JPH0560477B2 - - Google Patents
Info
- Publication number
- JPH0560477B2 JPH0560477B2 JP4916485A JP4916485A JPH0560477B2 JP H0560477 B2 JPH0560477 B2 JP H0560477B2 JP 4916485 A JP4916485 A JP 4916485A JP 4916485 A JP4916485 A JP 4916485A JP H0560477 B2 JPH0560477 B2 JP H0560477B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- anomer
- nucleoside
- compound
- lower alkyl
- 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
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 description 23
- -1 nucleoside compound Chemical class 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 description 6
- LVTNUSALLLYISD-KQYNXXCUSA-N 2-amino-7-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-oxo-1h-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid Chemical compound C1=C(C(O)=O)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O LVTNUSALLLYISD-KQYNXXCUSA-N 0.000 description 5
- QQXQGKSPIMGUIZ-AEZJAUAXSA-N queuosine Chemical compound C1=2C(=O)NC(N)=NC=2N([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)C=C1CN[C@H]1C=C[C@H](O)[C@@H]1O QQXQGKSPIMGUIZ-AEZJAUAXSA-N 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 150000000845 D-ribose derivatives Chemical class 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 108020004566 Transfer RNA Proteins 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 108020005098 Anticodon Proteins 0.000 description 1
- NHOWRHZUBSBNOX-UHFFFAOYSA-N COCN1C(=NC2=C(C1=O)C(=CN2)C)SC Chemical compound COCN1C(=NC2=C(C1=O)C(=CN2)C)SC NHOWRHZUBSBNOX-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000005515 coenzyme Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明はプリン誘導体とＤ−リボース誘導体と
を縮合反応しヌクレオシド化合物を製造する方法
に関する。
（従来の技術）
ヌクレオシド化合物はリボ核酸の構成成分であ
る以外に、補酵素や抗生物質としてその有用性が
認められている。例えば、特定tRNAに存在し、
アンチコドンの第一番目に位置しヌクレオシドＱ
と呼ばれている修飾ヌクレオシドは、その制癌作
用が期待されている。又、ストレプトミセス・ヒ
グロスコピクスの一菌株が生産するカデグオマイ
シン（特開昭58−92693号公報）も抗腫瘍ヌクレ
オシド化合物の一つとして注目されている。しか
し、これらヌクレオシド化合物は天然には極微量
しか存在せず。大量に製造する方法が望まれてお
り、例えば、ヌクレオシドＱとカデグオマイシン
の合成法が「T.Ohgiet al.，J.Am.Chem.Soc.，
101，3629（1979）」、「T.Kondo et al.，
Tetrahedron Letters，24（34），3647（1983）」
等に発表されている。
又、一般的なヌクレオシドの合成法は、多くの
出版物に収載されている（例えば、高木康敬他
「核酸」，（昭45.4.30）、朝倉書店、73頁−78頁
等）。
（発明が解決しようとする問題点）
本発明は、ヌクレオシド化合物を効率よく製造
する方法を提供することを課題とする。
（問題点を解決するための手段）
本発明者らはヌクレオシド化合物の合成法につ
いて研究するうち、プリン誘導体とＤ−リボース
誘導体とを縮合反応しヌクレオシド化合物を製造
する方法、特にβ−アノマー体ヌクレオシドを選
択的に製造する方法を見出し、本発明を完成し
た。
本発明は、一般式（）
（式中、R1はアルコキシアルキル基、R2は水素、
低級アルキル基、アルキルチオ基、R3は水素、
低級アルキル基を表す）で表される化合物と、
一般式（）
（式中、R4はアシル基、アルアルキル基を表
す）で表される化合物とを反応させて、
一般式（）
（式中、R1はアルコキシアルキル基、R2は水
素、低級アルキル基、アルキルチオ基、R3は水
素、低級アルキル基、R4はアシル基、アルアル
キル基を表す。又、破線はα及びβの両アノマー
体を含むことを表す）で表されるヌクレオシド化
合物を製造する方法である。
上記の一般式において、R1はメトキシメチル、
エトキシメチル、メトキシエチル、エトキシエチ
ル基等のアルコキシアルキル基を表し、R2は水
素、低級アルキル基又は後にアミノ基に変換する
場合にはメチルチオ基等のアルキルチオ基を表
し，R3は水素若しくは低級アルキル基、好まし
くはメチル基、R4は一般のヌクレオシド化学に
おいて使用されている任意の保護基、例えば、ア
セチル、ベンゾイル基等のアシル基又はトリチ
ル、ベンジル基等のアルアルキル基、好ましくは
トリチル基を表す。
上記反応は、水素化アルキル金属等の強塩基、
好ましくは水素化ナトリウム存在下、陰イオン性
複素環化合物を可溶化する極性溶媒、例えばジメ
チルホルムアミド中、室温にて１乃至数時間行う
ことで目的を達せられる。
一般式（）で表されるクロル化糖は、「R.S.
