JP2674707B2 - L-Biopterin manufacturing method - Google Patents
L-Biopterin manufacturing methodInfo
- Publication number
- JP2674707B2 JP2674707B2 JP15221788A JP15221788A JP2674707B2 JP 2674707 B2 JP2674707 B2 JP 2674707B2 JP 15221788 A JP15221788 A JP 15221788A JP 15221788 A JP15221788 A JP 15221788A JP 2674707 B2 JP2674707 B2 JP 2674707B2
- Authority
- JP
- Japan
- Prior art keywords
- biopterin
- hydroxy
- manufacturing
- chem
- present
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明はＬ−ビオプテリンの製法に係り、殊に酵素法
による製法に係る。TECHNICAL FIELD The present invention relates to a method for producing L-biopterin, and particularly to an enzymatic method.
本発明方法により得られるＬ−ビオプテリンは、芳香
族アミノ酸水酸化酵素の補酵素であり且つ医薬としても
有用な5,6,7,8−テトラヒドロ−Ｌ−エリスロ−ビオプ
テリン（以下、「BH4」と略記する）やその関連物質を
合成するための前駆体として用いることができる。The L-biopterin obtained by the method of the present invention is 5,6,7,8-tetrahydro-L-erythro-biopterin (hereinafter, referred to as “BH 4 ”, which is a coenzyme of aromatic amino acid hydroxylase and is also useful as a medicine. Abbreviated) and its related substances.
（従来の技術） BH4は芳香族アミノ酸水酸化酵素の補酵素であり、従
ってドーパミン、ノルアドレナリン、アドレナリン、メ
ラトニンの生合成に必須の化合物であり、式 にて示される構造を有している。(Prior Art) BH 4 is a coenzyme of aromatic amino acid hydroxylase, and is therefore a compound essential for biosynthesis of dopamine, noradrenaline, adrenaline, and melatonin. It has the structure shown by.
このBH4が欠乏すると、悪性高フェニルアラニン血
症、パーキンソン病等の重篤な神経症が発症することが
判明しており、最近に至りこれら疾患による症状がBH4
の投与により著しく改善されることが判明している。更
に、BH4は小児自閉症や鬱病の治療にも有効であるとさ
れている。If the BH 4 is depleted, malignant hyperphenylalaninemia, has been found to severe neuropathy such as Parkinson's disease may develop, leading to recent symptoms BH 4 by these diseases
Has been found to be significantly improved by the administration of In addition, BH 4 is said to be effective in treating childhood autism and depression.
このように、有用な薬理学的性質を有しているため
に、BH4の合成に関しては従来から種々の研究がなされ
てきた［例えばE.L.Patterson等“J.Am.Chem.Soc."第78
巻、第5868頁（1956年）、H.Rembold等“Chem.Ber."第9
6巻、第1395頁（1963年）、E.C.Taylor等“J.Am.Chem.S
oc."第98巻、第2301頁（1976年）、M.Viscontini等“He
lv.Chim.Acta"第52巻、第1225頁（1969年）、同55巻、
第574頁（1972年）、同60巻、第211頁（1977年）、同62
巻、第2577頁（1979年）、K.J.M.Andrews等“J.Chem.So
c."（ｃ）第928頁（1969年）、S.Matsuura等“Bull.Che
m.Soc.Jpn."第48巻、第3767頁（1975年）、同52巻、第1
81頁（1979年）、“Chem.Lett."第735頁（1984年）、特
開昭59−21685、同59−82091、同60−204786等］。As described above, because of its useful pharmacological properties, various studies have been conducted in the past regarding the synthesis of BH 4 [eg, EL Patterson et al., “J. Am. Chem. Soc.” No. 78].
Volume, page 5868 (1956), H. Rembold et al., "Chem. Ber."
Volume 6, page 1395 (1963), EC Taylor et al. “J. Am. Chem. S.
oc. "Volume 98, page 2301 (1976), M. Viscontini et al.," He
lv.Chim.Acta "Volume 52, page 1225 (1969), Volume 55,
574 (1972), 60, 211 (1977), 62
Volume 2577 (1979), KJM Andrews et al. "J. Chem. So.
c. "(c) Page 928 (1969), S. Matsuura et al.," Bull. Che
m.Soc.Jpn. "48, 3767 (1975), 52, 1
81 (1979), "Chem. Lett." P. 735 (1984), JP-A-59-21685, 59-82091, 60-204786, etc.].
