JPH07116213B2 - Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same - Google Patents
Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the sameInfo
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- JPH07116213B2 JPH07116213B2 JP1052842A JP5284289A JPH07116213B2 JP H07116213 B2 JPH07116213 B2 JP H07116213B2 JP 1052842 A JP1052842 A JP 1052842A JP 5284289 A JP5284289 A JP 5284289A JP H07116213 B2 JPH07116213 B2 JP H07116213B2
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- salt
- disubstituted
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、新規なN6,2′−Ｏ−ジ置換−アデノシン−
３′,5′−環状リン酸（以下N6,2′−Ｏ−ジ置換−CAMP
と略称する）又はその塩、及びその新規な製法に関す
る。DETAILED DESCRIPTION OF THE INVENTION The present invention [relates] to novel N 6, 2'-O-di-substituted - adenosine -
3 ', 5'-cyclic phosphate (hereinafter N 6, 2'-O-disubstituted -CAMP
Or a salt thereof, and a new production method thereof.
アデノシン−３′,5′−環状リン酸（以下CAMPと略称す
る）及びその誘導体は、種々の生理活性を有し、生化学
的試薬や医薬としての種々の用途が期待されている。本
化合物は新規化合物であり、抗炎症作用、血小板凝集阻
害作用、血圧降下作用等の優れた薬理作用が期待され
る。Adenosine-3 ', 5'-cyclic phosphate (hereinafter abbreviated as CAMP) and its derivatives have various physiological activities, and are expected to have various uses as biochemical reagents and medicines. This compound is a novel compound, and is expected to have excellent pharmacological actions such as anti-inflammatory action, platelet aggregation inhibitory action, and blood pressure lowering action.
N6,2′−Ｏ−ジ置換−CAMP並びにこれを得る方法は知ら
れていない。N 6, 2'-O- disubstituted -CAMP and method of obtaining this is not known.
N6,2′−Ｏ−ジ置換−CAMPを得る方法については未だ報
告されておらず、本発明者らはこれらを得る方法につい
て鋭意検討を重ねた結果、CAMP又はその塩を水酸化カリ
ウム、水酸化ナトリウム、炭酸水素カルシウム等のアル
カリ金属又はアルカリ土類金属の水酸化物、炭酸水素塩
等あるいはナトリウムメトキシド等のアルコキサイド等
の塩基存在下、有機ハロゲン化物と反応させることによ
り、N6,2′−Ｏ−ジ置換−CAMP、又はその塩を効率良く
製造し得ることを見出した。N 6, 2'-O-not been reported yet about how to obtain the disubstituted -cAMP, the present inventors have conducted extensive study on how to obtain these, CAMP or potassium hydroxide salt thereof, By reacting with an organic halide in the presence of a base such as sodium hydroxide, a hydroxide of an alkali metal or an alkaline earth metal such as calcium hydrogencarbonate or the like, a hydrogencarbonate or the like or an alkoxide such as sodium methoxide, N 6 , It has been found that 2'-O-disubstituted-CAMP or a salt thereof can be efficiently produced.
本発明は、一般式 （式中Ｒはアルキル基又はアラアルキル基を示し、Ａは
水素イオン、アルカリ金属イオン、アンモニウムイオン
又は有機アンモニウムイオンを示す）で表わされるN6,
2′−Ｏ−ジ置換−アデノシン−３′,5′−環状リン酸
又はその塩であり、又本発明は 一般式 （式中Ａは水素イオン、アルカリ金属イオン、アンモニ
ウムイオン又は有機アンモニウムイオンを示す）で表わ
されるアデノシン−３′,5′−環状リン酸又はその塩
を、塩基存在下、一般式 RX （III） （式中Ｒはアルキル基又はアラアルキル基を示し、Ｘは
ハロゲン原子を示す）で表わされる有機ハロゲン化物と
反応させることを特徴とする一般式 （式中Ｒ及びＡは前記の意味を有する）で表わされる
N6,2′−Ｏ−ジ置換−アデノシン−３′,5′−環状リン
酸又はその塩の製法である。The present invention has the general formula N 6 of (wherein R represents an alkyl group or araalkyl group, A is a hydrogen ion, indicating an alkali metal ion, an ammonium ion or an organic ammonium ion) represented by,
2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphoric acid or a salt thereof. (Wherein A represents hydrogen ion, alkali metal ion, ammonium ion or organic ammonium ion), adenosine-3 ', 5'-cyclic phosphoric acid or a salt thereof is represented by the general formula RX (III) (Wherein R represents an alkyl group or an araalkyl group, and X represents a halogen atom), and is reacted with an organic halide represented by the general formula (Wherein R and A have the above-mentioned meanings)
N 6, 2'-O-di-substituted - adenosine-3 ', a process for preparing 5'-cyclic phosphoric acid or its salt.
