for handling toxic 
compounds such as zinc and the like during the reduction. In the absence 
of a method of selectively introducing an amino group to a desired 
position, the method (2) requires the complicated procedure of protecting 
and removing the protective groups from the positions which otherwise need 
not be modified. Notwithstanding the comparatively short processing steps 
involved, the method (3) has drawbacks in the high cost of the raw 
material 2-hydroxypyridine, the difficulty involved in the availability of 
this raw material, and the low overall yield of as low as about 8-10%. 
More recently, comparatively reasonable methods for synthesizing 
5-aminolevulinic acid have been disclosed. One comprises providing 
N-protected furfurylamine (furfurylamine of which the amino group has been 
protected), oxidating this compound by electrode or bromine in the 
presence of methanol, and reducing the oxidated compound, followed by 
further oxidation with KMnO.sub.4. In another method, 
tetrahydrofurfurylamine obtained by the reduction of furfurylamine is used 
as a raw material for oxidation with ruthenium oxide. 
One problem with these methods is the use of a large quantity of expensive 
chemical oxidizing agents, which gives rise to a high production cost. In 
particular, KMnO.sub.4 used in the former method cannot be recovered in 
the form usable as an oxidizer, and therefore must be discarded. 
Difficulties are encountered in the waste liquid treatment. In addition, 
because only an insufficient amount of oxidation is achieved in the first 
oxidation step, the oxidation must be carried out in two stages. 
SUMMARY OF THE INVENTION 
In view of this situation, the present inventors have undertaken extensive 
studies and found that 5-aminolevulinic acid can be industrially 
manufactured with advantage by using N-protected furfurylamine as a 
starting material, reacting this compound with oxygen (O.sub.2) under 
irradiation by light, and hydrogenating the resulting compound, followed 
by hydrolysis. This finding has led to the completion of the present 
invention. 
Accordingly, an object of the present invention is to provide a process for 
preparing 5-aminolevulinic acid or a salt thereof at a high yield by a 
simple procedure from a raw material which is inexpensive and readily 
available. 
This object of the present invention can be achieved by a process 
comprising, 
reacting furfurylamine, of which the amino group has been protected, with 
oxygen (O.sub.2) under irradiation by light in the presence of a 
sensitizer, 
hydrogenating the resulting compound in the presence of a metallic 
catalyst, and 
hydrolyzing the hydrogenated compound. 
Other and further objects, features and advantages of the present invention 
will appear more fully from the following description.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS 
The process of the present invention comprises the following three steps, 
(1) a step of reacting furfurylamine, of which the amino group has been 
protected, with oxygen under irradiation by light in the presence of a 
sensitizer (oxidation step), (2) a step of hydrogenating the oxidized 
compound in the presence of a metallic catalyst (reduction step), and (3) 
a step of hydrolyzing the hydrogenated compound (hydrolysis step). These 
steps are considered to proceed according to the following chemical 
reaction formulas, 
##STR1## 
wherein R.sup.1 and R.sup.2 represent protective groups for amino group 
and R.sup.3 is a hydrogen atom or an alkyl group. 
Each step of the process will now be illustrated in detail. 
(1) Oxidation Step 
The step (1) is a step for oxidizing N-protected furfurylamine (A). The 
N-protected furfurylamine (A) used as the raw material can be readily 
synthesized from furfurylamine by a common method (Lecture of New 
Experimental Chemistry, edited by The Chemical Society of Japan, Vol. 14, 
Synthesis and Reaction of Organic Compounds V, Maruzen Publishing Co. 
(1978), page 2558; Organic Syntheses, Vol. 5, John Wiley & Sons (1978), 
page 944). The protective group may be either a cyclic group, such as 
phthalimide, or a linear group, with an especially preferred group being 
acyl group. 
The oxidation step can be carried out by dissolving the raw material in a 
solvent, adding a sensitizer to the solution, and feeding in oxygen gas 
under irradiation by light. 
Pyridine is a preferable solvent used here. A mixture of pyridine (more 
than 25% by volume) and one or more organic solvents, such as acetone, 
methyl ethyl ketone, toluene, xylene, benzene, chloroform, 
dichloromethane, ethyl acetate, methyl acetate, methanol, ethanol, 
propanol, and isopropanol, can also be used. The amount of solvent used is 
preferably 3-30 ml per 1 mmol of N-protected furfurylamine. 
Commonly used organic coloring agents, such as Rose Bengal, erythrosine, 
methylene blue, chlorophyll, and hematoprophyrin, as well as polycyclic 
aromatic compounds, such as coronene and furalene, can be used as the 
sensitizer. The sensitizer can be used at a concentration of 10.sup.-2 
-10.sup.-5 mol/1 in the solvent, with the concentration of 10.sup.-3 
-10.sup.-4 mol/1 being preferred in view of the reaction efficiency and 
the economy, and for preventing mingling of the sensitizer in the 
succeeding steps. 
