JP2995448B2 - Method for producing (6S) -tetrahydro-D-neopterin - Google Patents
Method for producing (6S) -tetrahydro-D-neopterinInfo
- Publication number
- JP2995448B2 JP2995448B2 JP5346845A JP34684593A JP2995448B2 JP 2995448 B2 JP2995448 B2 JP 2995448B2 JP 5346845 A JP5346845 A JP 5346845A JP 34684593 A JP34684593 A JP 34684593A JP 2995448 B2 JP2995448 B2 JP 2995448B2
- Authority
- JP
- Japan
- Prior art keywords
- neopterin
- tetrahydro
- producing
- present
- amines
- 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 - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、次式：The present invention relates to the following formula:
【０００２】[0002]
【化１】 Embedded image
【０００３】で示される (６Ｓ）−テトラヒドロ−Ｄ−
ネオプテリンの工業的な製造法に関するものである。[0003] (6S) -tetrahydro-D-
The present invention relates to an industrial method for producing neopterin.
【０００４】[0004]
【従来の技術】テトラヒドロ−Ｄ−ネオプテリンは強い
ラジカル消去作用を有する為、各種虚血障害等の活性酸
素等が関与している症状に対して治療改善効果が認めら
れている（特願平04-304525)。更に、テトラヒドロ−Ｄ
−ネオプテリンは、癌転移抑制や制癌剤の副作用治癒に
有効である（特願平04-304525)。一方、テトラヒドロ−
Ｄ−ネオプテリンは、６Ｓ体、６Ｒ体及びそれらの混合
物において、同様な生理活性を有する。しかしながら、
６Ｓ体と６Ｒ体はジアステレオマーである為、本品を医
薬品として開発するためには、ジアステレオマー混合物
ではなく、高純度の６Ｓ体又は６Ｒ体が必要である。そ
の為、高純度の６Ｓ体又は６Ｒ体を選択的に又、経済的
に量産する製造法の開発が望まれている。特に６Ｓ体は
医薬品として望ましい化合物である。2. Description of the Related Art Since tetrahydro-D-neopterin has a strong radical scavenging effect, it has been recognized that it has an effect of improving the treatment of symptoms associated with active oxygen such as various ischemic injuries (Japanese Patent Application No. 04-110,1992). -304525). Further, tetrahydro-D
-Neopterin is effective in suppressing cancer metastasis and curing side effects of anticancer drugs (Japanese Patent Application No. 04-304525). On the other hand, tetrahydro-
D-neopterin has a similar biological activity in the 6S form, the 6R form and mixtures thereof. However,
Since the 6S-form and the 6R-form are diastereomers, a high-purity 6S-form or 6R-form is required instead of a diastereomer mixture in order to develop this product as a drug. Therefore, development of a production method for selectively and economically mass-producing 6S-form or 6R-form of high purity is desired. In particular, the 6S form is a desirable compound as a pharmaceutical.
【０００５】[0005]
【発明が解決しようとする課題】一般に、テトラヒドロ
−Ｄ−ネオプテリンを製造する方法としては、Ｄ−ネオ
プテリンを接触還元する方法が知られている。しかし、
この方法では、６Ｓ体と６Ｒ体の混合物を生じ、これら
は分割しなければならない。この分割は高速液体クロマ
トグラフィーを用いる方法（J. Biochem., 98, 1341 (1
985)) が開発されているが工業的に使用するには困難で
あり、現在有利な分割方法はない。更に、選択的に合成
する方法として、塩基性条件下での酸化白金による接触
還元法（Heterocycle, 23, 3115 (1985)) が開発されて
いるが、選択性はＳ／Ｒ比が2.7と低く、生成物より容
易な方法で６Ｓ体を単離することはできず、未だ満足な
方法は見いだされていない。Generally, as a method for producing tetrahydro-D-neopterin, a method for catalytically reducing D-neopterin is known. But,
This method produces a mixture of the 6S and 6R forms, which must be resolved. This separation is performed by a method using high performance liquid chromatography (J. Biochem., 98, 1341 (1
985)) has been developed, but it is difficult to use industrially, and there is no advantageous division method at present. Furthermore, as a method for selective synthesis, a catalytic reduction method using platinum oxide under basic conditions (Heterocycle, 23, 3115 (1985)) has been developed, but the selectivity is as low as 2.7 with an S / R ratio of 2.7. The 6S form cannot be isolated by an easier method than the product, and a satisfactory method has not yet been found.