以下、本発明を詳述する。Hereinafter, the present invention will be described in detail.
本発明の出発物質として用いられるCAMP又はその塩は、
例えば次のようにして製造できる。アデニン、キシロー
スもしくはリボース及び無機リン酸塩を含む培地を用い
て、ミクロバクテリウム属に属し、アデニン、キシロー
スもしくはリボースと無機リン酸塩とからCAMPを生産す
る能力を有する菌を培養し、培養物よりCAMPを採取する
（特許第651781号明細書参照）。更に遊離のCAMPにアル
カリ金属又はアルカリ土類金属の水酸化物、炭酸塩、炭
酸水素塩等あるいは有機アミン好ましくはトリアルキル
アミンを作用させると、CAMPのリン酸部におけるアルカ
リ金属塩、例えばナトリウム塩、カリウム塩等、アルカ
リ土類金属塩、例えばカルシウム塩、マグネシウム塩
等、有機アンモニウム塩、例えばトリエチルアンモニウ
ム塩等を得ることができる。CAMP or a salt thereof used as a starting material of the present invention,
For example, it can be manufactured as follows. Using a medium containing adenine, xylose or ribose and inorganic phosphate, a bacterium belonging to the genus Microbacterium and capable of producing CAMP from adenine, xylose or ribose and inorganic phosphate is cultured, and the culture is CAMP is collected from the sample (see Japanese Patent No. 651781). When free CAMP is further reacted with an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogen carbonate or the like or an organic amine, preferably a trialkylamine, an alkali metal salt in the phosphoric acid part of CAMP, for example, sodium salt. , Potassium salts and the like, alkaline earth metal salts such as calcium salts and magnesium salts, and organic ammonium salts such as triethylammonium salts.
一般式（III）で表わされる有機ハロゲン化物における
Ｒとしては、炭素数１〜16、特に２〜14のアルキル基、
例えばメチル基、エチル基、プロピル基、イソプロピル
基、ブチル基、イソブチル基、ペンチル基、イソペンチ
ル基、ヘキシル基、イソヘキシル基、ヘプチル基、オク
チル基、ノニル基、デシル基、ドデシル基、テトラデシ
ル基、ヘキサデシル基等の直鎖状もしくは分枝状のアル
キル基、アラアルキル基、例えばベンジル基、ニトロベ
ンジル基、クロロベンジル基、メチルベンジル基、ハイ
ドロキシベンジル基、フェネチル基、フェニルプロピル
基等が挙げられる。R in the organic halide represented by the general formula (III) is an alkyl group having 1 to 16 carbon atoms, particularly 2 to 14 carbon atoms,
For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group, hexyl group, isohexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, tetradecyl group, hexadecyl group. Examples thereof include linear or branched alkyl groups such as groups and araalkyl groups such as benzyl group, nitrobenzyl group, chlorobenzyl group, methylbenzyl group, hydroxybenzyl group, phenethyl group and phenylpropyl group.
本発明を実施するに際しては、式（II）の化合物を水酸
化カリウム、水酸化ナトリウム、炭酸水素カルシウム等
のアルカリ金属又はアルカリ土類金属の水酸化物、炭酸
水素塩等あるいはナトリウムメトキシド等のアルコキサ
イド等の塩基存在下、また、アルカリ金属又はアルカリ
土類金属の水酸化物、炭酸水素塩を用いる場合、好まし
くは18−クラウン−６、15−クラウン−５等の対応する
クラウンエーテル存在下、式（III）の有機ハロゲン化
物と反応させて、式（Ｉ）の化合物を得る。In carrying out the present invention, the compound of the formula (II) is converted into a hydroxide of an alkali metal or an alkaline earth metal such as potassium hydroxide, sodium hydroxide or calcium hydrogen carbonate, a hydrogen carbonate or the like or sodium methoxide or the like. In the presence of a base such as alkoxide, and in the case of using a hydroxide or hydrogen carbonate of an alkali metal or an alkaline earth metal, preferably in the presence of a corresponding crown ether such as 18-crown-6 or 15-crown-5, Reacting with an organic halide of formula (III) gives a compound of formula (I).