Oxygen used as the oxidizer can be oxygen in the air or commercially 
available oxygen gas. Oxygen atom or ozone is excluded. Oxygen may be used 
diluted with an inert gas such as nitrogen. The amount of oxygen gas 
supplied can be suitably determined depending on the concentration of 
oxygen in the gas, the amount of the solvent, the concentration of the raw 
material, and the reaction temperature. For instance, when the oxygen gas 
is fed in under the conditions of a raw material concentration of 100 
mmol/l, a Rose Bengal concentration of 10.sup.-4 mmol/l, and at 0.degree. 
C., a preferable feed rate of the oxygen gas is 5-50 ml/min for 100 ml of 
the reaction mixture. Because the reaction is effected by the dissolved 
oxygen, an excessive amount of oxygen is unnecessary, but too small an 
amount cannot cause the reaction to proceed. 
There are no specific limitations as to the source of the light used for 
irradiation. Any optional sources, such as sunlight, fluorescent lamp, 
tungsten-halogen lamp, and high-pressure mercury lamp, can be used. Among 
these, especially preferred are fluorescent lamp, tungsten-halogen lamp, 
and high-pressure mercury lamp, because of the high energy efficiency of 
visible lights. 
Although a temperature above -80.degree. C. can be employed for the 
reaction, a range of 0.degree.-25.degree. C. is preferred in view of the 
efficiency of the reaction and the safety. The reaction is normally 
completed within 3-15 hours at a temperature in this range. 
After the completion of the reaction, the solvent is evaporated to obtain 
N-protected-5-aminomethyl-5-hydroxy-2,5-dihydrofuran-2-one or its 
ring-opened isomer, 4-oxo-5-phthalimidopentenic acid, represented by the 
above formula (B). These are tautomers, changing the properties in the 
reaction system or depending on the external conditions such as analytical 
conditions. Although the oxidation product may be purified and isolated by 
a conventional procedure such as recrystallization, it may be transferred 
without purification to the next step after decoloration using activated 
carbon. 
(2) Reduction Step (Hydrogenation) 
This step is a step for reducing the oxidation product obtained in the 
preceding oxidation step. 
Although any conventionally known method may be applied to this step, 
hydrogenation using a metallic catalyst is preferred in view of economy of 
the reaction. The use of a Group VIII metal as the catalyst is preferred. 
Typical catalysts are palladium, nickel, and Raney nickel, supported on a 
carrier. 
Specifically, this step can be carried out, for example, in methanol in an 
amount of 5-20 times the raw material using 5% palladium-on-carbon as the 
catalyst under a hydrogen atmosphere of 1-3 atm and at 
0.degree.-50.degree. C. A lower alcohol, such as ethanol or propanol, or a 
low aliphatic fatty acid, such as acetic acid, can be used as a solvent. 
Even though alkylation of R.sup.3 may take place in the reaction using a 
lower alcohol as a solvent, the alkylated product may be processed as is 
without any problem in the preparation of 5-aminolevulinic acid. 
After the reaction, the catalyst is removed by filtration and the solvent 
is evaporated to obtain a solid product, which can be used as is in the 
next step. 
(3) Hydrolysis Step 
This step is a step for obtaining 5-aminolevulinic acid by hydrolysis. 
The use of an acid is preferable for carrying out the hydrolysis. Because 
the acid becomes a component of a salt of 5-aminolevulinic acid after the 
hydrolysis, any optional acids, such as acetic acid, toluenesulfonic acid, 
hydrochloric acid, and sulfuric acid, can be selected depending on the 
purposes to which the product is directed. 
As a solvent, water or a mixture of water and a water-soluble organic 
solvent, such as dioxane, tetrahydrofuran, or methanol, can be used. 
After the reaction, the solvent is evaporated to obtain the salt of 
5-aminolevulinic acid. This salt can be purified by conventionally known 
methods, such as recrystallization using a water-ethanol mixture or an 
ethyl acetate-ethanol mixture. 
The salt of 5-aminolevulinic acid may be converted to free 5-aminolevulinic 
acid by neutralization with an equivalent amount of alkali. 
The 5-aminolevulinic acid thus prepared can be used as an intermediate for 
the production of haem, vitamin B.sub.12, cytochrome, and the like, as an 
agricultural chemical, or as a raw material for the manufacture of various 
chemicals. 
According to the process of the present invention, 5-aminolevulinic acid 
can be prepared at a high yield by a simple procedure from a raw material 
which is inexpensive and readily available. The process thus bears a high 
value industrially. 
Other features of the invention will become apparent in the course of the 
following description of the exemplary embodiments which are given for 
illustration of the invention and are not intended to be limiting thereof. 