（発明が解決しようとする課題） 従来提案されてきたBH4の合成法は、側鎖の不斉源と
して、何れも高価な糖を出発原料としている点に先ず問
題があり、更に合成に多段階を要し、不安定な中間体を
経由し、又反応処理が煩雑であるために、収率や純度の
低下を招き、然かも精製が面倒であり、従って工業的構
造に適用し難いのが実情であった。(Problems to be Solved by the Invention) The previously proposed methods for synthesizing BH 4 have a problem in that expensive sugars are used as a starting material in each of the asymmetric sources of side chains. It requires steps, passes through an unstable intermediate, and the reaction process is complicated, so that the yield and the purity are lowered, and the purification is troublesome, so that it is difficult to apply it to an industrial structure. Was the reality.
（課題を解決するための手段及び作用） 本発明者等は、BH4の実用的な合成法を開発するため
に、出発原料が廉価なこと、合成工程数が少ないこと、
収率が良好なこと、出来得ればBH4のみならず関連物
質、即ちBH4類縁体の合成にも適用可能なこと等を考慮
して研究を重ねた結果、BH4及びその関連物質の合成用
原料として有用なＬ−ビオプテリンが２−アミノ−４−
ヒドロキシ−６−（１′−ヒドロキシ−２′−オキソプ
ロピル）プテリジンにセピアプテリン還元酵素を作用さ
せることにより容易に且つ有利に得られることを見い出
し、本発明を完成するに至った。即ち、２−アミノ−４
−ヒドロキシ−６−（１′−ヒドロキシ−２′−オキソ
プロピル）プテリジンを還元処理する場合に生成する化
合物としては、下記の工程図に示されるように、４種類
の化合物が考えられるが、本発明方法によれば、目的と
するＬ−ビオプテリン（化合物１）のみが立体特異的に
得られるのである。(Means and Actions for Solving the Problem) The present inventors have developed a practical synthesis method of BH 4 by using inexpensive starting materials, and having a small number of synthesis steps.
Yield be good, related substances not only BH 4 In Ere be, i.e. BH 4 results also extensive research in consideration of such things can be applied to the synthesis of analogs of BH 4 and related substances L-Biopterin useful as a starting material for synthesis is 2-amino-4-
The inventors have found that it can be easily and advantageously obtained by reacting hydroxy-6- (1'-hydroxy-2'-oxopropyl) pteridine with sepiapterin reductase, and completed the present invention. That is, 2-amino-4
As shown in the process chart below, four types of compounds are considered as the compounds formed when the reduction treatment of -hydroxy-6- (1'-hydroxy-2'-oxopropyl) pteridine is carried out. According to the method of the invention, only the desired L-biopterin (Compound 1) can be obtained stereospecifically.
（実施例） 次に、実施例により本発明を更に詳細に且つ具体的に
説明する。 (Examples) Next, the present invention will be described in more detail and specifically with reference to Examples.
実施例 ２−アミノ−４−ヒドロキシ−６−（１′−ヒドロキ
シ−２′−オキソプロピル）プテリジン23.6mg（100μm
ol）を蒸留水100ml中に溶解させ、0.2M燐酸緩衝液（pH
6.4）100mlに溶解させたβ−ニコチンアミドアデニンジ
ヌクレオチド燐酸（還元型）167mgを上記の溶液に添加
した。更に、ラット赤血球由来のものであって、末岡等
の方法［“Biochim.Biophys.Acta"第717巻、第265頁（1
982年））により部分精製したセピアプテリン還元酵素
を１単位量添加し、得られた溶液を30℃で５時間、振盪
しながらインキュベートし、次いで限外濾過膜により濾
過した後に、凍結乾燥させた。この凍結乾燥物を60mlの
0.1N酢酸/MeOH混液（95/5,V/V）に溶解させ、デベロシ
ルODSカラムを用い高速液体クロマトグラフィーにより
精製した。得られたＬ−ビオプテリン含有画分から溶媒
を留去させた後に、残留物を少量の蒸留水に懸濁させ、
凍結乾燥することにより、所望のＬ−ビオプテリンを淡
黄色粉末として10.5mg得た（収率:44％）。Example 2-amino-4-hydroxy-6- (1′-hydroxy-2′-oxopropyl) pteridine 23.6 mg (100 μm
ol) in 100 ml of distilled water and 0.2M phosphate buffer (pH
6.4) 167 mg of β-nicotinamide adenine dinucleotide phosphate (reduced form) dissolved in 100 ml was added to the above solution. Furthermore, it is derived from rat erythrocytes and is derived from the method of Sueoka et al. ["Biochim.Biophys.Acta" Vol. 717, p. 265 (1
982)), 1 unit of partially purified sepiapterin reductase was added, and the resulting solution was incubated at 30 ° C. for 5 hours with shaking, and then filtered through an ultrafiltration membrane, followed by freeze-drying. . 60 ml of this lyophilizate
It was dissolved in a 0.1N acetic acid / MeOH mixed solution (95/5, V / V) and purified by high performance liquid chromatography using a Develosil ODS column. After distilling off the solvent from the obtained L-biopterin-containing fraction, the residue was suspended in a small amount of distilled water,
By freeze-drying, 10.5 mg of the desired L-biopterin was obtained as a pale yellow powder (yield: 44%).