Klein et al.，J.Carbohydrates，Nucleosides，
Nucleotides，１，265（1974）」の方法に従つて
Ｄ−（−）−リボースから容易に合成でき、そのク
ロル基はβ配位である。上記の縮合反応はSN２
型反応で進むと考えられており、従つて、反応生
成物のヌクレオシドはα−アノマー体が優先的に
生成する。
しかし、ヌクレオシドＱやカデグオマイシン等
の天然のヌクレオシド化合物はβ−アノマー体で
あるので、かかる化合物の製造上はヌクレオシド
化合物合成中間体のβアノマー体が必要である。
本発明は上記反応系中にハロゲン塩を共存さ
せ、一般式（）で表される化合物のハロゲンを
反転させることにより、生成するヌクレオシド化
合物のα／β−アノマー体比を調節する一般式
（）で表されるヌクレオシド化合物の製造方法
である。
本発明製造方法によつて生成したα，β−アノ
マー混合体はシリカゲルクロマトグラフイーや
HPLC等の通常の方法によつてα体とβ体への分
離が可能な場合と、分離が困難な場合がある。分
離困難な場合は通常用いられている方法により、
置換基を脱離若しくは変換することにより目的を
達することができる。例えば、３，４−ジヒドロ
−３−メトキシメチル−５−メチル−２−メチル
チオ−７−（２，３−Ｏ−イソプロピリデン−５
−Ｏ−トリフエニルメチル−Ｄ−リボフラノシ
ル）−7H−ピロロ〔２，３−ｄ〕ピリミジン−４
−オンは、２位のメチルチオ基をアセチルアミノ
化し、糖部分の脱トリチル化を行つた後、シリカ
ゲルカラムクロマトグラフイーにより容易に分離
できる。
（実施例）
以下に、実施例により本発明製造方法の一例を
示す。尚、下記実施例中の化合物は、蒸溜、クロ
マトグラフイー、再結晶等の通常の手段により精
製し、融点測定、IR，NMR，UV、マススペク
トル、旋光度等により同定を行つた。
実施例 １
臭化ナトリウム7.0ｇを減圧下乾燥後、これに
4.2ｇの３，４−ジヒドロ−３−メトキシメチル
−５−メチル−２−メチルチオ−7H−ピロロ
〔２，３−ｄ〕ピリミジン−４−オン（化合物
１）、12.0ｇの２，３−Ｏ−イソプロピリデン−
５−Ｏ−トリフエニルメチル−β−Ｄ−リボフラ
ノシル塩化物（化合物２）及び水素化ナトリウム
1.1ｇを加え、再び乾燥し窒素置換した。次に、
乾燥ジメチルホルムアミド60mlを加え、室温下数
時間攪拌後、反応混合物を氷水中に注ぎ酢酸エチ
ルで抽出した。有機層を水、飽和塩化ナトリウム
水で洗い、無水硫酸ナトリウム上で乾燥後、減圧
下溶媒を留去し粗生成物を得た。これをシリカゲ
ルカラムで精製して9.5ｇの３，４−ジヒドロ−
３−メトキシメチル−５−メチル−２−メチルチ
オ−７−（２，３−Ｏ−イソプロピリデン−５−
Ｏ−トリフエニルメチル−Ｄ−リボフラノシル）
−7H−ピロロ〔２，３−ｄ〕ピリミジン−４−
オン（化合物３）を得た。（収率81％）
UV（MeOH）：λmax＝307nm
λmax＝271nm
IR（Neat），（α／β＝1/2：2925，1690，
1517，1448，1206，1097，782，760，703
cm-1
NMR（CDCl3），（α／β＝1/2）：
δ＝1.36（ｓ，3H），1.62（ｓ，3H），1.94
