JPH0689042B2 - Method for producing glycosphingolipid-related compound - Google Patents
Method for producing glycosphingolipid-related compoundInfo
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- JPH0689042B2 JPH0689042B2 JP30743186A JP30743186A JPH0689042B2 JP H0689042 B2 JPH0689042 B2 JP H0689042B2 JP 30743186 A JP30743186 A JP 30743186A JP 30743186 A JP30743186 A JP 30743186A JP H0689042 B2 JPH0689042 B2 JP H0689042B2
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- toluene
- nmr
- cdcl
- solvent
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Description
〔産業上の利用分野〕 本発明は、フコース置換ラクト系列スフィンゴ糖脂質関
連化合物の製造法に関する。 〔従来の技術〕 分化抗原の１つであるSSEA−１抗原（Stagespecific Em
bryonic Antigen）は、1978年、ソルター（Solter）と
ノウズ（Knowles）等（ディー・ソルター及びビー・ビ
ー・ノウルズ:Proc.Natl.Acad.Sci.USA.,75、5565〜556
9、1978）が、マウスのテラトカルチノーマ細胞F9を同
系マウスに免疫して得たモノクローナル抗体が認識する
抗原である。その構造は非還元末端に抗原決定基として
Lex構造を有したフコース置換ラクト系列スフィンゴ糖
脂質であることが、1982年、箱守等〔アール．カンナ
ギ，イー・ヌーデルマン，エス・ビー・レベリー及びエ
ス・ハコモリ（R.Kannagi,E.Nudelman,S.B.Levery and
S.Hakomori）:J.Biol.Chem.,257、14865〜14874、1982;
アール．カンナギ，イー・ヌーデルマン及びエス・ハコ
モリ（R.Kannagi,E.Nudelman,and S.Hakomori）:Proc.N
atl.Acad.Sci.USA.,79:3470〜3474、1982〕により、明
らかにされた。 これらは当初考えられていた、単一な抗原分子ではな
く、そのＮ−アセチルラクトサミン構造の活発な延長
と、フコシル化の程度により、多種多様な糖鎖群を形成
し、各種ガン組織から、ガン関連糖脂質として単離され
て来た。〔エッチ・ジェイ・ヤング及びエス・ハコモリ
（H.J.Yang and S.Hakomori）:J.Biol.Chem.,246、119
2、1971;エス・ハコモリ，イー・ヌーデルマン，エス・
ビー・レベリー及びアール・カンナギ（S.Hakomori,E.N
udelman,S.B.Levery and R.Kannagi）:J.Biol.Chem.,25
9、4672、1982;ワイ・フクシ，エス・ハコモリ，イー・
ヌーデルマン及びエヌ・エー・コチラン（Y.Fukushi,S.
Hakomori,E.Nudelman and N.A.Cochran）:259、4681〜4
685、1984。〕 本発明者らはこうしたSSEA−１抗原群の基本構造ともい
える５糖残基からなる Galβ１→４ GlcNAcβ１→3Galβ１→4Glcβ１→Cer Fucα１→３ の合成に成功している。 〔発明が解決しようとする問題点〕 さらに、高次にガン化と密接に関連していると思われ
る、Lexをくり返し構造として有した８糖残基からなる
糖脂質 の精密合成は、これら、ガン関連糖鎖の生化学的役割の
解明を有機化学的見地から、推進する上で必要不可欠で
あり、またこれらの糖脂質は将来的には、診断、治療等
への応用が期待されるなど、意義あるものである。 本発明の目的は、この８糖残基からなるスフィンゴ糖脂
質関連化合物の製造法を提供することである。 〔問題点を解決するための手段〕 本発明は、一般式〔Ｉ〕で表わされるスフィンゴ糖脂質
関連化合物の製造法を提供するものである。 （ただしR1は水素原子、ベンジル基またはアセチル基で
あり、R2は または−NHOCCH3であり、R3は ，−Ｏ−OCCH3, または であり、R4は水素原子またはジフェニルターシャリィブ
チルシリル基である） また本発明の製造法は下記の工程（ａ）〜（ｆ）からな
る。 （ａ） 化合物〔15〕及び化合物〔16〕を反応せしめて
化合物〔17〕を製造する。 （ただし、Bnはベンジル基、Phthはフタロイル基を表わ
す。） （ｂ） 化合物〔17〕をヒドラジン処理してフタロイル
基を脱離し、次いでアセチル化して化合物〔19〕を製造
する。 （ｃ） 化合物〔19〕を脱ベンジル化し、次いでアセチ
ル化して化合物〔20〕を製造する。 （ｄ） 化合物〔20〕をヒドラジン／酢酸で処理した
後、トリクロロアセトニトリルで処理して化合物〔21〕
を製造する。 （ｅ） 化合物〔21〕とセラミド化合物〔22〕を反応せ
しめ、化合物〔23〕を製造する。 （ただしPhはフェニル基を表す。） （ｆ） 化合物〔23〕の保護基を脱離し、化合物〔１〕
を製造する。 以下本発明のスフィンゴ糖脂質関連化合物の製造法につ
いて、更に詳細に説明する。 まず公知の化合物〔２〕にNaOCH3,NaOEt,Na2CO3,NaHCO3
等の塩基の存在下、メタノール、エタノール等の溶媒中
で−10℃〜80℃にて５分間〜１日間反応せしめ、脱アセ
チル化して新規な化合物〔３〕を得る。 次いでDMF（ジメチルホルムアミド）、アセトン、THF
（テトラヒドロフラン）、トルエンまたはジオキサンの
ような溶媒中で、トルエンスルホン酸、ベンゼンスルホ
ン酸、無水塩酸または塩化亜鉛等の存在下、化合物
〔３〕をジメトキシプロパンと０℃〜120℃で１時間〜
２日間反応させイソプロピリデン化して、新規な化合物
〔４〕を得る。この際副生物として新規な化合物〔５〕
も得られる。 次いでDMF、THFまたはジオキサン等の溶媒中で化合物
〔４〕にベンジルブロマイド、酸化銀及びヨウ化カリウ
ムを−20〜100℃で５分間〜１日間反応させ、ベンジル
化して新規な化合物〔６〕を得る。 更に化合物〔６〕をトリフルオロ酢酸／水、酢酸／水ま
たは希塩酸等によって、−10゜〜100℃で５分間〜１日
間処理してイソプロピリデン基をはずし、新規な化合物
〔８〕を得る。この際、フコースが脱離した新規な化合
物〔７〕も副生物として生成する。 次いでピリジン、ジクロロエタン、ジクロロメタン、ク
ロロホルム、THFまたはジオキサン等の溶媒中、化合物
〔８〕を温度−10〜80℃で５分間〜２日間無水酢酸と反
応させてアセチル化し、新規な化合物[Field of Industrial Application] The present invention relates to a method for producing a fucose-substituted lacto-series glycosphingolipid-related compound. [Prior Art] SSEA-1 antigen (Stage specific Em) which is one of the differentiation antigens
bryonic Antigen) was founded in 1978 by Solter and Knowles (Die Salter and BB Knowles: Proc.Natl.Acad.Sci.USA., 75, 5565-556).
