JPH07103149B2 - Method for producing cytosine derivative - Google Patents
Method for producing cytosine derivativeInfo
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- JPH07103149B2 JPH07103149B2 JP30288987A JP30288987A JPH07103149B2 JP H07103149 B2 JPH07103149 B2 JP H07103149B2 JP 30288987 A JP30288987 A JP 30288987A JP 30288987 A JP30288987 A JP 30288987A JP H07103149 B2 JPH07103149 B2 JP H07103149B2
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- derivative
- uracil
- formula
- general formula
- reaction
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Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明はシトシン誘導体の製造法に関するものである。TECHNICAL FIELD The present invention relates to a method for producing a cytosine derivative.
シチジン二リン酸コリン（CDPコリン）などの製造に必
要なシトシン誘導体のウラシル誘導体からの製造法とし
ては、たとえば、４−Ｏ−トリメチルシリルウラシル
誘導体を中間体として経由する方法（***特許第212291
号など参照）、４−ハロゲノ−ピリミジ−２（1H）−
オン誘導体を中間体として経由する方法（Nucleic acid
Chem.,１,223（1978）など参照）、４−Ｏ−アルキ
ルウラシル誘導体を中間体として経由する方法（J.Med.
Chem.,24,743（1981）など参照）、４−Ｏ−有機スル
ホニウムウラシル誘導体を中間体として経由する方法
（特開昭62−89667号公報など参照）、４−ピリジニ
ウム−ピリミジ−２（1H）−オン誘導体を中間体として
経由する方法（Chem.Scr.,26,3（1986）など参照）、
４−（トリアゾ−１−イル）−ピリミジ−２（1H）−オ
ン誘導体を中間体として経由する方法（J.C.S.PerkinI,
1171（1982）など参照、従来法６）、４−（３−メチ
ル−イミダゾ−１−イル）−ピリミジ−２（1H）−オン
誘導体を中間体として経由する方法（Chem.Pharm.Bul
l.,33,2575（1985）など参照、従来法７）などがすでに
報告されている。Examples of a method for producing a cytosine derivative from a uracil derivative necessary for producing cytidine choline diphosphate (CDP choline) or the like include, for example, a method in which a 4-O-trimethylsilyluracil derivative is used as an intermediate (West German Patent No. 212291).
No.), 4-halogeno-pyrimidi-2 (1H)-
Method via an on-derivative as an intermediate (Nucleic acid
Chem., 1 , 223 (1978) etc.), a method using a 4-O-alkyluracil derivative as an intermediate (J. Med.
Chem., 24 , 743 (1981), etc.), a method using a 4-O-organosulfoniumuracil derivative as an intermediate (see JP-A-62-89667, etc.), 4-pyridinium-pyrimidi-2 (1H). ) -One derivative as an intermediate (see Chem. Scr., 26 , 3 (1986), etc.),
A method via a 4- (triazo-1-yl) -pyrimidi-2 (1H) -one derivative as an intermediate (JCSPerkinI,
1171 (1982), etc., conventional method 6), a method via a 4- (3-methyl-imidazo-1-yl) -pyrimidi-2 (1H) -one derivative as an intermediate (Chem.Pharm.Bul.
L., 33 , 2575 (1985), etc., the conventional method 7) etc. have already been reported.
上述の従来法は、満足する収率を得ることができなかっ
たり、特殊な装置、取り扱い困難な試薬または高価な試
薬を必要とし、このため工業的には有利な製造法といえ
なかった。特に従来法６および７は上記従来法の中でも
優れた方法であるが、90％以上の収率で目的化合物を得
ることは困難であった。The above-mentioned conventional methods cannot be said to be industrially advantageous because they cannot obtain a satisfactory yield and require special equipment, difficult-to-handle reagents or expensive reagents. In particular, the conventional methods 6 and 7 are excellent methods among the above conventional methods, but it was difficult to obtain the target compound with a yield of 90% or more.