（ｓ，3H），2.27（ｄ，3H，Ｊ＝1.0Hz），
2.44（ｄ，3H，Ｊ＝1.0Hz），2.53（ｄ，
3H），3.15（dd，1H，J1＝2.4Hz，J2＝10.3
Hz），3.33（dd，1H，J1＝2.4Hz，J2＝10.5
Hz），3.35（dd，1H，J1＝2.4Hz，J2＝10.5
Hz），3.44（ｓ，3H），3.45（ｓ，3H），3.62
（dd，1H，J1＝2.2Hz，J2＝10.3Hz），4.3−
4.4（ｍ，1H），4.84（dd，1H，J1＝3.2Hz，
J2＝6.4Hz），4.95（ｄ，1H，Ｊ＝6.1Hz），
5.0−5.1（ｍ，1H），5.56and5.58
（ABquartet，2H，Ｊ＝12.0Hz），6.26（ｄ，
1H，Ｊ＝3.4Hz），6.60（ｄ，1H，Ｊ＝1.0
Hz），6.97（ｄ，1H，Ｊ＝1.0Hz），7.08（ｄ，
1H，Ｊ＝3.9Hz），7.1−7.6（ｍ，15H）EI
Mass：ｍ／z653（M+）
実施例 ２
上記実施例１で得られた化合物３の置換基を以
下の方法で変換して、α−アノマー体とβ−アノ
マー体に分離した。
化合物３を6.4ｇ乾燥後、アセトアミド32ｇと
水素化ナトリウム3.2ｇを加え窒素置換した。油
浴中135℃で2.5時間攪拌し、減圧下アセトアミド
を留去し残査に氷を加え、塩化アンモニウムで中
和後ベンゼンで抽出した。ベンゼン層を水、飽和
塩化ナトリウムで洗浄後、無水硫酸ナトリウム上
で乾燥し溶媒を留去した。生成物をシリカゲルカ
ラムで精製した後、塩化メチレンに溶かした。冷
却後、冷臭化水素ガスの塩化メチレン溶液330ml
を加え10分間攪拌した。更に室温で20分間攪拌し
た後、飽和炭酸水素ナトリウム水を加え、有機層
を無水硫酸ナトリウム上で乾燥し溶媒を留去し
た。得られた粗生成物をシリカゲルカラムで精製
し、ｎ−ヘキサン・ベンゼンより再結晶して白色
針状結晶の５−アセチルアミノ−３，４−ジヒド
ロ−３−メトキシメチル−５−メチル−７−（２，
３−Ｏ−イソプロピリデン−Ｄ−リボフラノシ
ル）−7H−ピロロ〔２，３−ｄ〕ピリミジン−４
−オンのβ−アノマー体1.48ｇ及びα−アノマー
体0.85ｇを得た。（収率：β−アノマー体44％，
α−アノマー体25％）
融点：α−アノマー体；145−147℃
β−アノマー体；182−184℃
UV（MeOH）：α−アノマー体； λmax＝304nm
λmax＝207nm
β−アノマー体； λmax＝302nm
λmax＝208nm
IR（KBr）：α−アノマー体；3440，3300，1693，
1675，1588，1293，1110，1069，854，770
cm-1
β−アノマー体；3478，3299，1702，
1661，1590，1302，1109，1070，852，725
cm-1
NMR（CDCl3）：α−アノマー体；δ＝1.32（ｓ，
3H），1.51（ｓ，3H），1.7（br.s，1H），
2.38（ｄ，3H，Ｊ＝1.5Hz），2.42（ｓ，
3H），3.42（ｓ，3H），3.7−3.9（ｍ，2H），
4.3−4.4（ｍ，1H），4.7−5.0（ｍ，2H），
5.51（br.s，2H），6.48（ｄ，1H，Ｊ＝7.5
Hz），6.88（ｄ，1H，Ｊ＝1.5Hz），8.39（br.
