JPH0714952B2 - Sialic acid derivative - Google Patents
Sialic acid derivativeInfo
- Publication number
- JPH0714952B2 JPH0714952B2 JP18646686A JP18646686A JPH0714952B2 JP H0714952 B2 JPH0714952 B2 JP H0714952B2 JP 18646686 A JP18646686 A JP 18646686A JP 18646686 A JP18646686 A JP 18646686A JP H0714952 B2 JPH0714952 B2 JP H0714952B2
- Authority
- JP
- Japan
- Prior art keywords
- sialic acid
- acid derivative
- acid
- present
- acylthiosialic
- 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
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- Saccharide Compounds (AREA)
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、医薬品、生化学試薬等の原料、中間体として
有用な新規なシアル酸誘導体及びその製造法に関する。TECHNICAL FIELD The present invention relates to a novel sialic acid derivative useful as a raw material for medicines, biochemical reagents and the like, an intermediate, and a method for producing the same.
シアル酸は生物の各種の組織に存在し、通常糖鎖を構成
する部分にその構成単位としてグリコシド結合して存在
する。シアル酸は糖脂質や糖タンパク質の重要な構成成
分である為、その機能研究の目的で、また、近年ガング
リオシドの様々な生理活性が非常に注目されているとこ
ろから、その医薬面での応用という見地から、その類縁
体、誘導体やグリコシド、シアロオリゴ糖についての合
成検討が盛んに行われており、各種誘導体が合成されつ
つあるが、未だ研究は緒についたばかりであり、更に新
たな誘導体の出現とそれに伴う更に新たなる展開が待た
れている。Sialic acid is present in various tissues of living organisms, and is usually present in a part constituting a sugar chain as a glycosidic bond as a constituent unit. Since sialic acid is an important constituent of glycolipids and glycoproteins, it is said that its application in medicine is intended for the purpose of functional studies and since various physiological activities of gangliosides have been receiving much attention in recent years. From the point of view, synthesis studies of its analogs, derivatives, glycosides, and sialo-oligosaccharides are being actively conducted, and various derivatives are being synthesized, but the research is still in its infancy and the emergence of new derivatives. Along with that, further new developments are awaited.
本発明は、上記した如き現状に鑑みなされたもので、種
々の医学的、生化学的成果が期待できる新規なシアル酸
誘導体とその製造法を提供することを目的とする。The present invention has been made in view of the current situation as described above, and an object thereof is to provide a novel sialic acid derivative which can be expected to have various medical and biochemical results, and a method for producing the same.
本発明は、（１）式、 で示される２β−アシルチオシアル酸誘導体、及び
（２）式、 で示されるシアル酸の２β−Cl体を弗化銀AgFと反応さ
せて式、 で示される２α−Ｆ体とした後、ルイス酸触媒の存在下
チオ酢酸CH3COSHと反応させることを特徴とする式、 で示される２β−アシルチオシアル酸誘導体の製造法の
発明である。The present invention is based on the formula (1), A 2β-acylthiosialic acid derivative represented by: The 2β-Cl form of sialic acid represented by A 2α-F compound represented by the following formula, which is reacted with thioacetic acid CH 3 COSH in the presence of a Lewis acid catalyst, Is an invention of a method for producing a 2β-acylthiosialic acid derivative represented by:
本発明の２β−アシルチオシアル酸誘導体は新規化合物
であり、医薬品、生化学試薬等の原料、中間体として種
々の展開が期待できる化合物である。即ち、これまで、
２α−アシルチオシアル酸誘導体はシアル酸の２β−Cl
体とチオ酢酸塩との反応により得られることが知られて
おり〔ジャーナル オブ カーボハイドレート ケミス
トリー５，（１）11−19（1986）〕、公知であったが、
２β−アシルチオシアル酸誘導体はこの方法によっては
全く得られず、また他の製法も知られておらず、これま
でその存在が確認されていなかった。The 2β-acylthiosialic acid derivative of the present invention is a novel compound, and is expected to be variously developed as a raw material or an intermediate for drugs, biochemical reagents and the like. That is, so far
The 2α-acylthiosialic acid derivative is 2β-Cl of sialic acid.
It has been known that it can be obtained by the reaction of thioacetic acid with thioacetate [Journal of Carbohydrate Chemistry 5 , (1) 11-19 (1986)], and it was known.
The 2β-acylthiosialic acid derivative was not obtained by this method at all, and no other manufacturing method was known, and its existence has not been confirmed so far.
本発明化合物の合成ルートは大略下記の通りである。The synthetic route of the compound of the present invention is roughly as follows.
