JPS61172876A - Production of (6r)-tetrahydro-l-biopterin - Google Patents

Abstract

PURPOSE:To produce the titled compound easily, economically on an industrial scale, in high asymmetric synthesis ratio (R/S) and high yield, by carrying out the catalytic reduction of an L-erythro-biopterin compound using platinum black catalyst under specific condition, and eliminating acyl group if any. CONSTITUTION:The objective compound of formula I can be produced by reducing L-erythro-biopterin or its acyl derivative of formula II (R is H or acyl) catalytically with hydrogen in water, alcohol or their mixture adjusted to 10-13pH with an amine, using platinum black as a catalyst at -10-+50 deg.C under H2 pressure of >=1kg/cm<2>, preferably 1-100kg/cm<2>, and deacylating the reaction product when it contains acyl group. The amine is e.g. methylamine, ethylamine, diethylamine, trimethylamine, tetramethylammonium hydroxide, etc. USE:Coenzyme of a phenylalanine hydroxylase and other aromatic amino acid hydroxylase.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing (6R)-tetrahydro-L-biobutyl y represented by the following formula (I), and more specifically, to a method for producing tetrahydro-L-biobutyl The present invention relates to an industrial production method capable of obtaining a high proportion of the 6R form of pterin.

[Conventional technology and problems]

Tetrahydro-biopterin (rBPH4J)
) exists in 6R and 6S isomers depending on the configuration of hydrogen at position 6 [Furrer.

H, J, et al: H@ly, Chm, Acta
, 62. 2577 (1979)'].

Above all, <(6R)-BPH4 is a coenzyme of phenylalanine hydroxylase, as well as a coenzyme of other aromatic amino acid hydroxylases.

Therefore, the deficiency of the neurotransmitter serotonin,
It causes a deficiency of do/4'mine, norato-9-renaline, adrenaline, etc., and causes severe neurological symptoms. In addition, malignant hyperphenylalaninemia, which is one of the congenital metabolic abnormalities, is an incurable disease that cannot be easily treated with conventional drug therapy. It is known that this occurs due to inhibition.

For the treatment of malignant hyperphenylalaninemia (6R) -BP
Administration of H4 is considered, but for this purpose it is desired to develop a method for economically producing this product with high purity.

As a method for producing tetrahydro-biopterin, a method of enzymatically or chemically reducing L-erythrobiopterin is known. Among them, the enzyme method is 6.
Although it has the advantage that only the R-isomer can be obtained, it is disadvantageous as an industrial method because the equipment and operations are complicated and the manufacturing cost is high. -According to Gallological method, 6R
This produces a mixture of 6S and 6S isomers, which must be separated, but this separation is extremely difficult and no advantageous method of separation is currently known.

Therefore, conventionally, (6R) -BP)I4 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 problems]

Under these circumstances, the present inventor has conducted extensive research and found that the asymmetric synthesis rate Is can be significantly increased by catalytically reducing L-erythro biogutilin or its acyl derivatives using platinum black as a catalyst under specific conditions. Moreover, if it has such a high value, it is easy to convert (6R)-BPH4
The present invention was completed based on the discovery that it is possible to separate and obtain the following.

Therefore, 1 the present invention provides L-erythro biogutilin or its acyl derivative (n) at pH 1o using platinum black as a catalyst.
This is a method for producing (6R)-tetrahydro-L-biopterin (I) by catalytic reduction and elimination of contact layer groups if present, and this is shown by the following reaction formula. It will be done.

Q OR (in the formula, R represents H or an acyl group) To carry out the present invention, L-erythrobiogutilin or its acyl derivative (II) is adjusted to pH 10 to 13 with a base.
Catalytic reduction is carried out using platinum black as a catalyst in water, alcohol, or a mixed solvent of these.

Alcohol solvents include methanol, ethanol,
Examples include methyl selenium, ethylene glycol, and the like. Examples of the base used to adjust - include sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate; ammonia: primary amines such as methylamine, ethylamine, and cyclohexylamine; secondary amines such as dimethylamine, diethylamine, piperidine, and morpholine; and trimethylamine.

