JPH09157270A - Production of (6r)-tetrahydro-l-biopterin hydrochloride - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain tetrahydrobiopterin hydrochloride useful for medicines, etc., in a high asymmetric synthesis degree in a high purity and in a high yield by catalytically reducing erythrobiopterin, etc., in the presence of an amine compound and platinum black as a catalyst in a prescribed alkaline pH region. SOLUTION: L-Erythrobiopterin or its acyl derivative represented by formula I (R is H, an acyl) is catalytically reduced in the presence of an amine compound and platinum black as a catalyst in water and/or an alcoholic solvent at a pH of 10-13 at a temperature of <=20 deg.C under a hydrogen gas pressure of >=20 kg/cm<2> . When the product has the acyl group, the acyl group is further removed. Thus, (6R)-tetrahydro-L-biopterin hydrochloride of formula II is obtained.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to the following formula (1):

[0002]

Embedded image

(6R) -tetrahydro-L represented by
The present invention relates to a method for producing biopterin, and more particularly to an industrial method for producing a 6R-form of tetrahydro-L-biopterin at a high ratio.

[0004]

2. Description of the Related Art Tetrahydro-L-biopterin (hereinafter abbreviated as "BPH ₄ ") has 6R-isomer and 6S-isomer due to the configuration of hydrogen at the 6-position. (Furrer, HJ et al .: Helv.Chim.Act
a, 62, 2577 (1979)]. And especially (6R) -BPH ₄ is a coenzyme of phenylalanine hydroxylase,
It is also a coenzyme for other aromatic amino acid hydroxylases. Therefore, the deficiency causes the deficiency of neurotransmitters such as serotonin, dopamine, noradrenaline, and adrenaline, causing severe neurological symptoms. Although malignant hyperphenylalaninemia, one of congenital metabolic disorders are intractable diseases that can not be treated as easily with existing drug therapy, which is converted to phenylalanine tyrosine by a deficiency of (6R) -BPH ₄ Is known to be caused by inhibition.

For the treatment of malignant hyperphenylalaninemia (6)
Although the administration of R) -BPH ₄ is considered, the development of a method to economically produce this product in high purity is desired for that.

[0006] As a method for producing tetrahydro-L-biopterin, a method for enzymatically or chemically reducing L-erythro-biopterin is known. Although the enzymatic method has the advantage that only the 6R form can be obtained,
The equipment and operation are complicated, the production cost is high, and the method is inevitably disadvantageous as an industrial method. On the other hand, the chemical method produces a mixture of the 6R and 6S forms, which must be resolved, but this resolution is very difficult and no advantageous method is currently known.

Therefore, it has been desired to develop a method for synthesizing (6R) -BPH ₄ in a high ratio, if possible, selectively, but a satisfactory method has not yet been found.

[0008]

Under such circumstances, the present inventor has conducted diligent research and as a result, if L-erythro-biopterin or an acyl derivative thereof is catalytically reduced under specific conditions using platinum black as a catalyst, The inventors have found that the asymmetric synthesis rate R / S can be remarkably increased, and that (6R) -BPH ₄ can be easily separated and obtained with such a high R / S value, and the present invention has been completed.

Therefore, according to the present invention, L-erythro-biopterin or its acyl derivative (2) is catalytically reduced at a pH of 10 to 13 in the presence of amines using platinum black as a catalyst. Is produced to produce (6R) -tetrahydro-L-biopterin (1), which is represented by the following reaction scheme.

[0010]

Embedded image

(In the formula, R represents H or an acyl group)

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION To carry out the present invention, platinum of L-erythro-biopterin or its acyl derivative (2) is adjusted to pH 10 to 13 with amines in water, alcohol or a mixed solvent thereof. Catalytic reduction is performed using black as a catalyst.

As the alcohol solvent, methanol,
Ethanol, methyl cellosolve, ethylene glycol and the like can be mentioned. Examples of the amines include primary amines such as methylamine, ethylamine and cyclohexylamine; secondary amines such as dimethylamine, diethylamine, piperidine and morpholine; tertiary amines such as trimethylamine and triethylamine; tetramethylammonium hydroxide; And quaternary amines such as tetraethylammonium hydroxide and benzyltrimethylammonium hydroxide. The amines may be added so as to have a pH of 10 to 13. When the pH is lower than this,
The asymmetric synthesis rate decreases, and as the rate increases, both the asymmetric synthesis rate R / S and the yield decrease.