本発明者は、ウリジン誘導体を原料化合物とするシチジ
ン誘導体の製造方法に関し上記従来法６および７で使用
しているトリアゾールおよび４−メチルイミダゾールに
代え、イミダゾールを使用し検討を重ねた結果、リン酸
化剤存在下、またはリン酸化剤と三級アミンの共存下ウ
ラシル誘導体をイミダゾールと反応させて４−（イミダ
ゾ−１−イル）−ピリミジ−２（1H）−オン誘導体を
得、該化合物をアミノ化反応に付すことにより特殊な装
置を必要とせず、簡便な操作で従来法より高収率でシト
シン誘導体を得ることができることを発見し、本発明を
完成した。The present inventor has conducted extensive studies using imidazole instead of the triazole and 4-methylimidazole used in the above conventional methods 6 and 7 regarding the method for producing a cytidine derivative using a uridine derivative as a starting compound, and as a result, phosphorylation The uracil derivative is reacted with imidazole in the presence of an agent or in the coexistence of a phosphorylating agent and a tertiary amine to obtain a 4- (imidazol-1-yl) -pyrimidi-2 (1H) -one derivative, and the compound is aminated. The present invention was completed by discovering that a cytosine derivative can be obtained in a higher yield than the conventional method by a simple operation without requiring a special device by subjecting it to the reaction.
すなわち、本発明は、一般式〔II〕 〔式中、R1は水素原子、ハロゲン原子またはアルキル
基、R2′は水酸基が保護された糖残基を示す。〕で表わ
されるウラシル誘導体をリン酸化剤の存在下イミダゾー
ルと反応せしめて、一般式〔III〕 〔式中、R1およびR2′は前記と同意義。〕で表わされる
４−（イミダゾ−１−イル）−ピリミジ−２（1H）−オ
ン誘導体を得、次に該化合物をアミノ化反応に付し、一
般式〔Ｉ〕 〔式中、R1は前記と同意義、R2は糖残基を意味する。〕
で表わされるシトシン誘導体を得ることを特徴とするシ
トシン誘導体の製造法に関するものである。That is, the present invention is represented by the general formula [II] [In the formula, R 1 represents a hydrogen atom, a halogen atom or an alkyl group, and R 2 ′ represents a sugar residue in which a hydroxyl group is protected. ] The uracil derivative represented by the formula [III] by reacting with imidazole in the presence of a phosphorylating agent. [In the formula, R 1 and R 2 ′ have the same meanings as described above. ] A 4- (imidazo-1-yl) -pyrimidi-2 (1H) -one derivative represented by the following formula is obtained, and then the compound is subjected to an amination reaction to give a compound of the general formula [I] [In the formula, R 1 has the same meaning as described above, and R 2 means a sugar residue. ]
The present invention relates to a method for producing a cytosine derivative, which comprises obtaining the cytosine derivative represented by
以下、本発明を詳細に説明する。Hereinafter, the present invention will be described in detail.
本発明方法の原料化合物であるウラシル誘導体は前記一
般式〔II〕で表されるものである。式中、R1で表される
ハロゲン原子としては、フッ素、臭素、ヨウ素、塩素な
ど、アルキル基としては、メチル、エチル、プロピル、
ブチルなどの炭素数１〜４の低級アルキル基を挙げるこ
とができ、該アルキル基は水酸基、ハロゲン原子などで
置換されていてもよい。またR2′の水酸基が保護された
糖残基としては、リボフラノシル、デオキシリボフラノ
シル（たとえば、２′−デオキシリボフラノシル、３′
−デオキシリボフラノシル、５′−デオキシリボフラノ
シル、２′,3′−ジデオキシリボフラノシル、２′,3′
−ジデオキシジデヒドロリボフラノシルなど）、アラビ
ノフラノシル、グリコフラノシル、キシロフラノシルな
どの糖残基の水酸基が保護基で保護されているものを挙
げることができる。前記保護基としては一級水酸基およ
び二級水酸基の保護基として常用されているものであれ
ばよく、たとえば、アセチル、プロピオニル、ブチリ
ル、ベンゾイル、トリル、ナフトイルなどのアシル基、
エチリデン、プロピリデン、イソプロピリデンなどのア
ルキリデン基、ベンジル、トリチルなどのアルアルキル
基、ｔ−ブチルジメチルシリル、トリメチルシリルなど
のシリル基、メシル、エタンスルホニル、トシル、トリ
イソプロピルベンゼンスルホニルなどのアリールまたは
アルキルスルホニル基などを挙げることができる。これ
らの保護基のなかでも特に本発明方法のアミノ化反応時