即ち、先ずシアル酸の２β−Cl体を適当な溶媒（例え
ば、アセトニトリル、ベンゼン、トルエン、キシレン
等）中、弗化銀AgFと室温乃至要すれば冷却下で数時間
反応させた後、常法により後処理を行い、要すればカラ
ムクロマトグラフィー等により精製して２β−Ｆ体を得
る。次いで、これを適当な溶媒（例えば、塩化メチレ
ン、ジクロルエタン、クロロホルム、ジオキサン、エー
テル類等）中、ルイス酸触媒（例えば、BF3、AgBF4、Ag
ClO4、ZnCl2等）の存在下、チオ酢酸CH3COSHと室温乃至
要すれば冷却下で数時間反応させた後、常法により後処
理を行ない、要すればカラムクロマトグラフィー等によ
り精製して本発明化合物を得る。 That is, first, the 2β-Cl form of sialic acid is reacted with silver fluoride AgF in a suitable solvent (for example, acetonitrile, benzene, toluene, xylene, etc.) at room temperature or, if necessary, under cooling for several hours, and then a conventional method is used. After the treatment, the product is purified by column chromatography or the like, if necessary, to obtain a 2β-F form. Then, this is added to a Lewis acid catalyst (eg, BF 3 , AgBF 4 , Ag) in a suitable solvent (eg, methylene chloride, dichloroethane, chloroform, dioxane, ethers, etc.).
ClO 4 , ZnCl 2 etc.), after reacting with thioacetic acid CH 3 COSH at room temperature or if necessary for cooling for several hours, after-treatment is carried out by a conventional method and, if necessary, purification by column chromatography etc. To obtain the compound of the present invention.
本発明の２β−アシルチオシアル酸誘導体の原料となる
シアル酸の２β−Cl体は、例えば、カーボハイドレート
リサーチ 110,11（1982）に記載の方法に従って天然
のノイラミン酸から容易に合成し得るので、このように
して得られたものを用いることで足りる。The 2β-Cl form of sialic acid, which is a raw material of the 2β-acylthiosialic acid derivative of the present invention, can be easily synthesized from natural neuraminic acid according to the method described in Carbohydrate Research 110 , 11 (1982). Therefore, it is sufficient to use the thus obtained product.
以下に実施例を挙げる。Examples will be given below.
実施例1. メチル ５−アセドアミド−4,7,8,9−テト
ラ−Ｏ−アセチル−２−Ｓ−アセチル−3,5−ジデオキ
シ−２−チオ−Ｄ−グリセロ−β−Ｄ−ガラクト−２−
ノヌロピラノソネート（本発明化合物）の合成 （１）メチル ５−アセトアミド−4,7,8,9−テトラ−
Ｏ−アセチル−２−フルオロ−2,3,5−トリデオキシ−
Ｄ−グリセロ−α−Ｄ−ガラクト−２−ノヌロピラノソ
ネート（シアル酸の２α−Ｆ体）の合成 シアル酸の２β−Cl体1.1gを乾燥アセトニトリル5mlに
溶解し、AgF300mg（1.1当量）を加えて遮光下室温で３
時間撹拌反応させた。反応後、反応液をセライト過
し、塩化メチレンで洗浄して液と洗液を合わせ、減圧
濃縮後得られたシラップを塩化メチレンで抽出した。塩
化メチレン層を飽和Na2S2O3水溶液、水、飽和NaCl水溶
液で順次洗浄し、Na2SO4乾燥後、濃縮して得たシラップ
をカラムクロマトグラフィー〔ワコーゲル Ｃ−200,溶
出液：酢酸エチル／ヘキサン（4/1）〕により精製し、
更にベンゼン−エーテル−ヘキサンで結晶化して、シア
ル酸の２β−Ｆ体980mgを得た。Example 1. Methyl 5-acedamide-4,7,8,9-tetra-O-acetyl-2-S-acetyl-3,5-dideoxy-2-thio-D-glycero-β-D-galacto-2 −
Synthesis of nonuropyranosonate (compound of the present invention) (1) Methyl 5-acetamido-4,7,8,9-tetra-
O-acetyl-2-fluoro-2,3,5-trideoxy-
Synthesis of D-glycero-α-D-galacto-2-nonuropyranosonate (2α-F form of sialic acid) 1.1 g of 2β-Cl form of sialic acid was dissolved in 5 ml of dry acetonitrile, and AgF 300 mg (1.1 equivalent) Add 3 at room temperature under dark
The reaction was allowed to stir for an hour. After the reaction, the reaction solution was filtered through Celite, washed with methylene chloride, the solution and the wash solution were combined, and the syrup obtained after concentration under reduced pressure was extracted with methylene chloride. The methylene chloride layer was washed successively with saturated Na 2 S 2 O 3 aqueous solution, water and saturated NaCl aqueous solution, dried over Na 2 SO 4 , and concentrated to obtain syrup, which was then subjected to column chromatography [Wakogel C-200, eluent: acetic acid. Ethyl / hexane (4/1)],
Further, it was crystallized from benzene-ether-hexane to obtain 980 mg of 2β-F form of sialic acid.