Examples include tertiary amines such as triethylamine; amines such as quaternary amines such as tetramethylammonium hydroxide and tetraethylammonium hydroxide; and amino acids such as L-alanine and L-gloline. Among these, (6R)-BP with high asymmetric synthesis rate Is and high yield
Primary to quaternary amines are particularly preferred since H4 can be obtained. This base may be added so as to give -10-131c; when - becomes lower by 1, the asymmetric synthesis rate decreases, and when it becomes higher, both the asymmetric synthesis rate fs and the yield decrease.

Among various catalysts, platinum black is unique among platinum-based catalysts, and has an extremely high asymmetric synthesis rate V compared to other catalysts.
Indicates S.

The method of the present invention can be carried out by a conventional catalytic reduction operation, and the reaction temperature is -10 DEG C. to 50 DEG C., and the H2 pressure is preferably 1 to 9/2 or more, particularly 1 to 100 U/2.

When doing this, at an asymmetric synthesis rate l of about 7 or more (6R
) -BPH4 or its acyl derivative can be obtained. Although some of the acyl groups are removed by the above reaction,
If it still remains, it can be easily removed by hydrolysis with hydrochloric acid or the like. By recrystallizing this product, high purity (6R)-BPH4 can be isolated and obtained.

〔Effect of the invention〕

As mentioned above, the present invention is an extremely excellent invention that succeeded in producing (6R)-BPH4, which was difficult to produce by conventional chemical synthesis methods, with a high asymmetric synthesis rate I and a high yield. be.

〔Example〕

Next, an example will be given and explained.

Example 18 L-erythro biogutilin 1.0.9 (4.22 mmol) and platinum black 0.201i were added to 95 ml of water, and 10% tetraethelammonium hydroxide was added to the mixture, pH=12. Adjusted to .0. Put this in an autoclave, H2 pressure 100kg/α2° temperature 0
The mixture was stirred at ~5° C., 2 rotations, and 100 Or, p, m, and reacted for 20 hours. Concentrated hydrochloric acid 5a was added to the reaction mixture, the catalyst was removed by filtration, and the residue was concentrated under reduced pressure at a bath temperature of 35°C or less.
It was recrystallized from a mixed melting medium of N-hydrochloric acid and ethanol.

White crystals with a melting point of 244.5°C (decomposition), (6R)-B
PH42HCl 1.13. I got F.

Elemental analysis value Theory (direct α) Analysis position) C2H,, Ct2N50. C34,413
4,50H5,455,41 N 22.29 22.58 Optical rotation [α) D, -6,39° (C, 0,68; 0.
I N HCt)'H-NMR (CD30D-D20)
: 4.10-3.70 (5H,m, H-C(
6, 7, 1', 2')).

1.40 (3H, d, J = 6Hz.

H-C(3')) Example 2゜L-erythrobiopterin 1. Q,! i'(4,2
2 mmol) and platinum black (0.20.9 μm) were added to 95 μm of water, and the bases shown in Table 1 were added thereto to adjust to a predetermined value. Put this into an autoclave and increase the H2 pressure to 100kg/cm.
'', stirred at a temperature of 0 to 5℃, 2 rotations of 100Or, p, m and allowed to react for 20 hours. 5M concentrated hydrochloric acid was added to the reaction mixture,
The catalyst was removed by filtration, and the F liquid part was analyzed by high performance liquid chromatography to determine the respective VS ratios and (R
The yield of S-isomer + S-isomer) was determined.

The results are shown in Table 1.

High performance liquid chromatography measurement conditions Detector: Ultraviolet absorption photometer (measurement wavelength: 275im) Column: Partisil-10SCX, 4.5X
250m mobile phase: 30mM ammonium phosphate, 3mM
Ammonium sulfite (pH=3.0) Flow rate: 2 d/m1n Margin below Table 1 Table *Example-1 Example 3 KOH, ) diethylamine, diethylamine, ethylamine and tetraethelammonium hydroxide were used as bases. The reaction temperature was adjusted to 12, and the same procedure as in Example 2 was carried out by changing the reaction temperature and H2 pressure. The result is the second
-This is the table 6.