に脱離するアシル基が好ましい。The uracil derivative which is the starting compound for the method of the present invention is represented by the above general formula [II]. In the formula, the halogen atom represented by R 1 is fluorine, bromine, iodine, chlorine or the like, and the alkyl group is methyl, ethyl, propyl,
Examples thereof include lower alkyl groups having 1 to 4 carbon atoms such as butyl, and the alkyl group may be substituted with a hydroxyl group, a halogen atom or the like. Examples of the sugar residue in which the hydroxyl group of R 2 ′ is protected include ribofuranosyl and deoxyribofuranosyl (for example, 2′-deoxyribofuranosyl, 3 ′
-Deoxyribofuranosyl, 5'-deoxyribofuranosyl, 2 ', 3'-dideoxyribofuranosyl, 2', 3 '
-Dideoxydidehydroribofuranosyl), arabinofuranosyl, glycofuranosyl, xylofuranosyl, and the like, and the hydroxyl groups of sugar residues are protected by a protecting group. The protective group may be one commonly used as a protective group for primary and secondary hydroxyl groups, for example, acetyl, propionyl, butyryl, benzoyl, tolyl, acyl groups such as naphthoyl,
Alkylidene groups such as ethylidene, propylidene and isopropylidene, aralkyl groups such as benzyl and trityl, silyl groups such as t-butyldimethylsilyl and trimethylsilyl, aryl or alkylsulfonyl groups such as mesyl, ethanesulfonyl, tosyl and triisopropylbenzenesulfonyl. And so on. Among these protecting groups, an acyl group which is eliminated during the amination reaction of the method of the present invention is particularly preferable.
このような原料化合物を具体的に例示すればウリジン、
５−フルオロ−１−（β−Ｄ−リボフラノシル）ウラシ
ル、５−メチル−１−（β−Ｄ−リボフラノシル）ウラ
シル、１−（２′−デオキシ−β−Ｄ−リボフラノシ
ル）ウラシル、１−（３′−デオキシ−β−Ｄ−リボフ
ラノシル）ウラシル、１−（２′,3′−ジデオキシ−β
−Ｄ−リボフラノシル）ウラシル、１−（２′,3′−ジ
デオキシジデヒドロ−β−Ｄ−リボフラノシル）ウラシ
ル、１−（５′−デオキシ−β−Ｄ−リボフラノシル）
ウラシル、１−β−Ｄ−アラビノフラノシルウラシル、
１−β−Ｄ−キシロフラノシルウラシルなどのウラシル
ヌクレオシド類の水酸基が上記保護基にて保護されてい
る化合物を挙げることができる。A specific example of such a raw material compound is uridine,
5-fluoro-1- (β-D-ribofuranosyl) uracil, 5-methyl-1- (β-D-ribofuranosyl) uracil, 1- (2′-deoxy-β-D-ribofuranosyl) uracil, 1- (3 ′ -Deoxy-β-D-ribofuranosyl) uracil, 1- (2 ′, 3′-dideoxy-β
-D-ribofuranosyl) uracil, 1- (2 ', 3'-dideoxydidehydro-β-D-ribofuranosyl) uracil, 1- (5'-deoxy-β-D-ribofuranosyl)
Uracil, 1-β-D-arabinofuranosyluracil,
Examples thereof include compounds in which the hydroxyl group of uracil nucleosides such as 1-β-D-xylofuranosyluracil is protected by the above protecting group.
本発明方法は上記原料化合物をリン酸化剤の存在下イミ
ダゾールと反応せしめ、４−（イミダゾ−１−イル）−
ピリミジ−２（1H）−オン誘導体を得、これをアミノ化
反応に付し、シトシン誘導体を得る方法である。In the method of the present invention, the above-mentioned starting compound is reacted with imidazole in the presence of a phosphorylating agent to give 4- (imidazol-1-yl)-
This is a method of obtaining a pyrimidi-2 (1H) -one derivative and subjecting this to an amination reaction to obtain a cytosine derivative.
本発明方法に用いることのできるリン酸化剤としては、
下記一般式〔IV〕をもって表すことができ、また、この
リン酸化剤は二種以上を混合して用いてもよい。As the phosphorylating agent that can be used in the method of the present invention,
It can be represented by the following general formula [IV], and two or more kinds of the phosphorylating agents may be mixed and used.