【０００６】このような経緯にもとづき、本発明は、テ
トラヒドロ−Ｄ−ネオプテリンの６Ｓ体を高い比率で得
ることができ、工業的に利用可能な（６Ｓ）−テトラヒ
ドロ−Ｄ−ネオプテリンの選択的製造法を提供するもの
である。[0006] Based on such circumstances, the present invention is capable of obtaining a 6S-form of tetrahydro-D-neopterin in a high ratio and selectively producing industrially usable (6S) -tetrahydro-D-neopterin. It provides the law.
【０００７】[0007]
【課題を解決するための手段】本発明者らは鋭意検討を
行った結果、Ｄ−ネオプテリンをアミン類の存在下pH10
〜13、圧力が80〜120kg/cm2 の条件下で接触還元するこ
とによって、不斉合成率Ｓ／Ｒを４以上に高めることが
出来、再結晶により容易にテトラヒドロ−Ｄ−ネオプテ
リンの６Ｓ体を得ることができる製造法を見出し、本発
明を完成した。The present inventors have conducted intensive studies and found that D-neopterin was converted to pH 10 in the presence of amines.
~ 13, the catalytic reduction under the conditions of pressure of 80 ~ 120kg / cm 2 can increase the asymmetric synthesis rate S / R to 4 or more and easily recrystallize the 6S form of tetrahydro-D-neopterin The present invention was completed by finding a production method capable of obtaining the following.
【０００８】すなわち、本発明は、Ｄ−ネオプテリンを
高圧塩基性存在下で接触還元して得られることを特徴と
する（６Ｓ）−テトラヒドロ−Ｄ−ネオプテリンの製造
法である。Namely, the present onset Ming, the D- neopterin characterized in that it is obtained by catalytic reduction in the presence of high pressure basic (6S) - is a process for the preparation of tetrahydro -D- neopterin.
【０００９】本発明は、前記接触還元の条件が、アミン
類の存在下にpH10〜13、圧力80〜120kg/cm2であること
を特徴とする。この製造法は次の反応式によって示され
る。The present invention is characterized in that the conditions for the catalytic reduction are a pH of 10 to 13 and a pressure of 80 to 120 kg / cm 2 in the presence of amines. This production method is represented by the following reaction formula.
【００１０】[0010]
【化２】 Embedded image
【００１１】本発明を実施するには、Ｄ−ネオプテリン
をアミン類でpH10〜13に調整した水、アルコール系又は
これらの混合溶媒中白金系触媒を用いて接触還元する。
白金系触媒としては、例えば白金黒、酸化白金(PtO2)、
白金炭素(Pt/C)、白金アルミナ(Pt/アルミナ) 等が挙げ
られる。また、アルコール系溶媒としては、例えばメタ
ノール、エタノール、エチレングリコール等が挙げられ
る。In order to carry out the present invention, D-neopterin is catalytically reduced using a platinum catalyst in water, alcohol or a mixed solvent thereof adjusted to pH 10 to 13 with amines.
Examples of the platinum-based catalyst include platinum black, platinum oxide (PtO 2 ),
Examples include platinum carbon (Pt / C) and platinum alumina (Pt / alumina). Examples of the alcohol solvent include methanol, ethanol, ethylene glycol and the like.
【００１２】アミン類としては、メチルアミン、エチル
アミン等の第１級アミン；ジメチルアミン、ジプロピル
アミン、ピペリジン等の第２級アミン；トリメチルアミ
ン、トリエチルアミン、トリプロピルアミン等の第３級
アミン；テトラメチルアンモニウムヒドロキシド、テト
ラエチルアンモニウムヒドロキシド等の第４級アンモニ
ウムが挙げられる。これらのアミン類は溶液のpHが10〜
13になる量において添加される。本発明においては、ア
ミン類の存在が必須であり、他の塩基、例えば水酸化ア
ルカリ等の無機塩基を使用してpHを上記範囲に調整して
も、不斉合成率Ｓ／Ｒは低く、収率も悪い。また、pHが
前記範囲以外では、不斉合成率Ｓ／Ｒは低い。Examples of amines include primary amines such as methylamine and ethylamine; secondary amines such as dimethylamine, dipropylamine and piperidine; tertiary amines such as trimethylamine, triethylamine and tripropylamine; And quaternary ammonium such as ammonium hydroxide and tetraethylammonium hydroxide. These amines have a solution pH of 10-
It is added in an amount of 13. In the present invention, the presence of amines is essential, and the asymmetric synthesis rate S / R is low even when the pH is adjusted to the above range using another base, for example, an inorganic base such as alkali hydroxide. Poor yield. When the pH is out of the above range, the asymmetric synthesis rate S / R is low.