9, 1978) is an antigen recognized by a monoclonal antibody obtained by immunizing syngeneic mice with mouse teratocarcinoma cell F9. Its structure is as an antigenic determinant at the non-reducing end
In 1982, Hakmori et al. [R. R. Kannagi, E. Nudelman, SBLevery and
S. Hakomori): J. Biol. Chem., 257, 14865-14874, 1982;
R. R.Kannagi, E.Nudelman, and S.Hakomori: Proc.N
atl.Acad.Sci.USA., 79: 3470-3474, 1982]. These are not initially thought to be a single antigen molecule, but rather form a wide variety of sugar chain groups depending on the active extension of the N-acetyllactosamine structure and the degree of fucosylation, and from various cancer tissues, It has been isolated as a cancer-related glycolipid. [HJ Yang and S. Hakomori: J. Biol. Chem., 246, 119
2, 1971; S. Hakomori, E. Nudermann, S.
Be Reverie and Earl Cannagi (S. Hakomori, EN
udelman, SBLevery and R.Kannagi): J. Biol. Chem., 25
9, 4672, 1982; Wai Fukushi, S. Hakomori, E.
Nudelmann and NA Cochilan (Y.Fukushi, S.
Hakomori, E. Nudelman and NACochran): 259, 4681 ~ 4
685, 1984. The present inventors have succeeded in synthesizing Galβ1 → 4 GlcNAcβ1 → 3Galβ1 → 4Glcβ1 → Cer Fucα1 → 3 composed of pentasaccharide residues, which can be said to be the basic structure of the SSEA-1 antigen group. [Problems to be Solved by the Invention] Furthermore, a glycolipid composed of 8 sugar residues having Lex as a repeating structure, which is considered to be closely related to carcinogenesis of higher order. Precise synthesis is essential for promoting the elucidation of the biochemical role of these cancer-related sugar chains from the perspective of organic chemistry, and these glycolipids will be used for diagnosis and treatment in the future. Is expected to be applied, which is significant. An object of the present invention is to provide a method for producing a glycosphingolipid-related compound composed of this octasaccharide residue. [Means for Solving Problems] The present invention provides a method for producing a glycosphingolipid-related compound represented by the general formula [I]. (However, R 1 is a hydrogen atom, a benzyl group or an acetyl group, and R 2 is Or --NHOCCH 3 and R 3 is , -O-OCCH 3 , Or And R 4 is a hydrogen atom or a diphenyltertiarybutylsilyl group.) The production method of the present invention comprises the following steps (a) to (f). (A) Compound [17] is produced by reacting compound [15] and compound [16]. (However, Bn represents a benzyl group and Phth represents a phthaloyl group.) (B) Compound [17] is treated with hydrazine to remove the phthaloyl group, and then acetylated to produce compound [19]. (C) The compound [19] is debenzylated and then acetylated to produce the compound [20]. (D) Compound [20] is treated with hydrazine / acetic acid and then treated with trichloroacetonitrile to give compound [21].
To manufacture. (E) Compound [21] is reacted with ceramide compound [22] to produce compound [23]. (However, Ph represents a phenyl group.) (F) The protecting group of the compound [23] is removed, and the compound [1] is removed.
To manufacture. Hereinafter, the method for producing the glycosphingolipid-related compound of the present invention will be described in more detail. First, the known compound [2] was added to NaOCH 3 , NaOEt, Na 2 CO 3 , NaHCO 3
Etc. in the presence of a base such as methanol, ethanol and the like at −10 ° C. to 80 ° C. for 5 minutes to 1 day, followed by deacetylation to obtain a novel compound [3]. Then DMF (dimethylformamide), acetone, THF
(Tetrahydrofuran), toluene or dioxane in a solvent such as toluenesulfonic acid, benzenesulfonic acid, anhydrous hydrochloric acid or zinc chloride in the presence of compound [3] with dimethoxypropane at 0 ° C to 120 ° C for 1 hour to
After reacting for 2 days and isopropylidene formation, a new compound [4] is obtained. In this case, a new compound as a by-product [5]
Can also be obtained. Then, the compound [4] is reacted with benzyl bromide, silver oxide and potassium iodide at −20 to 100 ° C. for 5 minutes to 1 day in a solvent such as DMF, THF or dioxane to benzylate the novel compound [6]. obtain. Further, the compound [6] is treated with trifluoroacetic acid / water, acetic acid / water, dilute hydrochloric acid or the like at −10 ° to 100 ° C. for 5 minutes to 1 day to remove the isopropylidene group to obtain a novel compound [8]. At this time, a novel compound [7] from which fucose has been eliminated is also produced as a by-product. Then, in a solvent such as pyridine, dichloroethane, dichloromethane, chloroform, THF or dioxane, the compound [8] is reacted with acetic anhydride at a temperature of −10 to 80 ° C. for 5 minutes to 2 days to acetylate to obtain a novel compound.