〔式中、R3およびR4はハロゲン原子、アルコキシル基ま
たはフェニロキシル基を示し、R3とR4は同一であって
も、異なっていてもよい。またＸはハロゲン原子を示
す。〕 上記一般式中〔IV〕、R3、R4およびＸのハロゲン原子と
しては、塩素、臭素、フッ素、ヨウ素を挙げることがで
き、特に塩素が好適である。また上記一般式中のR3およ
びR4のアルコキシル基としてはメトキシ、エトキシなど
の炭素数１〜３の低級アルコキシル基を挙げることがで
きる。アルコキシル基およびフェニロキシル基は塩素、
フッ素などのハロゲン原子で置換されていてもよい。こ
のような、リン酸化剤を具体的に例示すれば、ジフェニ
ルリン酸クロリド、ジフェニルリン酸ブロミド、フェニ
ルリン酸ジクロリド、オキシ塩化リン、ジメチルリン酸
クロリド、ジエチルリン酸クロリドなどを挙げることが
できる。これらのリン酸化剤のうちでも特にジフェニル
リン酸クロリドおよびフェニルリン酸ジクロリドが好適
である。 [In the formula, R 3 and R 4 represent a halogen atom, an alkoxyl group or a phenyloxyl group, and R 3 and R 4 may be the same or different. X represents a halogen atom. Examples of the halogen atom represented by [IV], R 3 , R 4 and X in the above general formula include chlorine, bromine, fluorine and iodine, and chlorine is particularly preferable. Examples of the alkoxyl group represented by R 3 and R 4 in the above general formula include lower alkoxyl groups having 1 to 3 carbon atoms such as methoxy and ethoxy. The alkoxyl group and phenyloxyl group are chlorine,
It may be substituted with a halogen atom such as fluorine. Specific examples of such a phosphorylating agent include diphenylphosphoric acid chloride, diphenylphosphoric acid bromide, phenylphosphoric acid dichloride, phosphorus oxychloride, dimethylphosphoric acid chloride and diethylphosphoric acid chloride. Among these phosphorylating agents, diphenylphosphoric acid chloride and phenylphosphoric acid dichloride are particularly preferable.
次に、本発明方法で使用するイミダゾールは、通常試薬
として市販されているものであれば、いずれのものであ
っても本発明方法に使用することができる。Next, any imidazole used in the method of the present invention can be used in the method of the present invention as long as it is commercially available as a reagent.
このようなリン酸化剤およびイミダゾールを用いた本発
明方法における反応は、反応溶媒を用いることなく、ま
たはジオキサン、ジグライム、トリグライム、アセトニ
トリル、アニソール、スルフォランなどの反応溶媒中、
原料化合物１モルに対して、リン酸化剤１〜２モル、好
ましくは１〜1.5モル、イミダゾール１〜５モル、好ま
しくは1.5〜３モルを用いて、反応温度70〜120℃で３〜
46時間反応させることにより実施することができる。The reaction in the method of the present invention using such a phosphorylating agent and imidazole, without using a reaction solvent, or in a reaction solvent such as dioxane, diglyme, triglyme, acetonitrile, anisole, sulfolane,
Using 1 to 2 mol of the phosphorylating agent, preferably 1 to 1.5 mol, and 1 to 5 mol of imidazole, preferably 1.5 to 3 mol, relative to 1 mol of the raw material compound, the reaction temperature is 70 to 120 ° C.
It can be carried out by reacting for 46 hours.
また、副反応生成物の生成を抑制し、最終収率を向上さ
せるために反応液中に三級アミンを添加してもよい。特
に原料化合物として、前記一般式〔II〕で表される化合
物のうちR2′が保護基を有するデオキシリボフラノシル
基で表されるものを使用する場合には、反応液中に三級
アミンを添加するのが好ましい。このような三級アミン
としてはトリアルキルアミン（たとえば、トリエチルア
ミン、トリブチルアミン、ジエチルイソプロピルアミン
など）、芳香族アミン（たとえば、N,N−ジメチルアニ
リン、N,N−ジエチルアニリンなど）などを一種または
二種以上を混合して用いることができる。三級アミンの
使用量は、原料化合物１モルに対して1.5〜４モル好ま
しくは２〜３モルより適宜選定することができる。Further, a tertiary amine may be added to the reaction solution in order to suppress the production of side reaction products and improve the final yield. In particular, when a compound represented by the general formula [II] in which R 2 ′ is a deoxyribofuranosyl group having a protecting group is used as a raw material compound, a tertiary amine is added to the reaction solution. It is preferable to add it. Examples of such tertiary amines include trialkylamines (eg, triethylamine, tributylamine, diethylisopropylamine, etc.), aromatic amines (eg, N, N-dimethylaniline, N, N-diethylaniline, etc.), etc. Two or more kinds can be mixed and used. The amount of the tertiary amine used can be appropriately selected from 1.5 to 4 mol, preferably 2 to 3 mol, per 1 mol of the raw material compound.
