JPH0413357B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention is based on the formula () The present invention relates to a method for producing (6R)-tetrahydro-L-biopterin represented by the formula, and more particularly to an industrial production method capable of obtaining a high proportion of 6R-biopterin. [Prior art and problems] Tetrahydro-L-biopterin (hereinafter abbreviated as " _BPH4 ") has isomers of 6R and 6S depending on the configuration of hydrogen at the 6-position [Furrer, HJ et al. :Helv.Chim.Acta, 62, 2577
(1979)]. Above all, (6R)-BPH ₄ is a coenzyme of phenylalanine hydroxylase, as well as a coenzyme of other aromatic amino acid hydroxylases. Therefore, its deficiency leads to a deficiency of neurotransmitters such as serotonin, dopamine, noradrenaline, and adrenaline, resulting in serious neurological symptoms. In addition, malignant hyperphenylalaninemia, which is one of _the inborn errors of metabolism, is an incurable disease that cannot be easily treated with conventional drug therapy. It is known that this occurs because the conversion to tyrosine is inhibited. For the treatment of malignant hyperphenylalaninemia (6R)-
Administration of BPH ₄ is considered, but for this purpose it is desired to develop a method to economically produce this product with high purity. As a method for producing tetrahydro-L-biopterin, a method of enzymatically or chemically reducing L-erythro-biopterin is known. Among them, the enzymatic method has the advantage that only the 6R form can be obtained, but it is disadvantageous as an industrial method because it requires complicated equipment and operations and has a high production cost. On the other hand, according to chemical methods, 6R and 6S
This results in a mixture of bodies, which must be divided, but this division is extremely difficult and no advantageous division method is currently known. Therefore, conventionally, (6R)-BPH ₄ is used at a high ratio,
If possible, it would be desirable to develop a method for selectively synthesizing this, but no satisfactory method has yet been found. [Means for Solving the Problem] Under these circumstances, the present inventor has conducted extensive research and found that if L-erythro-biopterin or its acyl derivative is catalytically reduced using platinum black as a catalyst under specific conditions. The present invention was completed based on the discovery that the asymmetric synthesis rate R/S can be significantly increased, and that (6R)-BPH ₄ can be easily separated and obtained with such a high R/S value. Therefore, the present invention provides catalytic reduction of L-erythro-biopterin or its acyl derivative () at pH 10 to 13 in the presence of amines using platinum black as a catalyst,
If an acyl group exists, it is removed to form (6R)-tetrahydro-L-biopterin ().
This is a method for producing , which is shown by the following reaction formula. (In the formula, R represents H or an acyl group.) To carry out the present invention, L-erythro-biopterin or its acyl derivative () is mixed with water, alcohol-based, or alcohol-based water whose pH is adjusted to 10 to 13 with amines. Catalytic reduction is carried out in a mixed solvent using platinum black as a catalyst. Examples of alcoholic solvents include methanol, ethanol, methylcellosolve, ethylene glycol, and the like. Examples of amines include primary amines such as methylamine, ethylamine, and cyclohexylamine; secondary amines such as dimethylamine, diethylamine, piperidine, and morpholine;
Examples include tertiary amines such as trimethylamine and triethylamine, and quaternary amines such as tetramethylammonium hydroxide, tetraethylammonium hydroxide, and benzyltrimethylammonium hydroxide. These amines have a pH of
It may be added so that the pH becomes 10 to 13. When the pH is lower than this, the asymmetric synthesis rate decreases, and when it becomes higher, both the asymmetric synthesis rate R/S and the yield decrease. Among various catalysts, especially platinum-based catalysts, platinum black is unique and exhibits an extremely high asymmetric synthesis rate R/S compared to other catalysts. The method of the present invention can be carried out by ordinary catalytic reduction operations, and the reaction temperature is -10°C to 50°C, but H ₂
The pressure is preferably 1 Kg/cm ² or more, particularly 1 to 100 Kg/cm ² . When doing so, (6S)-BPH ₄ or its acyl derivative can be obtained at an asymmetric synthesis rate R/S of about 7 or more. A part of the acyl group is removed by the above reaction, but if it still remains, it is easily removed by hydrolysis with hydrochloric acid or the like. By recrystallizing this product, highly pure (6R)-BPH ₄ can be isolated and obtained. [Effects of the invention] As described above, the present invention makes it possible to produce (6R)-BPH ₄ , which has been difficult to produce by conventional chemical synthesis methods, with a high asymmetric synthesis rate R/S and in a high yield. This is an extremely successful invention. [Example] Next, Example 1 will be described with reference to examples: 1.0 g (4.22 mmol) of L-erythro-biopterin and 0.20 g of platinum black were added to 95 ml of water,
10% tetraethylammonium hydroxide was added to this to adjust the pH to 12.0. Put this in an autoclave, _H2 pressure 100Kg/ ^cm2 , temperature 0-5
The mixture was stirred at a temperature of 1000 rpm and allowed to react for 20 hours. Add 5 ml of concentrated hydrochloric acid to the reaction mixture, remove the catalyst by filtration, and concentrate under reduced pressure at a bath temperature of 35°C or less to remove the residue.
It was recrystallized from a mixed catalyst of 3N hydrochloric acid and ethanol. White crystals with a melting point of 244.5℃ (decomposition), (6R)−
1.13g of BPH ₄ 2HCl was obtained. Elemental analysis value Theoretical value (%) Analytical value (%) C ₉ H ₁₇ Cl ₂ N ₅ O ₃ C 34.41 34.50 H 5.45 5.41 N 22.29 22.58 Optical rotation [α] ²⁵ _D : -6.39° (C, 0.68; 0.1N HCl) ¹ H−NMR (CD ₃ OD−D ₂ O): 4.10−3.70 (5H,
m, H-C (6, 7, 1', 2')), 1.40 (3H,
d, J = 6 Hz, H-C (3')) Example 2 1.0 g (4.22 mmol) of L-erythro-biopterin and 0.20 g of platinum black were added to 95 ml of water,
The bases shown in Table 1 were added to this and the pH was adjusted to a predetermined value. Put this in an autoclave, _H2 pressure 100Kg/ ^cm2 ,
The mixture was stirred at a temperature of 0 to 5° C. and a rotation speed of 1000 rpm, and reacted for 20 hours. 5 ml of concentrated hydrochloric acid was added to the reaction mixture, the catalyst was removed by filtration, and the liquid portion was analyzed by high performance liquid chromatography to determine the respective R/S ratios and yields of (R-isomer + S-isomer). The results are shown in Table 1. High performance liquid chromatography measurement conditions Detector: Ultraviolet absorption photometer (measurement wavelength:
275nm) Column: Partisil-10SCX, 4.5 x 250mm Mobile phase: 30mM ammonium phosphate, 3mM
Ammonium sulfite (PH=3.0) Flow rate: 2ml/min