〔９〕を得る。 更に酢酸水溶液、メタノールまたはエタノール等の溶媒
中で化合物Obtain [9]. Furthermore, the compound is added in a solvent such as acetic acid aqueous solution, methanol or ethanol
〔９〕を塩化パラジウムにより０〜120℃で3
0分間〜２日間処理し、化合物〔10〕を得る。 次いでクロロホルム、ジクロロメタン、ジクロロエタ
ン、トルエンまたはTHF等の溶媒中で、DBU（ジアザビシ
クロウンデカン）存在下、−20〜60℃で、５分間〜１日
間化合物〔10〕をトリクロロアセトニトリルと反応さ
せ、新規な化合物〔11〕を得る。 更にクロロホルム、ジクロロメタン、ジクロロエタン、
トルエンまたはTHF等の溶媒中でBF3.Ft2OまたはTMSOTf
（トリメチルシリルトリフレート）、等のグリコシル化
触媒存在下、化合物〔11〕に化合物〔12〕を反応させて
５糖残基からなる新規な化合物〔13〕を得る。副生物と
して化合物〔14〕も得られる。 次いで化合物〔13〕を、メタノール、エタノール等の溶
媒中、−10〜80℃で５分間〜１日間、NaOCH3,NaOC2H5,N
a2CO3またはNaHCO3により処理して脱アセチル化し、新
規な化合物〔15〕を得る。 更にクロロホルム、ジクロロメタン、ジクロロエタン、
トルエンまたはTHF等の溶媒中で、BF3・Et2OまたはTMSO
Tf等の触媒存在下、化合物〔15〕に公知の化合物〔16〕
を、−20〜60℃で５分間〜１日間反応させ新規な化合物
〔17〕及び副生物として新規な化合物〔18〕を得る。 更に化合物〔17〕を、メタノールまたはエタノール等の
溶媒中、０〜120℃で５分間〜２日間ヒドラジン処理し
て、フタロイル基を脱離した後、ピリジ、クロロホル
ム、ジクロロエタン、ジクロロメタンまたはTHF等の溶
媒中、−10〜80℃で30分間〜２日間必要により４−DMAP
（４−ジメチルアミノピリジン）存在下無水酢酸を、反
応させてアセチル化し、新規な化合物〔19〕を得る。 次いでメタノール、エタノールまたは酢酸等の溶媒中、
10％Pd−Ｃ、５％Pd−BaSO4、５％Pt−Ｃ等の触媒存在
下、化合物〔19〕を０〜100℃で１時間〜３日間水素接
触還元して脱ベンジル化した後、ピリジン、クロロホル
ム、ジクロロエタン、ジクロロメタンまたはTHF等の溶
媒中で、無水酢酸、ピリジン及び４−DMAPと、−10〜80
℃で30分間〜２日間反応させてアセチル化し、新規な化
合物〔20〕（収率78％）を得る。 次いでDMF、DMSO、THFまたはジオキサン等の溶媒中でヒ
ドラジン・酢酸存在下、化合物〔20〕を−10〜100℃で
５分間〜１日間処理して１位のアセチル基を脱離し、さ
らにクロロホルム、ジクロロメタン、ジクロロエタン、
トルエンまたはTHF等の溶媒中で、DBU存在下、−20℃〜
60℃で５分間〜１日間トリクロロアセトニトリルと反応
させて化合物〔21〕を得る。 次いでクロロホルム、ジクロロメタン、ジクロロエタ
ン、トルエンまたはTHF等の溶媒中で、BF3・Et2O及びTM
SOTf等の触媒存在下、−20〜60℃で５分間〜１日間、化
合物〔21〕とセラミド化合物〔22〕を反応せしめ新規な
化合物〔23〕を得る。また副生物として新規な化合物
〔24〕を得る。 次いでTHFまたはジオキサン等の溶媒中でｎ−Bu4NF存在
下、化合物〔23〕を−20〜100℃で５分間〜２日間反応
せしめた後、メタノール、エタノールまたはTHF等の溶
媒中で、NaOCH3、NaOC2H5、Na2CO3またはNaHCO3等の塩
基により、−10〜80℃で５分間〜１日間処理してアセチ
ル基を脱離し、目的の化合物〔１〕を得る。 上記反応工程の一例を次のスキームに示す。 （ただしAcはアセチル基を表わす。） 〔発明の効果〕 本発明のスフィンゴ糖脂質関連化合物は、ガン関連糖鎖
の生化学的役割の解明を有機化学的見地から推進するた
めに必要不可欠なものであり、将来的には、診断、治療
等への応用が期待される。 本発明の式（１）で表される化合物はSSEA−１抗原群の
基本構造である８糖残基からなる糖脂質であり、これを
抗原として形成された抗SSEA−１抗体は、血清腫瘍マー
カーとして、肺腺癌、卵巣癌、膵癌等の診断、治療等に
応用することができる。 また本発明のスフィンゴ糖脂質関連化合物の製造方法に
よって、スフィンゴ糖脂質関連化合物を収率よく製造す
ることができる。 次に参考例及び実施例によって本発明を更に具体的に説
明する。 〔参考例１〕 化合物〔３〕の合成 化合物〔２〕5.62g（4.73mM）をメタノール/THF（20ml/
20ml）に溶解し、これに、0.2N NaOCH3メタノール溶液5
mlを加え室温にて、１時間撹拌した。反応終了後、アン
バーリスト15を加え、反応溶液を中和後、ろ去し、ろ液
を減圧留去した。残渣をカラムクロマトグラフィー（ア
セトン／トルエン＝1/1展開）にて、精製し、油状物4.8
2g（収率、定量的）を得た。 Rf＝0.46（トルエン／アセトン＝1/1） 〔α▲〕25 D▼−19.9゜（Ｃ＝0.88、CHCl3） 元素分析値:C57H63NO16・1/2H2O＝1027.141 として 計算値 C;66.65 H;6.28 N;1.36 測定値 C;66.68 H;6.27 N;1.341 H−NMR（400MHz、CDCl3）δ； 7.75−6.98（m,24H,アロマチックＨ） 5.145（dd,1H,＝ＣＨ 2,J＝1.5,17.4Hz） 5.061（dd,1H,＝ＣＨ 2,J＝1.5,10.8Hz） 4.873（d,1H,H-1c,J＝2.7Hz） 4.489（d,1H,H-1b,J＝7.0Hz） 1.052（d,3H,H-6c,J＝6.4Hz）13 C−NMR（CDCl3）δ； 168.230（Ｃ＝０）,99.853（C-1b）,98.661（C-1a） 96.984（C-1c）,55.860（C-2a）,16.362（C-6c） 〔参考例２〕 化合物〔４〕及び〔５〕の合成 化合物〔３〕4.58g（4.5mM）を、DMF20mlに溶解し、こ
れに、ジメトキシプロパン4.68g（45mM）及びｐ−TsOH3
00mgを加え、室温にて、２日間撹拌した。反応終了後、
トリエチルアミンを加え中和後、酢酸エチルで抽出し、
水、飽和食塩水で順次洗浄後、硫酸マグネシウムで乾燥
し、溶媒を留去した。残渣をメタノール50mlに溶解し、
これにアンバーリスト15を加え、室温にて30分撹拌後、
ろ去し、ろ液を減圧留去した。残渣ををカラムクロマト
グラフィー（トルエン／アセトン＝5/1展開）にて精製
し、化合物〔４〕3.52g（収率 73.9％）及び化合物
〔５〕0.77g（収率16.2gを得た。 化合物〔４〕 Rf＝0.65 （トルエン／アセトン＝2/1） 〔α▲〕25 D▼−7.0゜（Ｃ＝0.79、CHCl3） 元素分析値:C60H67NO16＝1058.199として 計算値 C;68.10 H;6.38 N;1.32 測定値 C;67.92 H;6.43 N;1.271 H−NMR（400MHz、CDCl3）δ； 7.73-6.96（m,24H,アロマチックＨ） 5.140（dd,1H,＝ＣＨ 2,J＝1.5,17.4Hz） 5.055（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 4.784（d,1H,H-1c,J＝3.4Hz） 4.396（d,1H,H-1b,J＝8.2Hz） 1.052（d,3H,H-6c,J＝6.4Hz）13 C−NMR（CDCl3）δ； 98.718（C-1a）,96.984（C-1c）,55.914（C-2a） 化合物〔５〕 Rf＝0.43 （トルエン／アセトン＝2/1） 〔α▲〕24 D▼＋2.5゜（Ｃ＝0.56、CHCl3） 元素分析値:C60H67NO16・1/2H2O＝1067.206 計算値 C;67.53 H;6.42 N;1.31 測定値 C;67.49 H;6.39 N;1.211 H−NMR（400MHz、CDCl3）δ； 7.72-7.02（m,24H,アロマチックＨ） 5.113（d,1H,H-1a,J＝8.5Hz） 5.070（dd,1H,＝ＣＨ 2,J＝1.5,17.1Hz） 4.983（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 4.833（d,1H,H-1c,J＝3.7Hz） 4.551（d,1H,H-1b,J＝7.6Hz） 1.098（d,3H,H-6c,J＝6.4Hz）13 C−NMR（CDCl3）δ； 97.686（C-1a）,97.469（C-1c）,56.402（C-2a） 〔参考例３〕 化合物〔６〕の合成 アルゴンガス雰囲気下、酸化銀3.01g（13mM）の入った