このようにして調製した４−（イミダゾ−１−イル）−
ピリミジ−２（1H）−オン誘導体は必要により反応液か
ら単離するか、または単離することなく次のアミノ化反
応に供する。4- (imidazo-1-yl) -prepared in this way
The pyrimidi-2 (1H) -one derivative is, if necessary, isolated from the reaction solution or used for the next amination reaction without isolation.
アミノ化反応は常法に従って行えばよく、たとえばガス
状または液体状のアンモニアまたはアンモニア水を用い
て、該アンモニアを過剰量反応液に加え反応させる。ア
ミノ化反応は反応温度０〜150℃で0.5〜24時間反応させ
ることにより実施することができる。The amination reaction may be carried out according to a conventional method, for example, using gaseous or liquid ammonia or aqueous ammonia, and adding an excess amount of the ammonia to the reaction liquid to carry out the reaction. The amination reaction can be carried out by reacting at a reaction temperature of 0 to 150 ° C. for 0.5 to 24 hours.
このようにして調製したシトシン誘導体は、必要により
糖部水酸基の保護基を常法（たとえば、加水分解、接触
還元など）により除去し、ヌクレオシドの通常の単離精
製法（たとえば、再結晶、吸着またはイオン交換クロマ
トグラフィー法など）にて単離精製することができる。If necessary, the cytosine derivative thus prepared has the protecting group for the sugar group hydroxyl group removed by a conventional method (eg, hydrolysis, catalytic reduction, etc.), and the usual nucleoside isolation and purification method (eg, recrystallization, adsorption). Alternatively, it can be isolated and purified by an ion exchange chromatography method or the like).
本発明方法は、リン酸化剤の存在下、イミダゾールを用
いてウラシル誘導体を４−（イミダゾ−１−イル）−ピ
リミジ−２（1H）−オン誘導体へ変換し、これを常法の
アミノ化反応に付し、シトシン誘導体を調製する方法に
関するものである。このような極めて簡便な方法により
従来法６（収率約80％）および従来法７（収率約60％）
より収率よくかつ、中間体である４−（イミダゾ−１−
イル）−ピリミジ−２（1H）−オン誘導体を単離するこ
となく一つの反応器内でシトシン誘導体を調製すること
ができる。In the method of the present invention, a uracil derivative is converted to a 4- (imidazo-1-yl) -pyrimidi-2 (1H) -one derivative using imidazole in the presence of a phosphorylating agent, and this is converted into a conventional amination reaction. And a method for preparing a cytosine derivative. Conventional method 6 (yield approx. 80%) and conventional method 7 (yield approx. 60%) by such an extremely simple method
4- (imidazo-1-
The cytosine derivative can be prepared in one reactor without isolation of the yl) -pyrimidi-2 (1H) -one derivative.
また、反応液中に三級アミンを共存させることによりリ
ン酸化剤とイミダゾールだけを用いた場合より更に収率
が向上し、最終製品収率を90％以上にすることができ
る。特に従来副生成物が大量に生成するなどの問題の多
いデオキシリボフラノシルウラシル誘導体を原料化合物
として使用しても副反応生成物の生成を抑制し、90％以
上の高収率でデオキシリボフラノシルシトシン誘導体を
製造することが可能となった。In addition, the coexistence of a tertiary amine in the reaction solution further improves the yield as compared with the case where only the phosphorylating agent and imidazole are used, and the final product yield can be 90% or more. In particular, even when a deoxyribofuranosyluracil derivative, which has been problematic in that a large amount of by-products are conventionally generated, is used as a starting material compound, it suppresses the formation of side reaction products and produces deoxyribofuranosylcytosine in a high yield of 90% or more. It has become possible to produce derivatives.
以下、実施例を示し、本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described with reference to examples.