この反応は溶剤中で行ない、溶剤としては水、アルコー
ル類例えばメタノール、エタノール等、エーテル類、例
えばジオキサン、テトラヒドロフラン等、アミド類例え
ばジメチルホルムアミド、ジメチルアセトアミド等、有
機カルボン酸のエステル、例えば酢酸エチル等、又はジ
メチルスルホキサイド等、単独で又は２種以上の混合物
として適宜用いられる。This reaction is carried out in a solvent. As a solvent, water, alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, organic carboxylic acid esters such as ethyl acetate, etc. , Or dimethyl sulfoxide and the like, which are appropriately used alone or as a mixture of two or more kinds.
式（II）の化合物に対する式（III）の有機ハロゲン化
物の使用量は、通常２〜30倍モル、好ましくは５〜20倍
モル程度である。また、式（II）の化合物に対する塩基
の使用量は、通常２〜30倍モル、好ましくは５〜20倍モ
ル程度である。この反応は一般に10〜150℃、好ましく
は20〜70℃の温度において、静置もしくは撹拌下に１時
間以上、好ましくは２時間〜２日間行なわれる。The amount of the organic halide of the formula (III) used with respect to the compound of the formula (II) is usually 2 to 30 times mol, preferably 5 to 20 times mol. Further, the amount of the base used with respect to the compound of the formula (II) is usually 2 to 30 times mol, preferably 5 to 20 times mol. This reaction is generally carried out at a temperature of 10 to 150 ° C., preferably 20 to 70 ° C., for 1 hour or more, preferably 2 hours to 2 days, with standing or stirring.
式（Ｉ）の目的化合物を単離、精製するには、例えばシ
リカゲル、アルミナ、イオン交換樹脂、活性炭等を用い
るカラムクロマトグラフィ、再結晶法、pH調製による析
出法、食塩を用いる塩析法、有機溶媒を用いる抽出法等
の精製法を単独で又は適宜組み合わせて行なうことがで
きる。式（Ｉ）の化合物の遊離酸に、例えばアルカリ金
属又はアルカリ土類金属の水酸化物、炭酸塩、炭酸水素
塩等あるいはアンモニア又は有機アミン、例えばトリエ
チルアミン、トリブチルアミン等の三級アミンを作用さ
せることにより、式（Ｉ）の化合物の環状リン酸部にお
ける対応する塩に導くことができる。To isolate and purify the target compound of formula (I), for example, column chromatography using silica gel, alumina, ion exchange resin, activated carbon, etc., recrystallization method, precipitation method by pH adjustment, salting out method using salt, organic A purification method such as an extraction method using a solvent can be performed alone or in combination. The free acid of the compound of the formula (I) is reacted with, for example, an alkali metal or alkaline earth metal hydroxide, carbonate, hydrogen carbonate or the like or ammonia or an organic amine, for example, a tertiary amine such as triethylamine or tributylamine. This can lead to the corresponding salt in the cyclic phosphate moiety of the compound of formula (I).