フラスコに、化合物〔４〕2.65g（2.5mM）及びベンジル
ブロマイド4.27g（25mM）を乾燥DMF25mlに溶解して注入
した。氷冷下、この反応溶液に、ヨウ化カリウム2.16g
（13mM）を加え、１時間撹拌した。反応終了後、反応溶
液を酢酸エチルで希釈し、不溶物をセライトよりろ去
し、ろ液を水、希塩酸、飽和食塩水にて順次洗浄後、硫
酸マグネシウムで乾燥し、溶媒を留去した。残渣をカラ
ムクロマトグラフィー（トルエン／酢酸エチル＝7/1展
開）にて精製し、油状物2.72g（収率、87.9％）を得
た。 Rf＝0.59（トルエン／酢酸エチルン＝6/1） 〔α▲〕27 D▼−2.2゜（Ｃ＝0.87、CHCl3） 元素分析値:C74H79NO16＝1238.452として 計算値 C;71.77 H;6.43 N;1.13 測定値 C;71.80 H;6.43 N;1.131 H−NMR（400MHz、CDCl3）δ； 7.72-7.01（m,34H,アロマチックＨ） 5.069（dd,1H,＝ＣＨ 2,J＝1.5,17.1Hz） 4.983（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 4.805（d,1H,H-1c,J＝3.2Hz）， 4.155（t,1H,H-2a,J＝9.5Hz） 3.528（d,1H,H-4c,J＝1.5Hz）， 0.990（d,3H,H-6c,J＝6.4Hz）13 C−NMR（CDCl3）δ； 101.470（C-1b）,97.850（C-1a）,97.469（C-1c）， 56.510（C-2a）,28.011, 〔参考例４〕 化合物〔７〕及び〔８〕の合成 化合物〔６〕2.62g（2.11mM）をトリフルオロ酢酸/THF/
水（20ml/25ml/5ml）混合溶媒に溶解し、氷冷下、４時
間及び室温下２時間撹拌した。反応溶液を酢酸エチルで
抽出し、水、飽和重ソウ水、飽和食塩水にて、順次洗浄
後、硫酸マグネシウムにて乾燥し、溶媒を留去した。残
渣をカラムクロマトグラフィー（トルエン／酢酸エチル
＝3/1展開）にて精製し、化合物〔７〕517mg（収率、3
1.3％）及び化合物〔８〕1.72g（収率、68.0g）を得
た。 化合物〔７〕 Rf＝0.08 （トルエン／酢酸エチル＝3/1） 〔α▲〕27 D▼＋6.3゜（Ｃ＝0.73、CHCl3） 元素分析値:C44H47NO12＝781.866として 計算値 C;67.59 H;6.06 N;1.79 測定値 C;67.60 H;6.10 N;1.631 H−NMR（400MHz、CDCl3）δ； 7.85-7.16（m,19H,アロマチックＨ） 5.256（d,1H,H-1a,J＝8.5Hz） 5.132（dd,1H,＝ＣＨ 2,J＝1.5,17.4Hz） 5.047（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 4.340（d,1H,H-1b,J＝7.3Hz） 4.056（ddt,1H,O-CＨ 2CH＝CH2,J＝1.2,6.4,13.1Hz）13 C−NMR（CDCl3）δ； 103.537（C-1b）,97.361（C-1a） 56.239（C-2a） 化合物〔８〕 Rf＝0.45 （トルエン／酢酸エチル＝3/1） 〔α▲〕27 D▼−11.4゜（Ｃ＝0.76、CHCl3） 元素分析値:C71H75NO16＝1198.386として 計算値 C;71.16 H;6.31 N;1.17 測定値 C;71.70 H;6.38 N;1.491 H−NMR（400MHz、CDCl3）δ； 7.72-7.02（m,34H,アロマチックＨ） 5.162（d,1H,H-1a,J＝8.5Hz） 5.074（dd,1H,＝ＣＨ 2,J＝1.8,17.4Hz） 4.986（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 1.086（d,3H,H-6c,J＝6.4Hz）13 C−NMR（CDCl3）δ； 168.013（Ｃ＝０）,101.695（C-1b）,97.742（C-1a） 97.469（C-1c）,56.294（C-2a）,16.795（C-6c） 〔参考例５〕 化合物[9] with palladium chloride at 0-120 ° C for 3
Treatment for 0 minutes to 2 days gives compound [10]. Then, the compound [10] is reacted with trichloroacetonitrile for 5 minutes to 1 day at −20 to 60 ° C. in the presence of DBU (diazabicycloundecane) in a solvent such as chloroform, dichloromethane, dichloroethane, toluene or THF to give a novel compound. To obtain the compound [11]. Further, chloroform, dichloromethane, dichloroethane,
BF 3 .Ft 2 O or TMSOTf in a solvent such as toluene or THF
The compound [11] is reacted with the compound [12] in the presence of a glycosylation catalyst such as (trimethylsilyl triflate) to obtain a novel compound [13] having a pentasaccharide residue. Compound [14] is also obtained as a by-product. Then, the compound [13] was added to a solvent such as methanol or ethanol at −10 to 80 ° C. for 5 minutes to 1 day, and NaOCH 3 , NaOC 2 H 5 , N was added.
Deacetylation by treatment with a 2 CO 3 or NaHCO 3 gives the novel compound [15]. Further, chloroform, dichloromethane, dichloroethane,
BF 3 · Et 2 O or TMSO in a solvent such as toluene or THF
In the presence of a catalyst such as Tf, a known compound [16] in the compound [15]
Are reacted at −20 to 60 ° C. for 5 minutes to 1 day to obtain a novel compound [17] and a novel compound [18] as a by-product. Further, the compound [17] is treated with hydrazine at 0 to 120 ° C. for 5 minutes to 2 days in a solvent such as methanol or ethanol to remove the phthaloyl group, and then a solvent such as pyridi, chloroform, dichloroethane, dichloromethane or THF. Medium, -10 to 80 ℃ for 30 minutes to 2 days 4-DMAP if necessary
Acetic anhydride was reacted in the presence of (4-dimethylaminopyridine) to acetylate to obtain a novel compound [19]. Then in a solvent such as methanol, ethanol or acetic acid,