As the catalyst, platinum black is specific among various catalysts, especially platinum-based catalysts, and exhibits an extremely high asymmetric synthesis rate R / S as compared with other catalysts.

The process of the present invention can be carried out by a usual operation of catalytic reduction, and the reaction temperature is from -10 ° C to 50 ° C.
₂ pressure 1 kg / cm ² or more, especially 1 to 100 kg / cm ² is preferred.

In this case, (6R) -BPH ₄ or its acyl derivative can be obtained with 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, high-purity (6R) -BP
H ₄ can be isolated and obtained.

[0017]

INDUSTRIAL APPLICABILITY As described above, the present invention is intended to produce (6R) -BPH ₄ with a high asymmetric synthesis rate R / S and a high yield, which has been difficult to produce by the conventional chemical synthesis method. It is a very successful and successful invention.

[0018]

EXAMPLES Next, examples will be described.

Example 1 1.0 g (4.22 mmol) of L-erythro-biopterin and 0.20 g of platinum black were added to 95 ml of water, and 10% tetraethylammonium hydroxide was added thereto to adjust the pH to 12.0. It was adjusted. This was placed in an autoclave, stirred at an H ₂ pressure of 100 kg / cm ² , a temperature of 0 to 5 ° C., and a rotation speed of 1000 rpm to react for 20 hours. 5 ml of concentrated hydrochloric acid was added to the reaction product, and the catalyst was removed by filtration.
After concentrating at 5 ° C. or lower, the residue was recrystallized from a mixed solvent of 3N hydrochloric acid and ethanol.

White crystals having a melting point of 244.5 ° C. (decomposition)
1.13 g of (6R) -BPH ₄ 2HCl was obtained.

Elemental analysis value Theoretical value (%) Analysis 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] _D ²⁵ : −6.39 ° (C, 0.68;
^{1N HCl) 1 H-NMR (} CD 3 OD-D 2 O): 4.10-3.7
0 (5H, m, H-C (6,7,1 ', 2')), 1.
40 (3H, d, J = 6Hz, HC (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, and the base shown in Table 1 was added thereto to adjust to a predetermined pH. This was put in an autoclave, and the H ₂ pressure was 100 kg / cm ² , and the temperature was 0-5.
The mixture was stirred for 20 hours at a temperature of 1000 ° C. and a rotation speed of 1000 rpm. 5 ml of concentrated hydrochloric acid was added to the reaction product, and the catalyst was removed by filtration.
The filtrate was analyzed by high performance liquid chromatography, and the R / S ratio and the yield of (R-form + S-form) were determined. Table 1 shows the results.

High Performance Liquid Chromatography Measurement Conditions Detector: Ultraviolet absorptiometer (Measurement wavelength: 275 nm) Column: Partisil-10SCX, 4.5 × 250 mm Mobile phase: 30 mM ammonium phosphate, 3 mM ammonium sulfite (pH = 3.0) Flow rate: 2 ml / min

[0024]

[Table 1]

Example 3 The same operation as in Example 2 was carried out by adjusting the pH to 12 using triethylamine, diethylamine, ethylamine and tetraethylammonium hydroxide as bases, and changing the reaction temperature and H ₂ pressure. The results are as shown in Tables 2 to 5.

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Table 4]

[0029]

[Table 5]

Example 4 20 mg of L-erythro-biopterin and 4 mg of platinum black were 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. Put this in an autoclave, H ₂ pressure 100kg
/ Cm ^2, and allowed to react for 20 hours at 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-form +
The S form) yield was measured. Table 6 shows the results.