本発明により得られる式（Ｉ）のN6,2′−Ｏ−ジ置換−
CAMP及びその塩の例としては、次のものが挙げられ、
N6,2′−Ｏ−ジメチル−CAMP、N6,2′−Ｏ−ジエチル−
CAMP、N6,2′−Ｏ−ジプロピル−CAMP、N6,2′−Ｏ−ジ
イソプロピル−CAMP、N6,2′−Ｏ−ジブチル−CAMP、
N6,2′−Ｏ−ジイソブチル−CAMP、N6,2′−Ｏ−ジペン
チル−CAMP、N6,2′−Ｏ−ジイソペンチル−CAMP、N6,
2′−Ｏ−ジネオペンチル−CAMP、N6,2′−Ｏ−ジヘキ
シル−CAMP、N6,2′−Ｏ−ジイソヘキシル−CAMP、N6,
2′−Ｏ−ジヘプチル−CAMP、N6,2′−Ｏ−ジオクチル
−CAMP、N6,2′−Ｏ−ジノニル−CAMP、N6,2′−Ｏ−ジ
デシル−CAMP、N6,2′−Ｏ−ジウンデル−CAMP、N6,2′
−Ｏ−ジドデシル−CAMP、N6,2′−Ｏ−ジトリデシル−
CAMP、N6,2′−Ｏ−ジテトラデシル−CAMP、N6,2′−Ｏ
−ジペンタデシル−CAMP、N6,2′−Ｏ−ジヘキサデシル
−CAMP、N6,2′−Ｏ−ジベンジル−CAMP、N6,2′−Ｏ−
ジニトロベンジル−CAMP、N6,2′−Ｏ−ジクロロベンジ
ル−CAMP、N6,2′−Ｏ−ジメチルベンジル−CAMP、N6,
2′−Ｏ−ジハイドロキシベンジル−CAMP、N6,2′−Ｏ
−ジ−２−フェニルエチル−CAMP、N6,2′−Ｏ−ジ−３
−フェニルプロピル−CAMP等、及びこれらのアルカリ金
属塩、アンモニウム塩及び有機アンモニウム塩等であ
る。N 6 of formula obtained by the present invention (I), 2'-O- disubstituted -
Examples of CAMP and its salts include the following,
N 6, 2'-O- dimethyl -CAMP, N 6, 2'-O- diethyl -
CAMP, N 6, 2'-O- dipropyl -CAMP, N 6, 2'-O- diisopropyl -CAMP, N 6, 2'-O- dibutyl -cAMP,
N 6, 2'-O- diisobutyl -CAMP, N 6, 2'-O- dipentyl -CAMP, N 6, 2'-O- diisopentyl -CAMP, N 6,
2'-O- dineopentyl -CAMP, N 6, 2'-O- dihexyl -CAMP, N 6, 2'-O- diisohexyl -CAMP, N 6,
2'-O- diheptyl -CAMP, N 6, 2'-O- dioctyl -CAMP, N 6, 2'-O- dinonyl -CAMP, N 6, 2'-O- didecyl -CAMP, N 6, 2 ' -O- Jiunderu -CAMP, N 6, 2 '
-O- didodecyl -CAMP, N 6, 2'-O- ditridecyl -
CAMP, N 6, 2'-O- ditetradecyl -CAMP, N 6, 2'-O
- Jipentadeshiru -CAMP, N 6, 2'-O- dihexadecyl -CAMP, N 6, 2'-O- dibenzyl -CAMP, N 6, 2'-O-
Dinitrobenzyl -CAMP, N 6, 2'-O- dichlorobenzyl -CAMP, N 6, 2'-O- dimethylbenzyl -CAMP, N 6,
2'-O- di hydroxy benzyl -CAMP, N 6, 2'-O
- di-2-phenylethyl -CAMP, N 6, 2'-O- di -3
-Phenylpropyl-CAMP, etc., and their alkali metal salts, ammonium salts, organic ammonium salts, etc.
また本発明によれば、新規化合物であるN6,2′−Ｏ−ジ
置換−アデノシン−３′,5′−環状リン酸及びその塩を
効率良く製造することができる。According to the present invention, N 6 are novel compounds, 2'-O-di-substituted - adenosine-3 ', 5'-cyclic phosphoric acid and salts thereof can be efficiently produced.
本発明の新規なN6,2′−Ｏ−ジ置換−アデノシン−
３′,5′−環状リン酸及びその塩は、例えば抗炎症作
用、血小板凝集阻害作用、血圧降下作用等の優れた薬理
作用が期待されるものであり、また本発明は該化合物を
極めて効率良く提供することができるものであって、本
発明は産業上極めて有意義なものである。Novel N 6 of the present invention, 2'-O-di-substituted - adenosine -
The 3 ', 5'-cyclic phosphate and its salts are expected to have excellent pharmacological actions such as anti-inflammatory action, platelet aggregation inhibiting action and blood pressure lowering action, and the present invention makes the compound extremely efficient. It can be provided well, and the present invention is extremely significant industrially.
以下、実施例により本発明を具体的に示す。Hereinafter, the present invention will be specifically described with reference to examples.