s，1H），
β−アノマー体；δ＝1.37（ｓ，3H），1.60（ｓ，
3H），2.36（ｄ，3H，Ｊ＝1.0Hz），2.37
（ｓ，3H），3.20（br.s，1H），3.45（ｓ，
3H），3.7−3.95（ｍ，2H），4.30（ｑ，1H，
Ｊ＝3.0Hz），5.06（dd，1H，J1＝2.4Hz，J2
＝6.5Hz），5.15（dd，1H，J1＝3.6Hz，J2＝
6.5Hz），5.46and5.61（ABquartet，2H，Ｊ
＝11.0Hz），5.84（ｄ，1H，Ｊ＝3.6Hz），
6.63（ｄ，1H，Ｊ＝1.0Hz），8.38（br.s，
1H）
〔α〕D：
α−アノマー体；〔α11 D＝−71.3°（Ｃ＝0.11，
CHCl3）
β−アノマー体；〔α26 D＝−30.5°（Ｃ＝0.20，
CHCl3）EI Mass：ｍ／z422（M+）
本発明製造方法は、反応系中にハロゲン塩を共
存させ、クロル化糖のβ位のハロゲンを反転させ
α／β−アノマー体比を調節しうる点に特徴を有
するものであるが、表１に、本発明製造方法によ
るヌクレオシド化合物のα／β−アノマー体生成
比の変化、即ち、化合物１と化合物２とをジメチ
ルホルムアミド中、水素化ナトリウム存在下縮合
反応させ、生成した化合物(3)のα／β−アノマー
体比を調べた結果の一例を示す。
【表】
（発明の効果）
以上の実験結果より明らかなように、本発明製
造方法は生成する化合物３のα／β−アノマー体
比を調節することが可能で、特に、β−アノマー
体ヌクレオシドを選択的に製造したい場合に有用
である。即ち、従来の方法では3/1であつたα／
β−アノマー体比が本発明によれば、例えば臭化
ナトリウムを共存させることにより1/2にするこ
とができる等の著しい効果を有するものである。
従つて、本製造方法によりβ−アノマー体ヌクレ
オシド合成中間体を、従来方法の約2.5倍の収量
で得ることができ、ヌクレオシドＱやカデグオマ
イシン等を合成するに有用なヌクレオシド合成中
間体を選択的に高収率で得ることが可能になる。
又、前記一般式（）で表される化合物は、ヌ
クレオシドＱやカデグオマイシンのみならず、他
の多くのヌクレオシド化合物を製造する際の合成
中間体として用いることが可能であり、本発明は
様々なヌクレオシド化合物、特にそのβ−アノマ
ー体を製造する方法として非常に有用である。 DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a method for producing a nucleoside compound by condensing a purine derivative and a D-ribose derivative. (Prior Art) In addition to being a component of ribonucleic acid, nucleoside compounds are recognized to be useful as coenzymes and antibiotics. For example, present in a specific tRNA,
Nucleoside Q located at the first position of the anticodon
The modified nucleoside, called ``Nucleoside,'' is expected to have anticancer effects. Cadeguomycin (Japanese Unexamined Patent Publication No. 1982-92693) produced by a strain of Streptomyces hygroscopicus has also attracted attention as an antitumor nucleoside compound. However, these nucleoside compounds exist in extremely small amounts in nature. A method for producing large quantities is desired, and for example, a method for synthesizing nucleoside Q and cadeguomycin has been proposed by T. Ohgie et al., J. Am. Chem. Soc.
101, 3629 (1979),” T. Kondo et al.