▲［α］25 D▼＝−60゜（ｃ＝0.13,0.1N HCl） UVスペクトル（0.1N HCl）λmaxnm: 210,247,3201 H−NMRスペクトル（DMSO−D6）δppm: 1.06（3H,d,J＝6Hz,−CH3） 3.92（1H,m,2′−Ｈ） 4.44（1H,dd,J＝5Hz,5Hz,1′−Ｈ） 4.69（1H,d,J＝5Hz,2′−OH） 5.58（1H,d,J＝5Hz,1′−OH） 6.86（2H,s,2−NH2） 8.71（1H,s,7−Ｈ） 11.42（1H,br.s,3−NH） 尚、上記の比旋光度値はB.Green等の報告［“Chem.Be
r."第99巻、第2162頁（1966年）］における値と略一致
するものであり、UV及びNMRスペクトル値は標品におけ
る値と一致するものである。▲ [α] 25 D ▼ = -60 ° (c = 0.13,0.1N HCl) UV spectrum (0.1N HCl) λ max nm: 210,247,320 1 H-NMR spectrum (DMSO-D 6 ) δppm: 1.06 (3H, d , J = 6Hz, -CH 3 ) 3.92 (1H, m, 2'-H) 4.44 (1H, dd, J = 5Hz, 5Hz, 1'-H) 4.69 (1H, d, J = 5Hz, 2'- OH) 5.58 (1H, d, J = 5Hz, 1'-OH) 6.86 (2H, s, 2-NH 2) 8.71 (1H, s, 7-H) 11.42 (1H, br.s, 3-NH) The above specific rotation values are reported by B. Green et al. [“Chem.
r. "Vol. 99, p. 2162 (1966)], and the UV and NMR spectrum values are the same as those in the standard.
（発明の効果） 本発明方法によれば、２−アミノ−４−ヒドロキシ−
６−（１′−ヒドロキシ−２′−オキソプロピル）プテ
リジンから出発してＬ−ビオプテリンを容易に且つ立体
特異的に得ることができる。(Effect of the Invention) According to the method of the present invention, 2-amino-4-hydroxy-
L-Biopterin can be obtained easily and stereospecifically starting from 6- (1'-hydroxy-2'-oxopropyl) pteridine.
本発明方法により得られるＬ−ビオプテリンは医薬と
して有用なBH4やその関連物質合成用の原料として用い
ることができるので、本発明はこれらの医薬品の製造コ
ストの低廉化を可能にするものである。The L-biopterin obtained by the method of the present invention can be used as a raw material for synthesizing BH 4 and its related substances which are useful as a drug. Therefore, the present invention enables the production cost of these drugs to be reduced. .