実施例１ N6,2′−Ｏ−ジプロピル−CAMPの製造 CAMPのトリブチルアミン塩3.084gをジメチルスルホキサ
イド50mlに溶解し、これにナトリウムメトキサイド2.56
mlを添加し、30分後にｎ−プロピルブロマイド1.09mlを
加えて、室温で１日間撹拌する。この間ナトリウムメト
キサイドとｎ−プロピルブロマイドを上記の方法と同様
に５回添加する。次いで、反応液を水浴中50℃で１日間
撹拌し、その間ナトリウムメトキサイドとｎ−プロピル
ブロマイドを上記の方法と同様に５回添加する。反応液
を2N−塩酸で中和した後、溶媒を減圧留去した。残留す
る油状物質を少量の水に溶解し、2N−塩酸を加えてpH2
に調整し、これを活性炭カラム（2.1×34cm）に吸着さ
せ、水洗後、エタノール／水/28％水酸化アンモニウム
（容量比;10:10:1）を用いて溶出する区分を採取し、こ
れを減圧乾固する。得られたカラメル状物質を少量のメ
タノールに溶解し、2N−塩酸を加えて、pH3に調整し、
これをシリカゲル薄層クロマトグラフィ（展開溶媒；メ
タノール／クロロホルム、容量比;3:7）により分離精製
し、目的化合物のUV吸収帯（Rf値0.4付近）をかき取
り、メタノールで抽出し減圧乾固すると、N6,2′−Ｏ−
ジプロピル−CAMPを427mg（収率17.2％）得た。EXAMPLE 1 N 6, was dissolved tributylamine salt 3.084g of manufacturing CAMP of 2'-O- dipropyl -CAMP in dimethyl sulfoxide 50 ml, sodium methoxide 2.56 to
After 30 minutes, 1.09 ml of n-propyl bromide was added and the mixture was stirred at room temperature for 1 day. During this period, sodium methoxide and n-propyl bromide are added 5 times as in the above method. Then, the reaction solution is stirred in a water bath at 50 ° C. for 1 day, while sodium methoxide and n-propyl bromide are added 5 times as in the above method. The reaction solution was neutralized with 2N-hydrochloric acid, and the solvent was evaporated under reduced pressure. Dissolve the residual oily substance in a small amount of water and add 2N hydrochloric acid to adjust the pH to 2
And adsorb it onto an activated carbon column (2.1 x 34 cm), wash it with water, and then use ethanol / water / 28% ammonium hydroxide (volume ratio; 10: 10: 1) to collect the eluted fractions. To dryness under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3,
This is separated and purified by silica gel thin layer chromatography (developing solvent; methanol / chloroform, volume ratio; 3: 7), the UV absorption band (Rf value around 0.4) of the target compound is scraped off, extracted with methanol and dried under reduced pressure to dryness. , N 6, 2'-O-
427 mg (yield 17.2%) of dipropyl-CAMP was obtained.
mp:159〜161℃ Rf値:0.47（展開溶媒；メタノール／クロロホルム、容
量比;4:6以下同じ） 実施例２ N6,2′−Ｏ−ジブチル−CAMPの製造 CAMPのトリブチルアミン塩3.084gをジメチルスルホキサ
イド50mlに溶解し、これにナトリウムメトキサイド2.56
mlを添加し、30分後にｎ−ブチルブロマイド1.29mlを加
えて、室温で１日間撹拌する。この間ナトリウムメトキ
サイドとｎ−ブチルブロマイドを上記の方法と同様に５
回添加する。次いで、反応液を水浴中50℃で６時間撹拌
し、その間ナトリウムメトキサイドとｎ−ブチルブロマ
イドを上記の方法と同様に３回添加する。反応液を2N−
塩酸で中和した後、溶媒を減圧留去した。残留する油状
物質を少量の水に溶解し、2N−塩酸を加えてpH2に調整
し、これを活性炭カラム（2.1×31cm）に吸着させ、水
洗後、エタノール／水/28％水酸化アンモニウム（容量
比;10:10:1）を用いて溶出する区分を採取し、これを減
圧乾固する。得られたカラメル状物質を少量のメタノー
ルに溶解し、2N−塩酸を加えてpH3に調整し、これをシ
リカゲル薄層クロマトグラフィ（展開溶媒；メタノール
／クロロホルム、容量比;3:7）により分離精製し、目的
化合物のUV吸収帯（Rf値0.4付近）をかき取り、メタノ
ールで抽出し減圧乾固すると、N6,2′−Ｏ−ジブチル−
CAMPを534mg（収率20.2％）得た。 mp: 159-161 ° C. Rf value: 0.47 (developing solvent: methanol / chloroform, volume ratio; 4: 6 hereinafter) Example 2 N 6, tributylamine salt 3.084g of manufacturing CAMP of 2'-O- dibutyl -CAMP Is dissolved in 50 ml of dimethyl sulfoxide, and sodium methoxide 2.56 is added to this.