[0031]

[Table 6]

Example 5 To 2 ml of water or an organic solvent, 20 mg of triacetyl-L-erythro-biopterin, 4 mg of platinum black and a base were added, and in an autoclave, H ₂ atmospheric pressure 100 kg / cm ² , temperature 20 ° C.
And reacted for 20 hours. 2 ml of 3N hydrochloric acid was added to the reaction product, the catalyst was filtered off, 0.5 ml of concentrated hydrochloric acid was added to 1.5 ml of the filtrate, and the mixture was left for 3 days for deacetylation. Example 2
High performance liquid chromatography under the same conditions as for R /
The yields of S and (R form + S form) were measured. The results are shown in Table 7.

[0033]

[Table 7]

[Procedure amendment]

[Submission date] July 23, 1996

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Name of invention

[Correction method] Change

[Correction contents]

Title of the invention (6R) -Tetrahydro-L-biopterin hydrochloride production method

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0007

[Correction method] Change

[Correction contents]

Accordingly, conventionally the (6R) -BPH ₄ a high proportion, if Ere can selectively synthesize this, although the development of a method for Shutoku isolation is desired, seen yet satisfactory way Not issued.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0008

[Correction method] Change

[Correction contents]

[0008]

Under such circumstances, the present inventor has conducted earnest research, and as a result, if L-erythro-biopterin or an acyl derivative thereof is catalytically reduced under a specific condition using platinum black as a catalyst, The asymmetric synthesis rate R / S can be remarkably increased, and if it has such a high R / S value, it can be easily used as a hydrochloride salt of high purity (6R) -BP.
The H ₄ found to be able to separate Shutoku at high yield, thereby completing the present invention.

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction contents]

Therefore, according to the present invention, L-erythro-biopterin or its acyl derivative (2) is catalytically reduced at a pH of 10 to 13 in the presence of amines using platinum black as a catalyst. Of (6R) -tetrahydro-L-biopterin (1), which comprises isolating and collecting the compound as a hydrochloride, and the catalytic reduction reaction is carried out according to the following reaction formula. Shown.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0016

[Correction method] Change

[Correction contents]

[0016] When such may be obtained by asymmetric synthesis rate R / S to about 7 or more (6R) -BPH ₄ or acyl derivatives thereof. 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, high-purity (6R) -BP
The hydrochloride salt of H ₄ can be Shutoku isolated.

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0017

[Correction method] Change

[Correction contents]

[0017]

INDUSTRIAL APPLICABILITY As described above, according to the present invention, (6R) -BPH ₄ was synthesized at a high asymmetric synthesis rate R / S, which was difficult to produce by the conventional chemical synthesis method, and the 6R form was hydrochloric acid. It is an extremely excellent industrial production method that has been successfully isolated and obtained as a salt with high purity and high yield.

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0032

[Correction method] Change

[Correction contents]

Example 5 Triacetyl-L-erythro- was added to 2 ml of water or an organic solvent.
Bio pterin 20 mg, a base platinum black 4mg and Table 7 was added, it was adjusted to a predetermined pH, in an autoclave, _{H 2}
The reaction was carried out at a pressure of 100 kg / cm ² and a temperature of 20 ° C. for 20 hours. 2 ml of 3N hydrochloric acid was added to the reaction product, the catalyst was removed by filtration, 0.5 ml of concentrated hydrochloric acid was added to 1.5 ml of the filtrate, and the mixture was left for 3 days to deacetylate. This was analyzed by high performance liquid chromatography under the same conditions as in Example 2 to determine the R / S and the (R-form + S-form) yield. The results are shown in Table 7.

Claims (4)

[Claims] 1. A pH of L-erythro-biopterin or its acyl derivative in the presence of amines using platinum black as a catalyst.
Catalytic reduction with 10 to 13 is carried out to eliminate an acyl group, if present, and then (6R) -tetrahydro-
A method for producing (6R) -tetrahydro-L-biopterin hydrochloride, which is isolated and obtained as L-biopterin hydrochloride. 2. The production method according to claim 1, wherein the catalytic reduction is carried out at a H ₂ pressure of 20 kg / cm ² or more. 3. The method according to claim 1, wherein the catalytic reduction is carried out at a temperature of 20 ° C. or lower. 4. The production method according to claim 1, wherein the reaction is carried out in water or / and an alcohol solvent.