[Table] *Example-1
Example 3 The same procedure as in Example 2 was carried out, using triethylamine, diethylamine, ethylamine and tetraethylammonium hydroxide as bases, adjusting the pH to 12, and changing the reaction temperature and _H2 pressure. The results are shown in Tables 2-5.

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[Table] Example 4 L-erythro-biopterin 20 mg, Shirogane Black 4
mg was added to 2 ml of the solvent shown in Table 6, and the base shown in Table 6 was added to adjust the pH to a predetermined value. This was placed in an autoclave and reacted for 20 hours at a H ₂ pressure of 100 Kg/cm ² and a temperature shown in Table 6. The reaction product was operated in the same manner as in Example 2, and the asymmetric synthesis rate R/S and (R-isomer+S-isomer) yield were measured. The results are shown in Table 6.

[Table] Example 5 20 mg of triacetyl-L-erythro-biopterin, 4 mg of platinum black, and a base were added to 2 ml of water or an organic solvent, and the mixture was heated in an autoclave with 100 kg of H ₂ atm.
cm ² and a temperature of 20°C for 20 hours. to the reactant
20 ml of 3N hydrochloric acid was added to remove the catalyst, 0.5 ml of concentrated hydrochloric acid was added to 1.5 ml of the solution, and the mixture was left to stand for 3 days for deacetylation. This was analyzed by high performance liquid chromatography under the same conditions as in Example 2, and R/S and (R body + S
body) yield was measured. The results are shown in Table 7.

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Claims (1)

[Claims] 1 L-erythro-biopterin or its acyl derivative in the presence of amines using platinum black as a catalyst
A method for producing (6R)-tetrahydro-L-biopterin, which comprises performing catalytic reduction at pH 10 to 13 and eliminating acyl groups, if present. 2. The production method according to claim 1, wherein the reaction is carried out in water/alcoholic solvent.