EXAMPLES 
Example 1 
(1) Oxidation Step 
2.27 g (10.0 mmol) of N-furfurylphthalimide was charged into a three-necked 
glass flask equipped with an oxygen feed tube, a thermometer, and a reflux 
condenser, and dissolved in 100 ml of anhydrous pyridine. After the 
addition of 7.0 mg of Rose Bengal, oxygen gas was fed at a rate of 20 
ml/min at 10.degree.-20.degree. C. under irradiation by light. A 27 W 
white fluorescent lamp was used as a light source and the radiation was 
performed from the outside of the flask. After 7 hours, the irradiation 
was terminated and the pyridine was evaporated under reduced pressure to 
obtain 2.47 g of a light brown, semi-crystalline product. 
(2) Reduction Step (Hydrogenation) 
2.00 g of the semi-crystalline solid obtained in (1) was dissolved in 40 ml 
of methanol and stirred at 50.degree. C. in a hydrogen atmosphere under 
atmospheric pressure in the presence of 200 mg of 5% palladium-on-carbon 
catalyst. 
After five hours, the reaction was terminated and the mixture was allowed 
to cool to room temperature. The catalyst was removed by filtration and 
methanol was evaporated to obtain 2.11 g of white crystals. 
(3) Hydrolysis Step 
100 ml of 6N hydrochloric acid was added to 2.11 g of the white crystals 
obtained in (2), and the mixture was heated under reflux for 5 hours. 
After evaporating the hydrochloric acid under reduced pressure, a brown 
solid product was obtained and dissolved in ethanol. Acetone was added to 
the solution and the crystals produced were collected by filtration to 
obtain 0.689 g of 5-aminolevulinic acid hydrochloride. The yield based on 
N-furfurylphthalimide was 51%. 
Spectrum data of the 5-aminolevulinic acid hydrochloride are as follows. 
.sup.1 H-NMR (.delta. ppm in D.sub.2 O, 400 MHz): 2.72 (2H, t, J=6.5 Hz), 
2.91 (2H, t, J=6.5 Hz), 4.16 (2H, s). 
IR cm.sup.-1 (Nujor method): 3150, 3100, 3000, 1725, 1495, 1430, 1405, 
1395, 1390, 1215, 1195, 1145, 1100, 1080, 1000, 975, 955, 865, 840, 620. 
Example 2 
2.27 g (10.0 mmol) of N-furfurylphthalimide was charged into a three-necked 
glass flask equipped with an oxygen feed tube, a thermometer, and a lamp 
protection tube equipped with a water jacket, and dissolved in 100 ml of 
anhydrous pyridine. After the addition of 7.0 mg of Rose Bengal, oxygen 
gas was fed at a rate of 20 ml/min at 10.degree.-15.degree. C. under 
irradiation by light. A 100 W tungsten-halogen lamp was used as a light 
source and the radiation was performed from the inside of the flask. 
After three hours, the irradiation was terminated and pyridine was 
evaporated under reduced pressure to obtain a red tar-like product. This 
tar-like product was dissolved in 100 ml of water, insoluble components 
were removed by filtration, and the filtrate was concentrated and dried to 
obtain 2.57 g of the oxidation product in the form of light brown 
crystals. HPLC analysis of the crystals confirmed the presence of 
pyridine. The purity of this product, excluding the pyridine, was 85%. NMR 
analysis confirmed the presence of pyridine and 
4-oxo-5-phthalimidopentenic acid. The content of pyridine was measured and 
found to be 23%, equivalent to moles of the oxidation product. The yield 
of the oxidation product was 76%. 
Spectrum data of the oxidation product thus obtained are as follows. 
.sup.1 H-NMR (.delta. ppm in D.sub.2 O, 400 MHZ): 4.80 (2H, s), 6.84 (1H, 
d), 7.13 (1H, d), 7.30-8.20 (Ar 7H, m), 8.53-8.61 (Ar 2H, m). 
IR cm.sup.-1 (Nujor method): 1770, 1710, 1630, 1480, 1470, 1420, 1380, 
1310, 1195, 1110, 1090, 980, 950, 720, 690, 610, 535. 
(2) Reduction Step (Hydrogenation) 
2.50 g of the light brown crystals obtained in (1) was reduced in the same 
manner as in Example 1 to obtain 1.88 g of pale yellow crystals. The 
crystals were identified to be 5-phthalimido levulinic acid by NMR 
analysis. The yield was 97%. 
Spectrum data of 5-phthalimido levulinic acid thus obtained are as follows. 
.sup.1 H-NMR (.delta. ppm in CDCl.sub.3, 400 MHZ): 2.61 (2H, t), 2.84 (2H, 
t), 4.57 (2H, s), 7.57-7.95 (Ar 4H, m). 