実施例１ ２′−デオキシウリジン−ジアセテート31.2gをイミダ
ゾール10.21g、トリエチルアミン41.84ml、ジフェニル
リン酸クロライド31.05mlに加え、90℃１日撹拌反応さ
せた。室温に戻し、濃アンモニア水120mlを加え一夜反
応させた後、減圧下濃縮した。Example 1 31.2 g of 2'-deoxyuridine-diacetate was added to 10.21 g of imidazole, 41.84 ml of triethylamine and 31.05 ml of diphenylphosphoric acid chloride, and the mixture was reacted with stirring at 90 ° C for 1 day. The mixture was returned to room temperature, 120 ml of concentrated aqueous ammonia was added and reacted overnight, and then concentrated under reduced pressure.
得られたシロップ状残渣をエタノール200mlに溶解さ
せ、これに濃塩酸12.5mlを加え、冷蔵庫中一夜放置し、
生じた結晶を濾取し、少量のエタノールで洗い、減圧下
60℃で乾燥し、２′−デオキシシチジン塩酸塩24.74g
（収率93％）を得た。The obtained syrup-like residue was dissolved in 200 ml of ethanol, 12.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was left overnight in the refrigerator,
The crystals that formed are collected by filtration, washed with a small amount of ethanol, and concentrated under reduced pressure.
Dried at 60 ℃, 2'-deoxycytidine hydrochloride 24.74g
(Yield 93%) was obtained.
実施例２ ２′−デオキシウリジン−ジアセテート31.2gをイミダ
ゾール27.23g、ジフェニルリン酸クロライド31.05mlに
加え、90℃１日撹拌反応させた。室温に戻し、濃アンモ
ニア水120mlを加え一夜反応させた後、減圧下濃縮し
た。Example 2 31.2 g of 2'-deoxyuridine-diacetate was added to 27.23 g of imidazole and 31.05 ml of diphenylphosphoric acid chloride, and the mixture was reacted with stirring at 90 ° C for 1 day. The mixture was returned to room temperature, 120 ml of concentrated aqueous ammonia was added and reacted overnight, and then concentrated under reduced pressure.
得られたシロップ状残渣をエタノール200mlに溶解さ
せ、これに濃塩酸12.5mlを加え、冷蔵庫中一夜放置し、
生じた結晶を濾取し、少量のエタノールで洗い、減圧下
60℃で乾燥し、２′−デオキシシチジン塩酸塩19.95g
（収率75％）を得た。The obtained syrup-like residue was dissolved in 200 ml of ethanol, 12.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was left overnight in the refrigerator,
The resulting crystals are collected by filtration, washed with a small amount of ethanol, and then under reduced pressure.
Dried at 60 ℃, 2'-deoxycytidine hydrochloride 19.95g
(Yield 75%) was obtained.
実施例３ １−（２′,3′,5′−Ｏ−トリアセチル−β−Ｄ−アラ
ビノフラノシル）ウラシル37.0gをイミダゾール20.42
g、ジフェニルリン酸クロライド31.05mlに加え、90℃１
日撹拌反応させた。室温に戻し、濃アンモニア水120ml
を加えて一夜反応させた後、減圧下濃縮した。Example 3 37.0 g of 1- (2 ′, 3 ′, 5′-O-triacetyl-β-D-arabinofuranosyl) uracil was replaced with imidazole 20.42.
g, add to 31.05 ml of diphenyl phosphoryl chloride, 90 ℃ 1
The reaction was allowed to stir for one day. Return to room temperature, 120 ml of concentrated ammonia water
Was added and reacted overnight, and then concentrated under reduced pressure.
得られたシロップ状残渣をエタノール200mlに溶解さ
せ、これに濃塩酸12.5mlを加え、冷蔵庫中一夜放置し、
生じた結晶を濾取し、少量のエタノールで洗い、減圧下
60℃で乾燥し、１−（β−Ｄ−アラビノフラノシル）シ
トシン塩酸塩24.0g（収率85％）を得た。The obtained syrup-like residue was dissolved in 200 ml of ethanol, 12.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was left overnight in the refrigerator,
The crystals that formed are collected by filtration, washed with a small amount of ethanol, and concentrated under reduced pressure.
After drying at 60 ° C., 24.0 g (yield 85%) of 1- (β-D-arabinofuranosyl) cytosine hydrochloride was obtained.