In the presence of a catalyst such as 10% Pd-C, 5% Pd-BaSO 4 , 5% Pt-C, etc., the compound [19] is subjected to hydrogen catalytic reduction at 0 to 100 ° C. for 1 hour to 3 days for debenzylation, Acetic anhydride, pyridine and 4-DMAP in a solvent such as pyridine, chloroform, dichloroethane, dichloromethane or THF, -10 to 80
Acetylation is carried out by reacting at 30 ° C. for 30 minutes to 2 days to obtain a novel compound [20] (yield 78%). Then, in the presence of hydrazine / acetic acid in a solvent such as DMF, DMSO, THF or dioxane, the compound [20] is treated at -10 to 100 ° C for 5 minutes to 1 day to remove the acetyl group at the 1-position, and chloroform, Dichloromethane, dichloroethane,
In a solvent such as toluene or THF, in the presence of DBU, -20 ℃ ~
The compound [21] is obtained by reacting with trichloroacetonitrile at 60 ° C. for 5 minutes to 1 day. Then, in a solvent such as chloroform, dichloromethane, dichloroethane, toluene or THF, BF 3 · Et 2 O and TM
The compound [21] is reacted with the ceramide compound [22] at −20 to 60 ° C. for 5 minutes to 1 day in the presence of a catalyst such as SOTf to obtain a novel compound [23]. Also, a novel compound [24] is obtained as a by-product. Then, the compound [23] is reacted at −20 to 100 ° C. for 5 minutes to 2 days in the presence of n-Bu 4 NF in a solvent such as THF or dioxane, and then NaOCH 3 in a solvent such as methanol, ethanol or THF. 3, the NaOC 2 H 5, Na 2 CO 3 or NaHCO 3 or the like of a base, for 5 minutes to 1 day at -10 to 80 ° C. the acetyl group desorbed to give the desired compound [1]. An example of the above reaction process is shown in the following scheme. (However, Ac represents an acetyl group.) [Effect of the invention] The glycosphingolipid-related compound of the present invention is indispensable for promoting the elucidation of the biochemical role of cancer-related sugar chains from the viewpoint of organic chemistry. Therefore, in the future, application to diagnosis, treatment, etc. is expected. The compound represented by the formula (1) of the present invention is a glycolipid consisting of octasaccharide residues which is a basic structure of the SSEA-1 antigen group, and the anti-SSEA-1 antibody formed using this as a antigen is a serum tumor. As a marker, it can be applied to diagnosis, treatment and the like of lung adenocarcinoma, ovarian cancer, pancreatic cancer and the like. Further, the glycosphingolipid-related compound can be produced in good yield by the method for producing a glycosphingolipid-related compound of the present invention. Next, the present invention will be described more specifically by reference examples and examples. [Reference Example 1] Synthesis of compound [3] Compound [2] 5.62 g (4.73 mM) was added to methanol / THF (20 ml /
20 ml) and add 0.2 N NaOCH 3 in methanol 5
ml was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, Amberlyst 15 was added to neutralize the reaction solution and then filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (acetone / toluene = 1/1 development) to give an oil 4.8
2 g (yield, quantitative) were obtained. Rf = 0.46 (toluene / acetone = 1/1) [α ▲] 25 D ▼ -19.9 ° (C = 0.88, CHCl 3 ) Elemental analysis value: Calculated as C 57 H 63 NO 16・ 1 / 2H 2 O = 1027.141 Value C; 66.65 H; 6.28 N; 1.36 Measured value C; 66.68 H; 6.27 N; 1.34 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.75-6.98 (m, 24 H, aromatic H) 5.145 (dd, 1H, = C H 2 , J = 1.5,17.4Hz) 5.061 (dd, 1H, = C H 2 , J = 1.5,10.8Hz) 4.873 (d, 1H, H-1c, J = 2.7Hz ) 4.489 (d, 1H, H-1b, J = 7.0Hz) 1.052 (d, 3H, H-6c, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 168.230 ( C = 0), 99.853 ( C-1b), 98.661 (C-1a) 96.984 (C-1c), 55.860 (C-2a), 16.362 (C-6c) [Reference Example 2] Synthesis of compounds [4] and [5] Compound [3] 4.58 g (4.5 mM) was dissolved in 20 ml DMF, to which was added 4.68 g (45 mM) dimethoxypropane and p-TsOH3.