Tetrahedron Letters, 24 (34), 3647 (1983).
etc. has been published. Further, general methods for synthesizing nucleosides are described in many publications (for example, Yasutaka Takagi et al., "Nucleic Acids", (April 30, 1972), Asakura Shoten, pp. 73-78, etc.). (Problems to be Solved by the Invention) An object of the present invention is to provide a method for efficiently producing a nucleoside compound. (Means for Solving the Problems) While researching methods for synthesizing nucleoside compounds, the present inventors discovered a method for producing nucleoside compounds by condensation reaction of purine derivatives and D-ribose derivatives, particularly for β-anomeric nucleosides. We have discovered a method for selectively producing , and completed the present invention. The present invention is based on the general formula () (In the formula, R 1 is an alkoxyalkyl group, R 2 is hydrogen,
Lower alkyl group, alkylthio group, R 3 is hydrogen,
(represents a lower alkyl group) and a compound represented by the general formula () (In the formula, R 4 represents an acyl group or an aralkyl group) by reacting with a compound represented by the general formula () (In the formula, R 1 represents an alkoxyalkyl group, R 2 represents hydrogen, a lower alkyl group, or an alkylthio group, R 3 represents hydrogen, a lower alkyl group, and R 4 represents an acyl group or an aralkyl group. This is a method for producing a nucleoside compound represented by (indicating that it contains both anomer forms of β). In the above general formula, R 1 is methoxymethyl,
Represents an alkoxyalkyl group such as ethoxymethyl, methoxyethyl, or ethoxyethyl group, R 2 represents hydrogen, a lower alkyl group, or an alkylthio group such as a methylthio group when later converted to an amino group, and R 3 represents hydrogen or a lower alkyl group. an alkyl group, preferably a methyl group, R 4 is any protecting group used in general nucleoside chemistry, such as an acyl group such as acetyl or benzoyl group or an aralkyl group such as trityl or benzyl group, preferably a trityl group represents. The above reaction requires a strong base such as an alkyl metal hydride,
This objective can be achieved by carrying out the reaction preferably in the presence of sodium hydride in a polar solvent that solubilizes the anionic heterocyclic compound, such as dimethylformamide, at room temperature for one to several hours. The chlorinated sugar represented by the general formula () is “RS
Klein et al., J. Carbohydrates, Nucleosides,
It can be easily synthesized from D-(-)-ribose according to the method of Nucleotides, 1 , 265 (1974), and its chlor group is in the β-coordination. The above condensation reaction is S N 2
It is thought that the reaction proceeds as a type reaction, and therefore, the α-anomer form of the reaction product nucleoside is preferentially produced. However, since natural nucleoside compounds such as nucleoside Q and cadeguomycin are β-anomeric forms, the β-anomeric form of a nucleoside compound synthesis intermediate is required for the production of such compounds. The present invention utilizes the general formula () to control the α/β-anomer ratio of the produced nucleoside compound by coexisting a halogen salt in the reaction system and inverting the halogen of the compound represented by the general formula (). This is a method for producing a nucleoside compound represented by The α,β-anomer mixture produced by the production method of the present invention can be analyzed by silica gel chromatography or
There are cases where it is possible to separate the α-form and β-form by conventional methods such as HPLC, and there are cases where separation is difficult. If separation is difficult, use commonly used methods.