実施例４ １−（２′,3′,5′−Ｏ−トリアセチル−β−Ｄ−アラ
ビノフラノシル）ウラシル37.0gをイミダゾール10.21
g、トリエチルアミン41.84ml、ジフェニルリン酸クロラ
イド31.05mlに加え、90℃１日撹拌反応させた。室温に
戻し、濃アンモニア水120mlを加えて一夜反応させた
後、減圧下濃縮した。Example 4 37.0 g of 1- (2 ′, 3 ′, 5′-O-triacetyl-β-D-arabinofuranosyl) uracil was replaced with imidazole 10.21.
g, triethylamine 41.84 ml, and diphenylphosphoric acid chloride 31.05 ml, and the mixture was reacted with stirring at 90 ° C. for 1 day. The mixture was returned to room temperature, 120 ml of concentrated aqueous ammonia was added and reacted overnight, and then concentrated under reduced pressure.
得られたシロップ状残渣をエタノール200mlに溶解さ
せ、これに濃塩酸12.5mlを加え、冷蔵庫中一夜放置し、
生じた結晶を濾取し、少量のエタノールで洗い減圧下60
℃で乾燥し、１−（β−Ｄ−アラビノフラノシル）シト
シン塩酸塩25.97g（収率92％）を得た。The obtained syrup-like residue was dissolved in 200 ml of ethanol, 12.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was left overnight in the refrigerator,
The crystals that formed are collected by filtration, washed with a small amount of ethanol, and concentrated under reduced pressure.
After drying at ° C, 25.97 g (yield 92%) of 1- (β-D-arabinofuranosyl) cytosine hydrochloride was obtained.
実施例５ １−（２′,3′,5′−Ｏ−トリアセチル−β−Ｄ−リボ
フラノシル）ウラシル37.0gをイミダゾール10.21g、ト
リエチルアミン41.84ml、ジフェニルリン酸クロライド3
1.05mlに加え、90℃１日撹拌反応させた。室温に戻し、
濃アンモニア水120mlを加えて一夜反応させた後、減圧
下濃縮した。Example 5 1- (2 ′, 3 ′, 5′-O-triacetyl-β-D-ribofuranosyl) uracil 37.0 g was added with imidazole 10.21 g, triethylamine 41.84 ml and diphenylphosphoric acid chloride 3.
The mixture was added to 1.05 ml and reacted with stirring at 90 ° C for 1 day. Return to room temperature,
After 120 ml of concentrated aqueous ammonia was added and the mixture was reacted overnight, it was concentrated under reduced pressure.
得られたシロップ状残渣をエタノール200mlに溶解さ
せ、これに濃塩酸12.5mlを加え、冷蔵庫中一夜放置し、
生じた結晶を濾取し、少量のエタノールで洗い減圧下60
℃で乾燥し、シチジン塩酸塩26.82g（収率95％）を得
た。The obtained syrup-like residue was dissolved in 200 ml of ethanol, 12.5 ml of concentrated hydrochloric acid was added thereto, and the mixture was left overnight in the refrigerator,
The crystals that formed are collected by filtration, washed with a small amount of ethanol, and concentrated under reduced pressure.
After drying at ℃, 26.82 g (yield 95%) of cytidine hydrochloride was obtained.
実施例６ ジフェニルリン酸クロライドに代え、フェニルリン酸ジ
クロライド27mlを用いて実施例５と同様に処理し、シチ
ジン塩酸塩25.69g（92％）を得た。Example 6 The same procedure as in Example 5 was carried out using 27 ml of phenylphosphoric acid dichloride instead of diphenylphosphoric acid chloride to obtain 25.69 g (92%) of cytidine hydrochloride.
実施例７ ５′−Ｏ−アセチル−２′,3′−ジデオキシウリジン2
8.6gをイミダゾール13.6g、N,N−ジエチルアミノアニリ
ン48ml、ジフェニルリン酸クロライド31.05mlに加え
て、90℃で１日撹拌反応させた。Example 7 5'-O-acetyl-2 ', 3'-dideoxyuridine 2
8.6 g was added to 13.6 g of imidazole, 48 ml of N, N-diethylaminoaniline, and 31.05 ml of diphenylphosphoric acid chloride, and the mixture was reacted with stirring at 90 ° C for 1 day.
室温に戻し、濃アンモニア水240mlを加えて１日反応さ
せた後、減圧下濃縮した。The mixture was returned to room temperature, 240 ml of concentrated aqueous ammonia was added, and the mixture was reacted for 1 day, then concentrated under reduced pressure.