IR cm.sup.-1 (Nujor method): 1770, 1720, 1710, 1690, 1610, 1460, 1410, 
1370, 1310, 1280, 1250, 1230, 1190, 1100, 1080, 1040, 1010, 980, 960, 900, 
750, 720, 710, 610, 530, 490, 470. 
(3) Hydrolysis Step 
The hydrolysis was carried out in the same manner as in Example 1 using 
1.80 g of the 5-phthalimido levulinic acid produced in (2) above, to 
obtain 0.862 g of 5-aminolevulinic acid hydrochloride. The yield based on 
N-furfurylphthalimide was 75%. 
Example 3 
The oxidation step was carried out in the same manner as in Example 2, 
except that a mixture of 60 ml of acetone and 40 ml of pyridine was used 
as the solvent instead of 100 ml of pyridine in Example 2, to obtain 2.46 
g of light brown crystals as the oxidation product, which consisted of 
pyridine, 5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, and 
4-oxo-5-phthalimidopentenic acid. The purity after removal of pyridine was 
87% and the yield of the oxidation product was 73%. 
This oxidation product was reduced in the same manner as in Example 1 and 
hydrolyzed to obtain 0.855 g of pale yellow crystals of 5-aminolevulinic 
acid hydrochloride at an yield of 51% based on N-furfurylphthalimide. 
Example 4 
The oxidation step was carried out in the same manner as in Example 2, 
except that a mixture of 50 ml of methanol and 50 ml of pyridine was used 
as the solvent instead of 100 ml of pyridine in Example 2, to obtain 2.01 
g (yield: 59%) of pale yellow crystals as the oxidation product, which 
consisted of pyridine, 
5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, and 
4-oxo-5-phthalimidopentenic acid. 
This oxidation product was reduced in the same manner as in Example 1 and 
hydrolyzed to obtain 0.670 g of pale yellow crystals of 5-aminolevulinic 
acid hydrochloride at an yield of 40% based on N-furfurylphthalimide. 
Example 5 
The oxidation step was carried out in the same manner as in Example 2, 
except that a mixture of 50 ml of chloroform and 50 ml of pyridine was 
used as the solvent instead of 100 ml of pyridine in Example 2, to obtain 
2.21 g of light brown crystals as the oxidation product, which consisted 
of pyridine, 5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, and 
4-oxo-5-phthalimidopentenic acid. The purity after removal of pyridine was 
86% and the yield of the oxidation product was 65%. 
This oxidation product was reduced in the same manner as in Example 1 and 
hydrolyzed to obtain 0.788 g of pale yellow crystals of 5-aminolevulinic 
acid hydrochloride at an yield of 47% based on N-furfurylphthalimide. 
Example 6 
The oxidation step was carried out in the same manner as in Example 3, 
except that 50 mg of coronene was used as a sensitizer instead of 7.0 mg 
of Rose Bengal, to obtain 2.26 g of pale yellow crystals as the oxidation 
product, which consisted of pyridine, 
5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, and 
4-oxo-5-phthalimidopentenic acid. The yield of the oxidation product was 
67%. 
This oxidation product was reduced in the same manner as in Example 1 and 
hydrolyzed to obtain 0.771 g of pale yellow crystals of 5-aminolevulinic 
acid hydrochloride at an yield of 46% based on N-furfurylphthalimide. 
Example 7 
The oxidation step was carried out in the same manner as in Example 5, 
except that 10 mg of furalene (C.sub.60) was used as the sensitizer 
instead of 7.0 mg of Rose Bengal, to obtain 2.54 g of light brown crystals 
as the oxidation product, which consisted of pyridine, 
5-phthalimidomethyl-5-hydroxy-2,5-dihydrofuran-2-one, and 
4-oxo-5-phthalimidopentenic acid. The yield of the oxidation product was 
75%. 
This oxidation product was reduced in the same manner as in Example 1 and 
hydrolyzed to obtain 0.838 g of pale yellow crystals of 5-aminolevulinic 
acid hydrochloride at an yield of 50% based on N-furfurylphthalimide. 
Comparative Example 1 
The oxidation step was carried out in the same manner as in Example 2, 
except that 100 ml of toluene was used as a solvent instead of 100 ml of 
pyridine in Example 2. The reaction mixture was analyzed by HPLC after 
three hours and five hours to confirm that no reaction took place. 
Comparative Example 2 
The oxidation step was carried out in the same manner as in Example 2, 
except that a mixture of 50 ml of acetone and 50 ml of triethylamine was 
used as a solvent instead of 100 ml of pyridine in Example 2. The reaction 
mixture was analyzed by HPLC after three hours and five hours to confirm 
that no reaction took place. 
Obviously, numerous modifications and variations of the present invention 
are possible in light of the above teachings. It is therefore to be 
understood that within the scope of the appended claims, the invention may 
be practiced otherwise than as specifically described herein.