JPH07188233A - Production of (6s)-tetrahydro-d-neopterin - Google Patents

Production of (6s)-tetrahydro-d-neopterin

Info

Publication number
JPH07188233A
JPH07188233A JP5346845A JP34684593A JPH07188233A JP H07188233 A JPH07188233 A JP H07188233A JP 5346845 A JP5346845 A JP 5346845A JP 34684593 A JP34684593 A JP 34684593A JP H07188233 A JPH07188233 A JP H07188233A
Authority
JP
Japan
Prior art keywords
neopterin
tetrahydro
isomer
pressure
mixture
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.)
Granted
Application number
JP5346845A
Other languages
Japanese (ja)
Other versions
JP2995448B2 (en
Inventor
Naoki Mochizuki
直樹 望月
Nobuo Uemitsu
信男 上満
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asahi Breweries Ltd
Original Assignee
Asahi Breweries Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Asahi Breweries Ltd filed Critical Asahi Breweries Ltd
Priority to JP5346845A priority Critical patent/JP2995448B2/en
Publication of JPH07188233A publication Critical patent/JPH07188233A/en
Application granted granted Critical
Publication of JP2995448B2 publication Critical patent/JP2995448B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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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

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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

PURPOSE:To obtain an industrially utilizable process for the selective production of 6S isomer of tetrahydro-D-neopterin at a high ratio. CONSTITUTION:D-neopterin of formula I is catalytically reduced in water, an alcoholic solvent or their mixture adjusted to pH10-13 under 80-120kg/cm<2> pressure at -5 to +30 deg.C (preferably // 0-l0 deg.C) using a platinum-based catalyst to obtain (6S)-tetrahydro-Dneopterin of formula II. The asymmetric synthesis ratio S/R can be increased to >=4 by this process and 6S isomer of tetrahydro-D- neopterin can easily be obtained by recrystallization. Tetrahydroneopterin is effective for the treatment and amelioration of symptoms relating to active oxygen, etc., such as various ischemic disorders because of the strong radical elimination action of the compound. The same physiological activity is observed in 6S isomer, 6R isomer and their mixture, however, 6S isomer is especially preferable as pharmaceuticals.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は、次式：The present invention has the following formula:

【０００２】[0002]

【化１】 [Chemical 1]

【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。(6S) -tetrahydro-D-
The present invention relates to an industrial production method of 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 Prior Art Tetrahydro-D-neopterin has a strong radical scavenging action, and therefore, it has been recognized that it has a therapeutic effect on various ischemic disorders and other symptoms involving active oxygen. -304525). Furthermore, tetrahydro-D
-Neopterin is effective in suppressing cancer metastasis and healing side effects of anticancer agents (Japanese Patent Application No. 04-304525). On the other hand, tetrahydro-
D-neopterin has similar physiological activity in 6S form, 6R form and mixtures thereof. However,
Since the 6S and 6R forms are diastereomers, a high-purity 6S form or 6R form is required in order to develop this product as a drug, not as a mixture of diastereomers. Therefore, it is desired to develop a manufacturing method for mass-producing the 6S or 6R isomer with high purity selectively and economically. Particularly, the 6S form is a desirable compound as a drug.

【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 of producing tetrahydro-D-neopterin, a method of catalytically reducing D-neopterin is known. But,
This method produces a mixture of 6S and 6R forms, which must be resolved. This resolution is performed using high performance liquid chromatography (J. Biochem., 98, 1341 (1.
985)) has been developed but is difficult to use industrially, and there is currently no advantageous division method. Furthermore, as a selective synthesis method, a catalytic reduction method using platinum oxide under basic conditions (Heterocycle, 23, 3115 (1985)) has been developed, but the selectivity has a low S / R ratio of 2.7. However, the 6S form cannot be isolated by a method easier 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。Based on such a background, the present invention can obtain a 6S form of tetrahydro-D-neopterin in a high ratio, and selectively produces 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。Means for Solving the Problems As a result of intensive investigations by the present inventors, D-neopterin was adjusted to pH 10 in the presence of amines.
~ 13, pressure 80 ~ 120kg / cm 2 by catalytic reduction, the asymmetric synthesis rate S / R can be increased to 4 or more, easily recrystallized tetrahydro-D-neopterin 6S form. The present invention has been completed by finding a manufacturing method capable of obtaining

【０００８】すなわち、本発明の第一は、Ｄ−ネオプテ
リンを高圧塩基性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
の製造法である。That is, the first aspect of the present invention is a method for producing (6S) -tetrahydro-D-neopterin, which is obtained by catalytic reduction of D-neopterin under high-pressure basic conditions.

【０００９】本発明は、好ましくは接触還元の条件が、
アミン類の存在下にて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。In the present invention, preferably, the conditions for catalytic reduction are
It is characterized by having a pH of 10 to 13 and a pressure of 80 to 120 kg / cm 2 in the presence of amines. This manufacturing method is shown by the following reaction formula.