【００１３】本発明方法は通常の接触還元の操作によっ
て行うことができ、反応温度は−５℃〜30℃で特に０〜
10℃が好ましい。反応温度が−５℃以下では反応が進み
難く、また30℃を超えると副反応が多くなるので望まし
くない。H2圧力は80〜120kg/cm2 にすることが好まし
い。80kg/cm2未満では反応が進み難く、120kg/cm2 を超
えると反応は進むが、経済性の面から望ましくない。The process of the present invention can be carried out by the usual operation of catalytic reduction.
10 ° C is preferred. If the reaction temperature is lower than −5 ° C., the reaction hardly proceeds. H 2 pressure is preferably in 80~120kg / cm 2. If it is less than 80 kg / cm 2 , the reaction hardly proceeds. If it exceeds 120 kg / cm 2 , the reaction proceeds, but it is not desirable in terms of economy.
【００１４】このようにするとき、不斉合成率Ｓ／Ｒが
約4.0以上にて（６Ｓ）−テトラヒドロ−Ｄ−ネオプテ
リンを得ることができる。この生成物から再結晶するこ
とにより、高純度の（６Ｓ）−テトラヒドロ−Ｄ−ネオ
プテリンを単離収得することができる。In this case, (6S) -tetrahydro-D-neopterin can be obtained at an asymmetric synthesis rate S / R of about 4.0 or more. By recrystallizing from this product, high purity (6S) -tetrahydro-D-neopterin can be isolated and obtained.
【００１５】[0015]
【実施例】次に実施例を挙げて説明する。 実施例１ Ｄ−ネオプテリン20g、白金ブラック4.0gを水600ml に
加え、これにトリエチルアミン48gを加え、pH12.0に調
整した。これをオートクレーブに入れ、H2圧力100kg/cm
2、温度０〜５℃、回転数1000r.p.m.で攪拌し20時間反
応させた。反応物に濃塩酸96mlを加え、触媒を濾過して
除去し、減圧下浴温35℃以下で濃縮し、残留物をメタノ
ールで再結晶し茶白色結晶、（６Ｓ）−テトラヒドロ−
Ｄ−ネオプテリン・２塩酸塩（結晶水１分子含）を9.89
g得た。Next, an embodiment will be described. Example 1 20 g of D-neopterin and 4.0 g of platinum black were added to 600 ml of water, and 48 g of triethylamine was added to adjust the pH to 12.0. This was placed in an autoclave, H 2 pressure of 100kg / cm
2. The mixture was stirred at a temperature of 0 to 5 ° C. and a rotation speed of 1000 rpm for 20 hours. 96 ml of concentrated hydrochloric acid was added to the reaction product, the catalyst was removed by filtration, concentrated under reduced pressure at a bath temperature of 35 ° C. or lower, and the residue was recrystallized from methanol to give brown white crystals, (6S) -tetrahydro-
9.89 D-neopterin dihydrochloride (including one molecule of water of crystallization)
g obtained.