00 mg was added, and the mixture was stirred at room temperature for 2 days. After the reaction,
After adding triethylamine to neutralize, extract with ethyl acetate,
After washing with water and saturated saline solution in that order, it was dried over magnesium sulfate and the solvent was distilled off. Dissolve the residue in 50 ml of methanol,
Amberlyst 15 was added to this, and after stirring at room temperature for 30 minutes,
After filtration, the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (toluene / acetone = 5/1 development) to obtain 3.52 g of compound [4] (yield 73.9%) and 0.77 g of compound [5] (yield 16.2 g). [4] Rf = 0.65 (toluene / acetone = 2/1) [α ▲] 25 D ▼ -7.0 ° (C = 0.79, CHCl 3 ) Elemental analysis: C 60 H 67 NO 16 = 1058.199 Calculated value C; 68.10 H; 6.38 N; 1.32 measured value C; 67.92 H; 6.43 N; 1.27 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.73-6.96 (m, 24 H, aromatic H) 5.140 (dd, 1H, = C H 2 , J = 1.5,17.4Hz) 5.055 (dd, 1H, = C H 2 , J = 1.5,10.4Hz) 4.784 (d, 1H, H-1c, J = 3.4Hz ) 4.396 (d, 1H, H-1b, J = 8.2Hz) 1.052 (d, 3H, H-6c, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 98.718 (C-1a), 96.984 (C-1c), 55.914 (C-2a) Compound [5] Rf = 0.43 (toluene / acetone = 2/1) [α ▲] 24 D ▼ + 2.5 ° (C = 0.56, CHCl 3 ) Elemental analysis value: C 60 H 67 NO 16・ 1 / 2H 2 O = 1067.206 Calculated value C; 67.53 H; 6.42 N; 1.31 Measured value C; 67.49 H; 6.39 N; 1.21 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.72-7.02 (m, 24 H, aromatic H) 5.113 (d, 1H, H-1a, J = 8.5Hz) 5.070 (dd, 1H, = C H 2 , J = 1.5,17.1Hz) 4.983 (dd, 1H, = C H 2 , J = 1.5,10.4Hz ) 4.833 (d, 1H, H-1c, J = 3.7Hz) 4.551 (d, 1H, H-1b, J = 7.6Hz) 1.098 (d, 3H, H-6c, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 97.686 (C-1a), 97.469 (C-1c), 56.402 (C-2a) [Reference Example 3] Synthesis of compound [6] 2.65 g (2.5 mM) of compound [4] and 4.27 g (25 mM) of benzyl bromide in a flask containing 3.01 g (13 mM) of silver oxide in an atmosphere of argon gas and dried with 25 ml of DMF. It was dissolved in and injected. 2.16 g of potassium iodide was added to this reaction solution under ice cooling.
(13 mM) was added and stirred for 1 hour. After completion of the reaction, the reaction solution was diluted with ethyl acetate, the insoluble matter was filtered off from Celite, the filtrate was washed successively with water, diluted hydrochloric acid and saturated brine, dried over magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography (toluene / ethyl acetate = 7/1 development) to obtain an oily substance 2.72 g (yield, 87.9%). Rf = 0.59 (toluene / ethyl acetate = 6/1) [α ▲] 27 D ▼ −2.2 ° (C = 0.87, CHCl 3 ) Elemental analysis value: C 74 H 79 NO 16 ＝ 1238.452 Calculated value C; 71.77 H ; 6.43 N; 1.13 Measured value C; 71.80 H; 6.43 N; 1.13 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.72-7.01 (m, 34 H, aromatic H) 5.069 (dd, 1H, = C H 2 , J = 1.5,17.1Hz) 4.983 (dd, 1H, = C H 2 , J = 1.5,10.4Hz) 4.805 (d, 1H, H-1c, J = 3.2Hz ), 4.155 (t, 1H, H-2a, J = 9.5Hz) 3.528 (d, 1H, H-4c, J = 1.5Hz), 0.990 (d, 3H, H-6c, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 101.470 (C-1b), 97.850 (C-1a), 97.469 (C-1c), 56.510 (C-2a), 28.011, [Reference Example 4] Synthesis of compounds [7] and [8] 2.62 g (2.11 mM) of compound [6] was added to trifluoroacetic acid / THF /