収率91.3％。mp45〜47℃。▲〔α〕25 D▼−16.17゜（Ｃ
＝0.718,CH2Cl2）。Yield 91.3%. mp45-47 ° C. ▲ [α] 25 D ▼ -16.17 ° (C
= 0.718, CH 2 Cl 2) .
元素分析値:C20H28FNO12（M.W.493.44） 計算値（％）C:48.65,H:5.72 実測値（％）C:48.55,H:5.68。Elemental analysis value: C 20 H 28 FNO 12 (MW493.44) Calculated value (%) C: 48.65, H: 5.72 Measured value (%) C: 48.55, H: 5.68.
IR（Nujol）νmax:3300（NH）,1760,1670（CO,NHCO）,1
550,1440,1380,1230,1050cm-1。IR (Nujol) ν max : 3300 (NH), 1760,1670 (CO, NHCO), 1
550,1440,1380,1230,1050 cm -1 .
NMR（CDCl3）δ:1.92（s,3H,NCOCH3）,2.04,2.05,2.09,
2.15（4s,12H,4×OCOCH3）,2.70（ddd,1H,J3a,3e13.9,J
3e,F8.8Hz,H−3e）,3.85（s,3H,CH3）,4.11（m,1H,H−
５）,4.12（dd,1H,H−９）,4.24（d,1H,J5,611.0Hz,H−
６）,4.37（dd,1H,J9,9′0Hz,H−９）,5.22（ddd,1H,
J4,5＝J3a,49.2,J3e,45.5Hz,H−４）,5.32（near s,1H,
J6,70Hz,H−７）,5.32（near s,1H,J8,9＜2.2,J8,9′＝
J7,80Hz,H−８）,5.67（d,1H,J5,NH9.2Hz,NH）ppm.。NMR (CDCl 3 ) δ: 1.92 (s, 3H, NCOCH 3 ), 2.04,2.05,2.09,
2.15 (4s, 12H, 4 × OCOCH 3 ), 2.70 (ddd, 1H, J 3 a, 3 e13.9, J
3 e, F 8.8Hz, H−3e), 3.85 (s, 3H, CH 3 ), 4.11 (m, 1H, H−
5), 4.12 (dd, 1H, H-9), 4.24 (d, 1H, J 5 , 6 11.0Hz, H-
6), 4.37 (dd, 1H , J 9, 9 '0Hz, H-9), 5.22 (ddd, 1H,
J 4 , 5 = J 3 a, 4 9.2, J 3 e, 4 5.5Hz, H-4), 5.32 (near s, 1H,
J 6, 7 0Hz, H- 7), 5.32 (near s, 1H, J 8, 9 <2.2, J 8, 9 '=
J 7, 8 0Hz, H- 8), 5.67 (d, 1H, J 5, NH 9.2Hz, NH) ppm ..
（２）本発明化合物の合成 （１）で得たシアル酸の２α−Ｆ体800mgを乾燥塩化メ
チレン20mlに溶解し、これにCH3COSH1.76ml及びBF3・Ｏ
（C2H5）20.6mlを加えて室温で10時間撹拌反応させた。
反応液を塩化メチレンで抽出し、水洗、Na2SO4乾燥後濃
縮して得られたシラップをカラムクロマトグラフィー
〔ワコーゲルＣ−200,溶出液：酢酸エチル／ヘキサン
（4/1）〕により精製し、更にエーテル−ヘキサンで結
晶化して本発明化合物640mgを得た。(2) Synthesis of compound of the present invention 800 mg of 2α-F form of sialic acid obtained in (1) was dissolved in 20 ml of dry methylene chloride, and CH 3 COSH 1.76 ml and BF 3 · O were dissolved in this.
(C 2 H 5 ) 2 0.6 ml was added, and the mixture was reacted at room temperature for 10 hours with stirring.
The reaction solution was extracted with methylene chloride, washed with water, dried over Na 2 SO 4 and concentrated, and the resulting syrup was purified by column chromatography [Wakogel C-200, eluent: ethyl acetate / hexane (4/1)]. Further, it was crystallized from ether-hexane to obtain 640 mg of the compound of the present invention.