【００１０】[0010]

【化２】 [Chemical 2]

【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。To carry out the present invention, D-neopterin is catalytically reduced using a platinum-based catalyst in water, alcohol or a mixed solvent thereof in which the pH is adjusted to 10 to 13 with amines.
Examples of platinum-based catalysts include platinum black, platinum oxide (PtO 2 ),
Examples include platinum carbon (Pt / C), platinum alumina (Pt / alumina), and the like. Further, 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。The 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; tetramethyl. Examples thereof include 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 if the pH is adjusted to the above range using another base, for example, an inorganic base such as alkali hydroxide, The yield is also poor. Further, the asymmetric synthesis rate S / R is low when the pH is outside the above range.

【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 method of the present invention can be carried out by a usual catalytic reduction operation, and the reaction temperature is -5 ° C to 30 ° C, especially 0 to
10 ° C is preferred. If the reaction temperature is -5 ° C or lower, the reaction is difficult to proceed, and if it exceeds 30 ° C, side reactions increase, which is not desirable. The H 2 pressure is preferably 80 to 120 kg / cm 2 . If it is less than 80 kg / cm 2 , the reaction is difficult to proceed, and if it exceeds 120 kg / cm 2 , the reaction proceeds, but it is not desirable from the economical aspect.

【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 way, (6S) -tetrahydro-D-neopterin can be obtained with an asymmetric synthesis rate S / R of about 4.0 or more. By recrystallizing from this product, highly pure (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。EXAMPLES Next, examples 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 thereto to adjust the pH to 12.0. Put this in the autoclave, H 2 pressure 100kg / cm
2 , stirred at a temperature of 0 to 5 ° C. and a rotation speed of 1000 rpm, and reacted for 20 hours. 96 ml of concentrated hydrochloric acid was added to the reaction product, the catalyst was removed by filtration, the mixture was concentrated under reduced pressure at a bath temperature of 35 ° C. or lower, and the residue was recrystallized with methanol to give a brown white crystal, (6S) -tetrahydro
9.89 D-neopterin dihydrochloride (including 1 molecule of water of crystallization)
g got.

【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 the base shown in Table 1 was added thereto to adjust to a predetermined pH. Put this in the autoclave, H 2 pressure 100kg / cm 2 ,
The mixture was stirred at a temperature of 0 to 5 ° C and a rotation speed of 1000 rpm and reacted for 20 hours. Concentrated hydrochloric acid (0.75 ml) was added to the reaction product to remove the catalyst by filtration, and the filtrate portion was analyzed by high performance liquid chromatography to determine the respective S / R ratios and the (R-form + S-form) yields. The results are shown in Table 1.

【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: Ultraviolet absorptiometer (Measurement 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。INDUSTRIAL APPLICABILITY A method for easily producing (6S) -tetrahydro-D-neopterin could be provided by catalytically reducing D-neopterin under high-pressure basic conditions.

Claims (2)

【特許請求の範囲】[Claims] 【請求項１】 Ｄ−ネオプテリンを高圧塩基性条件下で
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 producing (6S) -tetrahydro-D-neopterin, which is obtained by catalytically reducing D-neopterin under high-pressure basic conditions. 【請求項２】 接触還元の条件が、アミン類の存在下pH
10〜13、圧力が80〜120kg/cm2 であることを特徴とする
請求項１記載の（６Ｓ）−テトラヒドロ−Ｄ−ネオプテ
リンの製造法。2. The condition of catalytic reduction is pH in the presence of amines.
The method for producing (6S) -tetrahydro-D-neopterin according to claim 1, wherein the pressure is 10 to 13 and the pressure is 80 to 120 kg / cm 2 .
JP5346845A 1993-12-27 1993-12-27 Method for producing (6S) -tetrahydro-D-neopterin Expired - Fee Related JP2995448B2 (en)

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 true JPH07188233A (en) 1995-07-25
JP2995448B2 JP2995448B2 (en) 1999-12-27

Family

ID=18386200

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Country Link
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0908182A1 (en) * 1996-08-30 1999-04-14 Suntory Limited Preventives or remedies for diseases induced by hypofunction of nitric oxide synthase (nos)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0908182A1 (en) * 1996-08-30 1999-04-14 Suntory Limited Preventives or remedies for diseases induced by hypofunction of nitric oxide synthase (nos)
EP0908182A4 (en) * 1996-08-30 2000-07-05 Suntory Ltd Preventives or remedies for diseases induced by hypofunction of nitric oxide synthase (nos)
US7820667B2 (en) 1996-08-30 2010-10-26 Daiichi Sankyo Company, Limited Methods of treating hypertension

Also Published As

Publication number Publication date
JP2995448B2 (en) 1999-12-27

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