It was dissolved in a mixed solvent of water (20 ml / 25 ml / 5 ml) and stirred under ice cooling for 4 hours and at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (toluene / ethyl acetate = 3/1 development), and compound [7] 517 mg (yield, 3
1.3%) and 1.72 g of compound [8] (yield, 68.0 g) were obtained. Compound [7] Rf = 0.08 (toluene / ethyl acetate = 3/1) [α ▲] 27 D ▼ + 6.3 ° (C = 0.73, CHCl 3 ) Calculated as elemental analysis value: C 44 H 47 NO 12 = 781.866 Value C; 67.59 H; 6.06 N; 1.79 Measured value C; 67.60 H; 6.10 N; 1.63 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.85-7.16 (m, 19 H, aromatic H) 5.256 (d, 1H, H-1a, J = 8.5Hz) 5.132 (dd, 1H, = C H 2 , J = 1.5,17.4Hz) 5.047 (dd, 1H, = C H 2 , J = 1.5,10.4Hz) ) 4.340 (d, 1H, H-1b, J = 7.3Hz) 4.056 (ddt, 1H, OC H 2 CH = CH 2 , J = 1.2,6.4,13.1Hz) 13 C-NMR (CDCl 3 ) δ; 103.537 (C-1b), 97.361 (C-1a) 56.239 (C- 2a) Compound [8] Rf = 0.45 (toluene / ethyl acetate = 3/1) [α ▲] 27 D ▼ -11.4 ° (C = 0.76, CHCl 3 ) Elemental analysis value: C 71 H 75 NO 16 = 1198.386 Calculated value C; 71.16 H; 6.31 N; 1.17 Measured value C; 71.70 H; 6.38 N; 1.49 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.72-7.02 (m, 34 H, aromatic H) 5.162 (d, 1H, H-1a, J = 8.5Hz) 5.074 (dd, 1H, = C H 2 , J = 1.8,17.4Hz) 4.986 (dd, 1H, = C H 2 , J = 1.5,10.4Hz) ) 1.086 (d, 3H, H-6c, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 168.013 (C = 0), 101.695 (C-1b), 97.742 (C-1a) 97.469 (C- 1c), 56.294 (C-2a), 16.795 (C-6c) [Reference Example 5] Compound
〔９〕の合成 化合物〔８〕450mg（0.37mM）を無水酢酸／ピリジン/4
−ジメチルアミノピリジン12ml/2ml/触媒量）に溶解
し、室温にて、終夜撹拌した。反応溶液を酢酸エチルで
抽出し、水、飽和重ソウ水、希塩酸、飽和食塩水にて、
順次洗浄後、硫酸マグネシウムにて乾燥し、溶媒を留去
した。残渣をカラムクロマトグラフィー（トルエン／酢
酸エチル＝6/1展開）にて精製して油状物420mg（収率、
87.3％）を得た。 Rf＝0.66 （トルエン／酢酸エチル＝5/1） 〔α▲〕26 D▼−7.9゜（Ｃ＝0.80、CHCl3） 元素分析値:C75H79NO18＝1282.462として 計算値 C;70.24 H;6.21 N;1.09 測定値 C;70.27 H;6.22 N;0.981 H−NMR（400MHz、CDCl3）δ； 7.72-6.99（m,34H,アロマチックＨ） 5.328（d,1H,H-4b,J＝2.7Hz） 5.109（d,1H,H-1a,J＝8.5Hz）， 5.065（dd,1H,＝ＣＨ 2,J＝1.5,17.4Hz）， 4.983（dd,1H,＝ＣＨ 2,J＝1.5,10.4Hz） 4.826（d,1H,H-1c,J＝3.6Hz）， 4.566（d,1H,H-1b,J＝7.6Hz） 3.884（dd,1H,H-3c,J＝2.7,10.1Hz）， 3.777（dd,1H,H-2c,J＝3.6,10.1Hz） 3.519（d,1H,H-4c,J＝3.1Hz）， 1.911,1.749（２×S,6H,COＣH3）， 1.128（d,3H,H-6C,J＝6.4Hz），13 C−NMR（CDCl3）δ； 169.747,169.530,168.013（Ｃ＝０）,101.968（C-1
b）， 97.794（C-1a）,97.469（C-1c）,56.402（C-2a）， 20.588（COCＨ ３）,17.012（C-6c） 〔参考例６〕 化合物〔10〕の合成 化合物Synthesis of [9] 450 mg (0.37 mM) of compound [8] was added to acetic anhydride / pyridine / 4
-Dimethylaminopyridine (12 ml / 2 ml / catalytic amount), and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, with water, saturated sodium bicarbonate water, diluted hydrochloric acid, and saturated saline,
After washing sequentially, the extract was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by column chromatography (toluene / ethyl acetate = 6/1 development) to give an oil (420 mg, yield,