Below is the margin Example 4 L-erythro biopterin 20M9, platinum black 4m9
was added to the two solvents listed in Table 7, and the bases listed in Table 7 were added to adjust to the specified pitch. This was placed in an autoclave and reacted for 20 hours at a H2 pressure of 100 kl/cm'' and the temperature shown in Table 7.The reaction product was operated in the same manner as in Example 2, and the asymmetric synthesis rate R
/S and (R body + S body) yields were measured. The result is the 7th
This is the front page.

Below is a blank space Example 5 To 2 d of water or an organic solvent, add 20 ■ of triacetyl-L-erythropyocypurin, 4 ■ of platinum black, and a base, and place in an autoclave at a pressure of 10 kg of H2, /α2, and a temperature of 2.
The reaction was carried out at 0°C for 20 hours. 2 d of 3N hydrochloric acid was added to the reaction product, the catalyst was removed, 0.5 M 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. Analyzed by high performance liquid chromatography,
R/S and (R body + S body) yield were measured. The results are shown in Table 8.

The following is a written amendment in the Kinpaku procedure (spontaneous) April 17, 1985 Patent Application No. 12477 of 1985 2. Title of the invention (6R) - Process for producing tetrahydro-L-biozothelin 3. Related Applicant Name Shiratori Pharmaceutical Co., Ltd. Name (190) Suntory Ltd. 6, “Claims” and “Detailed Description of the Invention” column 7 of the specification to be amended, Contents of the amendment (1) Description The claims are amended as shown in the attached sheet.

(2) In the specification, after the phrase "as a catalyst" on page 4, lines 14-15, "in the presence of amines" is fully inserted.

(3) Same page 5, line 9 from the bottom Correct the word "base" to read "amines."

(4) Page 5, line 4 from the bottom to page 6, line 11 “
Adjust the pH... What is this base? Correct the following sentence.

[Amines include primary amines such as methylamine, ethylamine, and cyclohexylamine, secondary amines such as dimethylamine, diethylamine, pipericine, and morpholine, and tertiary amines such as trimethylamine and triethylamine.
Examples include quaternary amines such as tetramethylammonium hydroxide, tetraethylammonium hydroxide, and pencil trimethylammonium hydroxide.

These amines are 6) "Table 1" on page 10 of the same page is corrected as follows.

Chapter 1 Table Seasonal example-1 (6)　Page 11, line 2 r Delete KDH, J.

σ) Same page 11, line 6 "Tables 2 to 6" should be corrected to "Tables 2 to 5."

(8) Delete the entire text of "Table 2" on page 12.

(9) Same page 13, line 1 "Table 3" should be corrected to "Table 2."

OI, page 14, line 1 "Table 4" should be corrected to "Table 3."

0υ　Page 15, line 1 ``Table 5'' is corrected to ``Table 4''.

α2　Page 16, line 1 ``Table 6'' is corrected to ``Table 5''.

α3 Correct "Table 7" to "Table 6" on page 17, line 3 (two places), page 17, line 5, and page 17, line 8.

04 "Table 7" on page 18 of the same page is corrected to the following "Table 6."

Margin below αta, page 19, line 10 ``Table 8 j is corrected to ``Table 7.''

aQ "Table 8" on page 20 of the same page is corrected to the following "Table 7."

The following margin claims 1.
(6R)-tetrahydro-, which is characterized by catalytic reduction in ~13 and elimination of the acyl group, if present.
Method for producing L-pyozoteline.

2. The production method according to claim 1, wherein the reaction is carried out in water and/or an alcoholic solvent.

Claims (1)

[Claims] 1. Catalytic reduction of L-erythro-biopterin or its acyl derivative at pH 10 to 13 using platinum black as a catalyst,
A method for producing (6R)-tetrahydro-L-biopterin, which comprises removing an acyl group, if present. 2. The production method according to claim 1, wherein the reaction is carried out in water or/and an alcoholic solvent in the presence of a basic substance. 3. The production method according to claim 2, wherein the basic substance is an alkali hydroxide, ammonia, amines, or an amino acid.