The objective can be achieved by eliminating or converting substituents. For example, 3,4-dihydro-3-methoxymethyl-5-methyl-2-methylthio-7-(2,3-O-isopropylidene-5
-O-triphenylmethyl-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4
-one can be easily separated by silica gel column chromatography after acetylaminating the 2-position methylthio group and detritylating the sugar moiety. (Example) An example of the manufacturing method of the present invention will be shown below by way of Example. The compounds in the following Examples were purified by conventional means such as distillation, chromatography, and recrystallization, and identified by melting point measurement, IR, NMR, UV, mass spectra, optical rotation, etc. Example 1 After drying 7.0 g of sodium bromide under reduced pressure,
4.2 g of 3,4-dihydro-3-methoxymethyl-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4-one (compound 1), 12.0 g of 2,3-O -isopropylidene-
5-O-triphenylmethyl-β-D-ribofuranosyl chloride (compound 2) and sodium hydride
1.1 g was added, and the mixture was dried again and replaced with nitrogen. next,
After adding 60 ml of dry dimethylformamide and stirring at room temperature for several hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was purified using a silica gel column and 9.5 g of 3,4-dihydro-
3-methoxymethyl-5-methyl-2-methylthio-7-(2,3-O-isopropylidene-5-
O-triphenylmethyl-D-ribofuranosyl)
-7H-pyrrolo[2,3-d]pyrimidine-4-
(Compound 3) was obtained. (Yield 81%) UV (MeOH): λmax = 307nm λmax = 271nm IR (Neat), (α/β = 1/2: 2925, 1690,
1517, 1448, 1206, 1097, 782, 760, 703
cm -1 NMR (CDCl 3 ), (α/β = 1/2): δ = 1.36 (s, 3H), 1.62 (s, 3H), 1.94
(s, 3H), 2.27 (d, 3H, J=1.0Hz),
2.44 (d, 3H, J=1.0Hz), 2.53 (d,
3H), 3.15 (dd, 1H, J 1 = 2.4Hz, J 2 = 10.3
Hz), 3.33 (dd, 1H, J 1 = 2.4Hz, J 2 = 10.5
Hz), 3.35 (dd, 1H, J 1 = 2.4Hz, J 2 = 10.5
Hz), 3.44 (s, 3H), 3.45 (s, 3H), 3.62
(dd, 1H, J 1 = 2.2Hz, J 2 = 10.3Hz), 4.3−
4.4 (m, 1H), 4.84 (dd, 1H, J 1 = 3.2Hz,
J 2 = 6.4Hz), 4.95 (d, 1H, J = 6.1Hz),
5.0−5.1 (m, 1H), 5.56and5.58
(ABquartet, 2H, J=12.0Hz), 6.26(d,
1H, J = 3.4Hz), 6.60 (d, 1H, J = 1.0
Hz), 6.97 (d, 1H, J=1.0Hz), 7.08 (d,
1H, J = 3.9Hz), 7.1-7.6 (m, 15H) EI
Mass: m/z653 (M + ) Example 2 The substituents of Compound 3 obtained in Example 1 above were converted by the following method to separate it into an α-anomer form and a β-anomer form. After drying 6.4 g of Compound 3, 32 g of acetamide and 3.2 g of sodium hydride were added, and the air was replaced with nitrogen. The mixture was stirred in an oil bath at 135°C for 2.5 hours, acetamide was distilled off under reduced pressure, ice was added to the residue, and the mixture was neutralized with ammonium chloride and extracted with benzene. The benzene layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off. The product was purified with a silica gel column and then dissolved in methylene chloride. After cooling, add 330 ml of cold hydrogen bromide gas to methylene chloride solution.
was added and stirred for 10 minutes. After further stirring at room temperature for 20 minutes, saturated aqueous sodium bicarbonate was added, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The obtained crude product was purified using a silica gel column and recrystallized from n-hexane/benzene to obtain white needle-like crystals of 5-acetylamino-3,4-dihydro-3-methoxymethyl-5-methyl-7- (2,
3-O-isopropylidene-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-4
1.48 g of β-anomer and 0.85 g of α-anomer of -one were obtained. (Yield: β-anomer 44%,
α-anomer 25%) Melting point: α-anomer; 145-147℃ β-anomer; 182-184℃ UV (MeOH): α-anomer; λmax=304nm λmax=207nm β-anomer; λmax= 302nm λmax=208nm IR (KBr): α-anomer; 3440, 3300, 1693,
1675, 1588, 1293, 1110, 1069, 854, 770
cm -1 β-anomer; 3478, 3299, 1702,
1661, 1590, 1302, 1109, 1070, 852, 725
cm -1 NMR (CDCl 3 ): α-anomer; δ = 1.32 (s,
3H), 1.51 (s, 3H), 1.7 (br.s, 1H),
2.38 (d, 3H, J=1.5Hz), 2.42 (s,
3H), 3.42 (s, 3H), 3.7-3.9 (m, 2H),
4.3-4.4 (m, 1H), 4.7-5.0 (m, 2H),
5.51 (br.s, 2H), 6.48 (d, 1H, J=7.5
Hz), 6.88 (d, 1H, J=1.5Hz), 8.39 (br.