After 30 minutes, 1.29 ml of n-butyl bromide was added and the mixture was stirred at room temperature for 1 day. During this period, sodium methoxide and n-butyl bromide were added in the same manner as in the above method.
Add twice. Then, the reaction solution is stirred in a water bath at 50 ° C. for 6 hours, during which time sodium methoxide and n-butyl bromide are added three times as in the above method. 2N-
After neutralizing with hydrochloric acid, the solvent was distilled off under reduced pressure. The residual oily substance is dissolved in a small amount of water, and 2N-hydrochloric acid is added to adjust the pH to 2. This is adsorbed on an activated carbon column (2.1 x 31 cm), washed with water, and then ethanol / water / 28% ammonium hydroxide (volume Collect the eluate fraction using the ratio 10: 10: 1) and dry it under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3, and this was separated and purified by silica gel thin layer chromatography (developing solvent; methanol / chloroform, volume ratio; 3: 7). , scraped UV absorption band of the desired compound (Rf value 0.4 around), the extraction with methanol and concentrated to dryness under reduced pressure, N 6, 2'-O-dibutyl -
534 mg of CAMP (yield 20.2%) was obtained.
mp:156〜158℃ Rf値:0.53 実施例３ N6,2′−Ｏ−ジペンチル−CAMPの製造 CAMPのトリブチルアミン塩3.084gをジメチルスルホキサ
イド100mlに溶解し、これにナトリウムメトキサイド2.5
6mlを添加し、30分後にｎ−アミルブロモイド1.48mlを
加えて、室温で21時間撹拌する。この間ナトリウムメト
キサイドとｎ−アミルブロマイドを上記の方法と同様に
５回添加する。反応液を2N−塩酸で中和した後、溶媒を
減圧留去した。残留する油状物質を少量の水に溶解し、
2N−塩酸を加えてpH2に調整し、これを活性炭カラム
（2.1×34cm）に吸着させ、水洗後、エタノール／水/28
％水酸化アンモニウム（容量比;10:10:1）を用いて溶出
する区分及びエタノール／水/28％水酸化アンモニウム
（容量比;10:5:1）を用いて溶出する区分を採取し、こ
れを減圧乾固する。得られたカラメル状物質を少量のメ
タノールに溶解し、2N−塩酸を加えてpH3に調整し、こ
れをシリカゲル薄層クロマトグラフィ（展開溶媒；メタ
ノール／クロロホルム、容量比;3:7）により分離精製
し、目的化合物のUV吸収帯（Rf値0.45付近）をかき取
り、メタノールで抽出し減圧乾固すると、N6,2′−Ｏ−
ジペンチル−CAMPを890mg（収率31.6％）得た。 mp: 156-158 ° C. Rf value: 0.53 Example 3 N 6, tributylamine salt 3.084g of manufacturing CAMP of 2'-O- dipentyl -CAMP was dissolved in dimethyl sulfoxide 100 ml, which sodium methoxide 2.5
6 ml was added, 30 minutes later, 1.48 ml of n-amyl bromide was added, and the mixture was stirred at room temperature for 21 hours. During this time, sodium methoxide and n-amyl bromide are added 5 times as in the above method. The reaction solution was neutralized with 2N-hydrochloric acid, and the solvent was evaporated under reduced pressure. Dissolve the residual oil in a small amount of water,
2N-hydrochloric acid was added to adjust the pH to 2, and this was adsorbed on an activated carbon column (2.1 x 34 cm), washed with water, and then ethanol / water / 28
Collect the fractions that elute with% ammonium hydroxide (volume ratio; 10: 10: 1) and the fractions that elute with ethanol / water / 28% ammonium hydroxide (volume ratio; 10: 5: 1), This is dried under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3, and this was separated and purified by silica gel thin layer chromatography (developing solvent; methanol / chloroform, volume ratio; 3: 7). , scraped UV absorption band of the desired compound (Rf value 0.45 vicinity) and extracted with methanol and concentrated to dryness under reduced pressure, N 6, 2'-O-
890 mg (yield 31.6%) of dipentyl-CAMP was obtained.