Claims (1)
−ヒドロキシ−２′−オキソプロピル）プテリジンにセ
ピアプテリン還元酵素を作用させることを特徴とする、
Ｌ−ビオプテリンの製法。1. 2-Amino-4-hydroxy-6- (1 '
-Hydroxy-2'-oxopropyl) pteridine is treated with sepiapterin reductase,
Production method of L-biopterin.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15221788A JP2674707B2 (en) | 1988-06-22 | 1988-06-22 | L-Biopterin manufacturing method |
| US07/277,109 US4937342A (en) | 1987-11-30 | 1988-11-29 | Intermediates for synthesizing BH4 and its derivatives |
| DE3853711T DE3853711T2 (en) | 1987-11-30 | 1988-11-29 | Intermediates for the synthesis of 5,6,7,8-tetrahydro-L-erythro-biopterin and its derivatives. |
| CA000584504A CA1334654C (en) | 1987-11-30 | 1988-11-29 | Intermediates for synthesizing bh _and its derivatives |
| EP88119891A EP0318926B1 (en) | 1987-11-30 | 1988-11-29 | Intermediates for synthesizing 5,6,7,8-tetrahydro-L-erythro-biopterin and its derivatives |
| US07/515,962 US5037981A (en) | 1987-11-30 | 1990-04-27 | Intermediates for synthesizing BH4 and its derivatives |
| CA000616950A CA1338149C (en) | 1987-11-30 | 1994-12-13 | Intermediates for synthesizing bh- and its derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP15221788A JP2674707B2 (en) | 1988-06-22 | 1988-06-22 | L-Biopterin manufacturing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01320993A JPH01320993A (en) | 1989-12-27 |
| JP2674707B2 true JP2674707B2 (en) | 1997-11-12 |
Family
ID=15535637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP15221788A Expired - Lifetime JP2674707B2 (en) | 1987-11-30 | 1988-06-22 | L-Biopterin manufacturing method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2674707B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7361759B2 (en) | 2004-12-27 | 2008-04-22 | Shiratori Pharmaceutical Co., Ltd | Method for producing L-biopterin |
| US8178670B2 (en) | 2008-01-07 | 2012-05-15 | Biomarin Pharmaceutical Inc. | Method of synthesizing tetrahydrobiopterin |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60138029D1 (en) * | 2000-08-31 | 2009-04-30 | Asubio Pharma Co Ltd | PROCESS FOR THE PRODUCTION OF BIOPTERINES |
-
1988
- 1988-06-22 JP JP15221788A patent/JP2674707B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7361759B2 (en) | 2004-12-27 | 2008-04-22 | Shiratori Pharmaceutical Co., Ltd | Method for producing L-biopterin |
| US8178670B2 (en) | 2008-01-07 | 2012-05-15 | Biomarin Pharmaceutical Inc. | Method of synthesizing tetrahydrobiopterin |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01320993A (en) | 1989-12-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2844532B2 (en) | Preparation method of optically active compound | |
| Kis et al. | Biosynthesis of riboflavin. Studies on the reaction mechanism of 6, 7-dimethyl-8-ribityllumazine synthase | |
| EP0631581A1 (en) | Intermediates and a process for synthesis of tetrahydropteridine c6-stereoisomers, including (6s)-tetrahydrofolate and n5-formyl-(6s)-tetrhydrofolate | |
| US4937342A (en) | Intermediates for synthesizing BH4 and its derivatives | |
| US20230054325A1 (en) | Compositions comprising folic acid derivatives, their preparations and methods of use | |
| PT92232B (en) | PROCESS FOR THE SEPARATION OF FOLINIC ACID | |
| US20150119574A1 (en) | Method for producing sepiapterin and tetrahydrolactoylpterin | |
| JP2674707B2 (en) | L-Biopterin manufacturing method | |
| JPS60204786A (en) | Synthesis of (6r)-tetrahydrobiopterin and its relating substance | |
| US4929551A (en) | Process for producing L(-)-tetrahydrofolic acid | |
| JP2711828B2 (en) | Method for producing (6R) -tetrahydro-L-biopterin hydrochloride | |
| Groehn et al. | Synthesis of optically pure diastereoisomers of reduced folates | |
| JPH0586393B2 (en) | ||
| JP2567639B2 (en) | Pteridine derivative | |
| JP2611790B2 (en) | Tetrahydrofuranyl pyrimidine derivative | |
| JPH0332553B2 (en) | ||
| BG62287B1 (en) | Method and intermediate product for oxytetracycline purification | |
| CN114933558B (en) | Method for preparing chiral amino compound by catalytic reduction of chiral nitro compound | |
| JPH0813817B2 (en) | Process for producing 9- (hydroxy-alkyl) -hypoxanthines | |
| JP2817001B2 (en) | 2'-Ketopantothenonitrile | |
| Hiller et al. | Pyrimidine nucleoside analogues X. 5-Substituted l-(l, 3-dihydroxypropyl-2) uracils | |
| WO2021249468A1 (en) | Preparation method for chlorinated compound | |
| JPS5982091A (en) | Preparation of biopterin | |
| JPH06135971A (en) | New cyclonucloside, its production and antiviral agent containing the compound | |
| US20080090274A1 (en) | Process For The Synthesis Of (S)-1-(3,5-Bis (Trifluoromethyl)-Phenyl-Ethan-1-Ol |