s, 1H), β-anomer; δ = 1.37 (s, 3H), 1.60 (s,
3H), 2.36 (d, 3H, J=1.0Hz), 2.37
(s, 3H), 3.20 (br.s, 1H), 3.45 (s,
3H), 3.7-3.95 (m, 2H), 4.30 (q, 1H,
J = 3.0Hz), 5.06 (dd, 1H, J 1 = 2.4Hz, J 2
= 6.5Hz), 5.15 (dd, 1H, J 1 = 3.6Hz, J 2 =
6.5Hz), 5.46and5.61(ABquartet, 2H, J
= 11.0Hz), 5.84 (d, 1H, J = 3.6Hz),
6.63 (d, 1H, J=1.0Hz), 8.38 (br.s,
1H) [α] D : α-anomer; [α 11 D = −71.3° (C = 0.11,
CHCl 3 ) β-anomer; [α 26 D = −30.5° (C = 0.20,
CHCl 3 ) EI Mass: m/z422 (M + ) The production method of the present invention involves coexisting a halogen salt in the reaction system, inverting the halogen at the β-position of the chlorinated sugar, and adjusting the α/β-anomer ratio. Table 1 shows the changes in the production ratio of α/β-anomers of nucleoside compounds according to the production method of the present invention. An example of the results of examining the α/β-anomer ratio of compound (3) produced by condensation reaction in the presence of the compound (3) is shown below. [Table] (Effects of the Invention) As is clear from the above experimental results, the production method of the present invention makes it possible to adjust the α/β-anomer ratio of Compound 3, and in particular, the β-anomer nucleoside This is useful when you want to selectively manufacture . In other words, α/ which was 3/1 in the conventional method
According to the present invention, the β-anomer ratio can be reduced to 1/2 by coexisting sodium bromide, which is a remarkable effect.
Therefore, by this production method, β-anomeric nucleoside synthesis intermediates can be obtained in a yield approximately 2.5 times that of the conventional method, and nucleoside synthesis intermediates useful for synthesizing nucleoside Q, cadeguomycin, etc. can be selectively obtained. This makes it possible to obtain high yields. Furthermore, the compound represented by the general formula () can be used not only as a synthetic intermediate for producing nucleoside Q and cadeguomycin, but also many other nucleoside compounds. It is very useful as a method for producing compounds, especially their β-anomers.
Claims (1)
素、低級アルキル基、アルキルチオ基、R3水素、
低級アルキル基を表す）で表される化合物と、 一般式 （） （式中、R4はアシル基、アルアルキル基を表す）
で表される化合物とを反応させて、 一般式 （） （式中、R1はアルコキシアルキル基、R2は水
素、低級アルキル基、アルキルチオ基、R3は水
素、低級アルキル基、R4はアシル基、アルアル
キル基を表す）で表されるヌクレオシド化合物を
製造する方法。[Claims] 1 General formula () (In the formula, R 1 is an alkoxyalkyl group, R 2 is hydrogen, lower alkyl group, alkylthio group, R 3 is hydrogen,
(representing a lower alkyl group) and a compound represented by the general formula () (In the formula, R 4 represents an acyl group or an aralkyl group)
By reacting with a compound represented by the general formula () (In the formula, R 1 represents an alkoxyalkyl group, R 2 represents hydrogen, a lower alkyl group, or an alkylthio group, R 3 represents hydrogen, a lower alkyl group, and R 4 represents an acyl group or an aralkyl group) How to manufacture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4916485A JPS61207400A (en) | 1985-03-11 | 1985-03-11 | Production of nucleoside compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4916485A JPS61207400A (en) | 1985-03-11 | 1985-03-11 | Production of nucleoside compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61207400A JPS61207400A (en) | 1986-09-13 |
| JPH0560477B2 true JPH0560477B2 (en) | 1993-09-02 |
Family
ID=12823438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4916485A Granted JPS61207400A (en) | 1985-03-11 | 1985-03-11 | Production of nucleoside compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61207400A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| YU25500A (en) * | 1999-05-11 | 2003-08-29 | Pfizer Products Inc. | Process for the synthesis of nucleosite analogues |
-
1985
- 1985-03-11 JP JP4916485A patent/JPS61207400A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61207400A (en) | 1986-09-13 |
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