mp:152〜153℃ Rf値:0.58 実施例４ N6,2′−Ｏ−ジヘプチル−CAMPの製造 CAMPのトリブチルアミン塩3.084gをジメチルスルホキサ
イド100mlに溶解し、これにナトリウムメトキサイド2.5
6mlを添加し、30分後にｎ−ヘプチルブロマイド1.88ml
を加えて、室温で20時間撹拌する。この間ナトリウムメ
トキサイドとｎ−ヘプチルブロマイドを上記の方法と同
様に３回添加する。反応液を2N−塩酸で中和した後、溶
媒を減圧留去した。残留する油状物質を少量の水に溶解
し、2N−塩酸を加えてpH2に調整し、これを活性炭カラ
ム（2.1×32cm）に吸着させ、水洗後、エタノール／水/
28％水酸化アンモニウム（容量比;10:10:1）を用いて溶
出する区分、及びエタノール／水/28％水酸化アンモニ
ウム（容量比;10:5:1）を用いて溶出する区分を採取
し、これを減圧乾固する。得られたカラメル状物質を少
量のメタノールに溶解し、2N−塩酸を加えてpH3に調整
し、これをシリカゲル薄層クロマトグラフィ（展開溶
媒；メタノール／クロロホルム、容量比;25:75）により
分離精製し、目的化合物のUV吸収帯（Rf値0.43付近）を
かき取り、メタノールで抽出し減圧乾固すると、N6,2′
−Ｏ−ジヘプチル−CAMPを985mg（収率31.3％）得た。 mp: 152-153 ° C. Rf value: 0.58 Example 4 N 6, tributylamine salt 3.084g of manufacturing CAMP of 2'-O- diheptyl -CAMP was dissolved in dimethyl sulfoxide 100 ml, which sodium methoxide 2.5
Add 6 ml, and 30 minutes later n-heptyl bromide 1.88 ml
And stir at room temperature for 20 hours. During this time, sodium methoxide and n-heptyl bromide are added three times as in the above method. The reaction solution was neutralized with 2N-hydrochloric acid, and the solvent was evaporated under reduced pressure. The residual oily substance is dissolved in a small amount of water, and 2N-hydrochloric acid is added to adjust the pH to 2, and this is adsorbed on an activated carbon column (2.1 x 32 cm), washed with water, and then ethanol / water /
Collect the sections that elute with 28% ammonium hydroxide (volume ratio; 10: 10: 1) and the sections that elute with ethanol / water / 28% ammonium hydroxide (volume ratio; 10: 5: 1) Then, this is dried under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3, and this was separated and purified by silica gel thin layer chromatography (developing solvent; methanol / chloroform, volume ratio; 25:75). , The UV absorption band (Rf value around 0.43) of the target compound is scraped off, extracted with methanol, and dried under reduced pressure to give N 6 , 2 '.
985 mg (yield 31.3%) of -O-diheptyl-CAMP was obtained.