【００１６】13C-NMR (2.9N DC1):δ(ppm) 158.90, 15
3.24, 149.25, 87.82, 75.17, 70.13, 64.56, 55.97, 4
2.79 ［α］D 25=＋17.18 (C=0.32, 0.1N HC1): IR. (KBr):(cm-1) 3260, 2971, 2689, 1709, 1647, 157
4, 1466, 1427, 1370, 1335,1293, 1157, 1088, 1057,
1022, 1003, 957, 911, 872, 818, 772, 737, 683,640,
579, 512 UV (0.1N HC1): λmax=256.2nm 13 C-NMR (2.9N DC1): δ (ppm) 158.90, 15
3.24, 149.25, 87.82, 75.17, 70.13, 64.56, 55.97, 4
2.79 [α] D 25 = +17.18 (C = 0.32, 0.1N HC1): IR. (KBr): (cm -1 ) 3260, 2971, 2689, 1709, 1647, 157
4, 1466, 1427, 1370, 1335,1293, 1157, 1088, 1057,
1022, 1003, 957, 911, 872, 818, 772, 737, 683,640,
579, 512 UV (0.1N HC1): λ max = 256.2nm
【００１７】実施例２ Ｄ−ネオプテリン20mg、白金ブラック4.0mgを水2ml に
加え、これに表１に示す塩基を加え、所定pHに調整し
た。これをオートクレーブに入れ、H2圧力100kg/cm2、
温度０〜５℃、回転数1000r.p.m.で攪拌し20時間反応さ
せた。反応物に濃塩酸0.75mlを加え触媒を濾過して除
き、この濾液部について高速液体クロマトグラフィーで
分析し、それぞれのＳ／Ｒ比および（Ｒ体＋Ｓ体) の収
率を求めた。その結果は表１の通りである。Example 2 20 mg of D-neopterin and 4.0 mg of platinum black were added to 2 ml of water, and a base shown in Table 1 was added thereto to adjust the pH to a predetermined value. This was placed in an autoclave, H 2 pressure of 100kg / cm 2,
The mixture was stirred at a temperature of 0 to 5 ° C. and a rotation number of 1000 rpm for 20 hours. 0.75 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 to determine the respective S / R ratio and the yield of (R-form + S-form). Table 1 shows the results.
【００１８】高速液体クロマトグラフィー測定条件 検出器: 紫外吸光光度計（測定波長：265nm) カラム: Partisil-10SCX, 4.6×250mm 移動相: 40mMリン酸アンモニウム・リン酸(pH=3.0) 流量: 1ml/minHigh-performance liquid chromatography measurement conditions Detector: UV absorption spectrophotometer (measuring wavelength: 265 nm) Column: Partisil-10SCX, 4.6 × 250 mm Mobile phase: 40 mM ammonium phosphate / phosphoric acid (pH = 3.0) Flow rate: 1 ml / min
【００１９】[0019]
【表１】 [Table 1]
【００２０】[0020]
【発明の効果】Ｄ−ネオプテリンを高圧塩基性の条件下
に接触還元することによって、容易に（６Ｓ）−テトラ
ヒドロ−Ｄ−ネオプテリンを製造する方法を提供するこ
とができた。The present invention has provided a method for easily producing (6S) -tetrahydro-D-neopterin by catalytically reducing D-neopterin under high-pressure basic conditions.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) C07D 475/04 B01J 23/42 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────の Continued on the front page (58) Field surveyed (Int. Cl. 6 , DB name) C07D 475/04 B01J 23/42 CA (STN) REGISTRY (STN)
Claims (1)
pH10〜13、圧力が80〜120kg/cm2の条件下で接触還元し
て得られることを特徴とする（６S）−テトラヒドロ−
Ｄ−ネオプテリンの製造法。1. A method for preparing D-neopterin in the presence of an amine,
(6S) -tetrahydro-, obtained by catalytic reduction under conditions of pH 10-13 and pressure 80-120 kg / cm 2
A method for producing D-neopterin.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5346845A JP2995448B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing (6S) -tetrahydro-D-neopterin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP5346845A JP2995448B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing (6S) -tetrahydro-D-neopterin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07188233A JPH07188233A (en) | 1995-07-25 |
| JP2995448B2 true JP2995448B2 (en) | 1999-12-27 |
Family
ID=18386200
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5346845A Expired - Fee Related JP2995448B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing (6S) -tetrahydro-D-neopterin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2995448B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998008516A1 (en) | 1996-08-30 | 1998-03-05 | Suntory Limited | Preventives or remedies for diseases induced by hypofunction of nitric oxide synthase (nos) |
-
1993
- 1993-12-27 JP JP5346845A patent/JP2995448B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| ＨＥＴＥＲＯＣＹＣＬＥＳ，Ｖｏｌ．２３，Ｎｏ．１２，（１９８５），ｐ．３１１５−３１２０ |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07188233A (en) | 1995-07-25 |
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