収率72％。mp140〜142℃。▲〔α〕25 D▼−77.38゜（Ｃ
＝0.672,CHCl3）。Yield 72%. mp 140-142 ° C. ▲ [α] 25 D ▼ -77.38 ° (C
= 0.672, CHCl 3).
元素分析値:C22H31NO13S（M.W.549.55） 計算値（％）C:48.08,H:5.69,N:2.55 実測値（％）C:48.20,H:5.58,N:2.41。Elemental analysis value: C 22 H 31 NO 13 S (MW549.55) Calculated value (%) C: 48.08, H: 5.69, N: 2.55 Measured value (%) C: 48.20, H: 5.58, N: 2.41.
IR（KBr）νmax:3300（NH）,1750,1660（CO,NHCO）,157
0,1440,1380,1240,1140,1100,1040cm-1。IR (KBr) ν max : 3300 (NH), 1750,1660 (CO, NHCO), 157
0,1440,1380,1240,1140,1100,1040 cm -1 .
NMR（CDCl3）δ:1.89（s,3H,NCOCH3）,2.03,2.04,2.07,
2.15（4s,12H,4×COCH3）,2.34（s,3H,SCOCH3）,2.52
（dd,1H,J3a,3e13.6Hz,H−3e）,3.84（s,3H,CH3）,4.09
（ddd,1H,H−５）,4.14（dd,1H,H−９）,4.22（dd,1H,J
3,610.3Hz,H−６）,4.62（dd,1H,J9,9′12.5Hz,H−
９′）,5.00（ddd,1H,J8,97.0,J8,9′2.2Hz,H−８）,5.
14（ddd,1H,J3e,44.8,J4,510.3,J3a,410.3Hz,H−４）,
5.35（d,1H,J5,NH10.3Hz,NH）,5.39（dd,1H,J6,72.2,
J7,84.0Hz,H−７）ppm.。NMR (CDCl 3 ) δ: 1.89 (s, 3H, NCOCH 3 ), 2.03,2.04,2.07,
2.15 (4s, 12H, 4 × COCH 3 ), 2.34 (s, 3H, SCOCH 3 ), 2.52
(Dd, 1H, J 3 a, 3 e13.6Hz, H-3e), 3.84 (s, 3H, CH 3 ), 4.09
(Ddd, 1H, H-5), 4.14 (dd, 1H, H-9), 4.22 (dd, 1H, J
3, 6 10.3Hz, H-6 ), 4.62 (dd, 1H, J 9, 9 '12 .5Hz, H-
9 '), 5.00 (ddd, 1H, J 8, 9 7.0, J 8, 9' 2.2Hz, H-8), 5.
14 (ddd, 1H, J 3 e, 4 4.8, J 4 , 5 10.3, J 3 a, 4 10.3Hz, H-4),
5.35 (d, 1H, J 5 , NH 10.3Hz, NH), 5.39 (dd, 1H, J 6 , 7 2.2,
J 7 , 8 4.0Hz, H-7) ppm.
以上述べた如く、本発明はこれまでに得られていなかっ
た新規なシアル酸誘導体を提供するものであり、種々の
医学的、生化学的成果が期待できるものである点に顕著
な効果を奏するものである。As described above, the present invention provides a novel sialic acid derivative that has not been obtained so far, and has a remarkable effect in that various medical and biochemical results can be expected. It is a thing.
Claims (2)
せて式、 で示される２α−Ｆ体とした後、ルイス酸触媒の存在下
チオ酢酸CH3COSHと反応させることを特徴とする式、 で示される２β−アシルチオシアル酸誘導体の製造法。2. A formula, The 2β-Cl form of sialic acid represented by A 2α-F compound represented by the following formula, which is reacted with thioacetic acid CH 3 COSH in the presence of a Lewis acid catalyst, A method for producing a 2β-acylthiosialic acid derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18646686A JPH0714952B2 (en) | 1986-08-08 | 1986-08-08 | Sialic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP18646686A JPH0714952B2 (en) | 1986-08-08 | 1986-08-08 | Sialic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6341492A JPS6341492A (en) | 1988-02-22 |
| JPH0714952B2 true JPH0714952B2 (en) | 1995-02-22 |
Family
ID=16188961
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP18646686A Expired - Lifetime JPH0714952B2 (en) | 1986-08-08 | 1986-08-08 | Sialic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0714952B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2328085C (en) | 1998-04-10 | 2006-08-22 | Mitsubishi Chemical Corporation | Solid dispersion containing sialic acid derivative |
-
1986
- 1986-08-08 JP JP18646686A patent/JPH0714952B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6341492A (en) | 1988-02-22 |
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