mp:118〜121℃ Rf値:0.64 実施例５ N6,2′−Ｏ−ジベンジル−CAMPの製造 水酸化カリウム5.28gを溶解した水30mlにCAMP3.29gを溶
解し、これに18−クラウン−６を7.93g溶解したジオキ
サン150mlを添加する。次いで、ベンジルブロマイド7.1
4mlを添加し、水浴中50℃で３時間撹拌する。反応液を2
N−塩酸で中和した後、溶媒を減圧留去した。残留する
油状物質を少量の水に溶解し、2N−塩酸を加えてpH2に
調整し、これを活性炭カラム（2.6×28cm）に吸着さ
せ、水洗後、エタノール／水/28％水酸化アンモニウム
（容量比;10:10:1）を用いて溶出する区分を採取し、こ
れを減圧乾固する。得られたカラメル状物質を少量のメ
タノールに溶解し、2N−塩酸を加えてpH3に調整し、こ
れをシリカゲル薄層クロマトグラフィ（展開溶媒；メタ
ノール／クロロホルム、容量比;4:6）により分離精製
し、目的化合物のUV吸収帯（Rf値0.5付近）をかき取
り、メタノールで抽出し減圧乾固すると、N6,2′−Ｏ−
ジベンジ−CAMPを2107mg（収率41.4％）得た。 mp: 118 to 121 ° C. Rf value: 0.64 Example 5 N 6, was dissolved CAMP3.29g in water 30ml dissolved production of potassium hydroxide 5.28g of 2'-O- dibenzyl -cAMP, this 18-crown - 150 ml of dioxane with 7.93 g of 6 dissolved is added. Then benzyl bromide 7.1
Add 4 ml and stir in a water bath at 50 ° C. for 3 hours. 2 reaction solutions
After neutralizing with N-hydrochloric acid, the solvent was distilled off under reduced pressure. Dissolve the residual oily substance in a small amount of water, adjust to pH 2 by adding 2N-hydrochloric acid, adsorb this on an activated carbon column (2.6 x 28 cm), wash with water, and then use ethanol / water / 28% ammonium hydroxide (volume Collect the eluate fraction using the ratio 10: 10: 1) and dry it under reduced pressure. The obtained caramel-like substance was dissolved in a small amount of methanol, 2N-hydrochloric acid was added to adjust the pH to 3, and this was separated and purified by silica gel thin layer chromatography (developing solvent; methanol / chloroform, volume ratio; 4: 6). , The UV absorption band (Rf value around 0.5) of the target compound is scraped off, extracted with methanol, and dried under reduced pressure to give N 6 , 2'-O-
2107 mg (yield 41.4%) of dibenz-CAMP was obtained.
mp:153〜156℃ Rf値:0.56 mp: 153-156 ℃ Rf value: 0.56
Claims (2)
水素イオン、アルカリ金属イオン、アンモニウムイオン
又は有機アンモニウムイオンを示す）で表わされるN6,
2′−Ｏ−ジ置換−アデノシン−３′,5′−環状リン酸
又はその塩。1. A general formula N 6 of (wherein R represents an alkyl group or araalkyl group, A is a hydrogen ion, indicating an alkali metal ion, an ammonium ion or an organic ammonium ion) represented by,
2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphoric acid or a salt thereof.
ウムイオン又は有機アンモニウムイオンを示す）で表わ
されるアデノシン−３′,5′−環状リン酸又はその塩
を、塩基存在下、一般式 RX （III） （式中Ｒはアルキル基又はアラアルキル基を示し、Ｘは
ハロゲン原子を示す）で表わされる有機ハロゲン化物と
反応させることを特徴とする一般式 （式中Ｒ及びＡは前記の意味を有する）で表わされる
N6,2′−Ｏ−ジ置換−アデノシン−３′,5′−環状リン
酸又はその塩の製法。2. General formula (Wherein A represents hydrogen ion, alkali metal ion, ammonium ion or organic ammonium ion), adenosine-3 ', 5'-cyclic phosphoric acid or a salt thereof is represented by the general formula RX (III) (Wherein R represents an alkyl group or an araalkyl group, and X represents a halogen atom), and is reacted with an organic halide represented by the general formula (Wherein R and A have the above-mentioned meanings)
N 6, 2'-O-di-substituted - adenosine-3 ', 5'-cyclic phosphate or preparation of a salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1052842A JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1052842A JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02233692A JPH02233692A (en) | 1990-09-17 |
| JPH07116213B2 true JPH07116213B2 (en) | 1995-12-13 |
Family
ID=12926098
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1052842A Expired - Lifetime JPH07116213B2 (en) | 1989-03-07 | 1989-03-07 | Novel N-6,2'-O-disubstituted-adenosine-3 ', 5'-cyclic phosphate and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07116213B2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69132067T2 (en) * | 1990-09-20 | 2000-11-16 | Kabushiki Kaisha Nippon Conlux, Tokio/Tokyo | Device for processing coins |
| US7906491B2 (en) | 2002-06-07 | 2011-03-15 | Univisitair Medisch Centrum Utrecht | Compounds for modulating the activity of exchange proteins directly activated by cAMP (Epacs) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56148218A (en) * | 1980-04-18 | 1981-11-17 | Kikkoman Shoyu Co Ltd | Saccharide increasing method of vegetable |
-
1989
- 1989-03-07 JP JP1052842A patent/JPH07116213B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02233692A (en) | 1990-09-17 |
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