得られたシロップ状残渣をエタノール100mlに溶解させ
た後、濃塩酸を加え約pH2とし、冷蔵庫中一夜放置し生
じた結晶を濾取し、２′,3′−ジデオキシシチジン塩酸
塩22.53g（収率90％）を得た。The obtained syrup-like residue was dissolved in 100 ml of ethanol, concentrated hydrochloric acid was added to about pH 2, the mixture was left in a refrigerator overnight, and the resulting crystals were collected by filtration. 2 ', 3'-dideoxycytidine hydrochloride 90%).
実施例８ 実施例７中のN,N−ジエチルアミノアニリン48mlをトリ
エチルアミン41.84mlに代え、同様に処理し、２′,3′
−ジデオキシシチジン塩酸塩23g（収率92％）を得た。Example 8 In the same manner as in Example 7, except that 48 ml of N, N-diethylaminoaniline was replaced with 41.84 ml of triethylamine and treated in the same manner, 2 ′, 3 ′
23 g of dideoxycytidine hydrochloride (92% yield) were obtained.
Claims (2)
基、R2′は水酸基が保護された糖残基を示す。）で表わ
されるウラシル誘導体をリン酸化剤の存在下イミダゾー
ルと反応せしめて、一般式〔III〕 （式中、R1およびR2′は前記と同意義。）で表わされる
４−（イミダゾ−１−イル）−ピリミジ−２（1H）−オ
ン誘導体を得、次に該化合物をアミノ化反応に付し、一
般式〔Ｉ〕 （式中、R1は前記と同意義、R2は糖残基を示す。）で表
わされるシトシン誘導体を取得することを特徴とするシ
トシン誘導体の製造法。1. General formula [II] (In the formula, R 1 represents a hydrogen atom, a halogen atom or an alkyl group, and R 2 ′ represents a sugar residue in which a hydroxyl group is protected.), And a uracil derivative represented by General formula (III) (In the formula, R 1 and R 2 ′ have the same meanings as described above.) A 4- (imidazo-1-yl) -pyrimidi-2 (1H) -one derivative is obtained, and then the compound is subjected to an amination reaction. Attached to the general formula [I] (In the formula, R 1 has the same meaning as described above, and R 2 represents a sugar residue.) A method for producing a cytosine derivative, characterized in that the cytosine derivative is obtained.
とイミダゾールとの反応をリン酸化剤及び三級アミンの
存在下で行う、特許請求の範囲第１項記載のシトシン誘
導体の製造法。2. The process for producing a cytosine derivative according to claim 1, wherein the reaction of the uracil derivative represented by the general formula [II] with imidazole is carried out in the presence of a phosphorylating agent and a tertiary amine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30288987A JPH07103149B2 (en) | 1987-11-30 | 1987-11-30 | Method for producing cytosine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30288987A JPH07103149B2 (en) | 1987-11-30 | 1987-11-30 | Method for producing cytosine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01143892A JPH01143892A (en) | 1989-06-06 |
| JPH07103149B2 true JPH07103149B2 (en) | 1995-11-08 |
Family
ID=17914321
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30288987A Expired - Fee Related JPH07103149B2 (en) | 1987-11-30 | 1987-11-30 | Method for producing cytosine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07103149B2 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5627160A (en) * | 1993-05-25 | 1997-05-06 | Yale University | L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents |
| TW374087B (en) * | 1993-05-25 | 1999-11-11 | Univ Yale | L-2',3'-dideoxy nucleotide analogs as anti-hepatitis B(HBV) and anti-HIV agents |
| US5869461A (en) * | 1995-03-16 | 1999-02-09 | Yale University | Reducing toxicity of L-nucleosides with D-nucleosides |
| IT1277425B1 (en) | 1995-08-03 | 1997-11-10 | Pro Bio Sint Srl | METHOD FOR THE PREPARATION OF 1-B-D-ARABINOFURANOSILCITOSINA |
| EP1186612B1 (en) | 2000-04-13 | 2006-11-29 | Mitsui Chemicals, Inc. | Process for the preparation of cytidine derivatives |
| EP2102221B1 (en) * | 2006-12-11 | 2010-08-18 | F. Hoffmann-La Roche AG | Process for preparation of 4'-azido cytidine derivatives |
-
1987
- 1987-11-30 JP JP30288987A patent/JPH07103149B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01143892A (en) | 1989-06-06 |
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