87.3%). Rf = 0.66 (toluene / ethyl acetate = 5/1) [α ▲] 26 D ▼ −7.9 ° (C = 0.80, CHCl 3 ) Elemental analysis: C 75 H 79 NO 18 = 1282.462 Calculated C; 70.24 H ; 6.21 N; 1.09 measured value C; 70.27 H; 6.22 N; 0.98 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.72-6.99 (m, 34 H, aromatic H) 5.328 (d, 1H, H-4b, J = 2.7Hz) 5.109 (d, 1H, H-1a, J = 8.5Hz), 5.065 (dd, 1H, = C H 2 , J = 1.5,17.4Hz), 4.983 (dd, 1H, = C H 2 , J = 1.5,10.4Hz) 4.826 (d, 1H, H-1c, J = 3.6Hz), 4.566 (d, 1H, H-1b, J = 7.6Hz) 3.884 (Dd, 1H, H-3c, J = 2.7,10.1Hz), 3.777 (dd, 1H, H-2c, J = 3.6,10.1Hz) 3.519 (d, 1H, H-4c, J = 3.1Hz), 1.911,1.749 (2 × S, 6H, CO C H 3), 1.128 (d, 3H, H-6C, J = 6.4Hz), 13 C-NMR (CDCl 3) δ; 169.747,169.530,168.013 (C = 0), 101.968 (C-1
b), 97.794 (C-1a ), 97.469 (C-1c), 56.402 (C-2a), 20.588 (COC H 3), 17.012 (C-6c) Reference Example 6 Synthesis of Compound [10]
〔９〕405mg（0.316mM）、塩化パラジウム265mg
（1.5mM）及び酢酸ナトリウム123mg（1.5mM）を、90％
酢酸に溶解し、室温にて、４時間撹拌した。反応溶液を
酢酸エチルで希釈し、不溶物をセライトよりろ去し、ろ
液を水、飽和重ソウ水、飽和食塩水にて順次洗浄後、硫
酸マグネシウムにて乾燥し、溶媒を留去した。残渣をカ
ラムクロマトグラフィー（トルエン／酢酸エチル＝5/1
展開）にて精製し、油状物278mg（収率、70.9％）を得
た。 Rf＝0.58 （トルエン／酢酸エチル＝2/1） 〔α▲〕27 D▼＋1.6゜（Ｃ＝0.84、CHCl3） 元素分析値:C72H75NO18＝1242.396として 計算値 C;69.61 H;6.08 N;1.13 測定値 C;69.40 H;6.09 N;1.041 H−NMR（400MHz、CDCl3）δ； 7.71-6.89（m,34H,アロマチックＨ） 5.324（d,1H,H-4b,J＝2.7Hz） 4.830（d,1H,H-1c,J＝3.6Hz） 3.877（dd,1H,H-3c,J＝2.7,10.1Hz） 3.784（dd,1H,H-2c,J＝3.6,10.4Hz） 1.917,1.745（２×s,6H,COCH3） 1.135（d,3H,H-6c,J＝6.4Hz） 〔参考例７〕 化合物〔11〕の合成 アルゴンガス雰囲気下、化合物〔10〕232mg（0.186mM）
及びトリクロロアセトニトリル288mg（2mM）をジクロロ
メタン5mlに溶解し、これに、氷冷下、DBU30μ（0.2m
M）を注入し、１時間撹拌した。反応溶液を直接カラム
クロマトグラフィー（トルエン／酢酸エチル＝5/1展
開）にて精製し、油状物208mg（収率、81.2％）を得
た。 Rf＝0.46（トルエン／酢酸エチル＝5/1） 〔α▲〕27 D▼＋6.5゜（Ｃ＝1.0、CHCl3）1 H−NMR（400MHz、CDCl3）δ； 8.528（s,1H,NH） 7.69-6.99（m,34H,アロマチックＨ） 6.394（d,1H,H-1a,J＝8.8Hz） 5.328（d,1H,H-4b,J＝2.9Hz） 4.828（d,1H,H-1c,J＝3.6Hz） 4.627（d,1H,H-1b,J＝8.0Hz） 3.885（d,d,1H,H-3c,J＝2.4,10.2Hz） 3.786（dd,1H,H-2c,J＝3.6,10.2Hz） 1.915,1.759（２×S,6H,COCH3） 1.300（d,3H,H-6c,J＝6.6Hz） 〔参考例８〕 化合物〔13〕及び〔14〕の合成 アルゴンガス雰囲気下、事前に十分乾燥したM.S.（A.W.
400）1.5gの入った二径褐色フラスコに化合物〔11〕578
mg（0.42mM）及び〔12〕605mg（0.62mM）をジクロロエ
タン15mlに溶解し加えた。−23℃（CCl4−ドライアイ
ス）下、BF3・Et2O 50μ（0.42mM）を加え、１時間
撹拌した。トリエチルアミンを加え、反応を終了後、ク
ロロホルムで希釈し、不溶物をセライトよりろ去し、ろ
液を水、飽和重ソウ水、飽和食塩水にて順次洗浄し、硫
酸マグネシウムで乾燥後、溶媒を留去した。残渣をカラ
ムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝5/
1展開）にて精製し、化合物〔13〕472mg（収率、51.1
％）及び化合物〔14〕90mg（収率、17.5％）を得、化合
物〔12〕を372mg（収率、61.5％）を回収した。 化合物〔13〕 Rf＝0.40（ｎ−ヘキサン／酢酸エチル＝2/1） 〔α▲〕27 D▼−23.5゜（Ｃ＝0.52、CHCl3） 元素分析値:C133H137NO28＝2197.564 計算値 C;72.69 H;6.28 N;0.64 測定値 C;72.22 H;6.24 N;0.701 H−NMR（400MHz、CDCl3）δ； 7.38-6.84（m,69H,アロマチックＨ） 5.351（d,1H,H-4d,J＝3.6Hz） 5.345（d,1H,H-1c,J＝8.2Hz） 1.926,1.740（２×S,6H,COCＨ ３） 1.131（d,3H,H-6e,J＝6.7Hz）13 C−NMR（CDCl3）δ； 169.695,169.478,167.632（Ｃ＝０）,102.454（C-1a,C-
1b）,102.020（C-1d）,99.961（C-1c）,97.577（C-1
e）,57.106（C-2c）,20.534（COＣH3）,16.958（C-6e） 化合物〔14〕 Rf＝0.29（ｎ−ヘキサン／酢酸エチル） 〔α▲〕24 D▼−41.4゜（Ｃ＝0.69、CHCl3） 元素分析値:C72H74NO17＝1225.389として 計算値 C;70.57 H;6.09 N;1.14 測定値 C;70.63 H;6.03 N;1.081 H−NMR（400MHz、CDCl3）δ； 7.72-7.04（m,34H,アロマチックＨ） 6.714（s,1H,H-1a） 5.439（d,1H,H-4b,J＝2.7Hz） 4.955（dd,1H,H-3b,J＝3.6,10.4Hz） 4.797（d,1H,H-1c,J＝3.4Hz） 3.380（d,1H,H-4c,J＝1.5Hz） 2.039,1.952（２×S,6H,COCH3） 0.836（d,3H,H-6c,J＝6.7Hz）13 C−NMR（CDCl3）δ； 170.015,169.851,168.013（Ｃ＝０） 107.655（C-1a）,102.779（C-1b）,98.661（C-1c） 20.642（COＣH3）,16.525（C-6c） 〔参考例９〕 化合物〔15〕の合成 化合物〔13〕446mg（0.203mM）をメタノール/THF（10ml
/4ml）に溶解し、これに、0.2N NaOMeメタノール溶液2m
lを加え、室温にて、２時間撹拌した。反応終了後、ア
ンバーリスト15を加え、反応溶液を中和後、ろ去し、ろ
液を留去した。残渣をカラムクロマトグラフィー（トル
エン／酢酸エチル＝5/1展開）にて精製し、油状物374mg
（収率、87.2％）を得た。 Rf＝0.46（トルエン／酢酸エチル＝3/1） 〔α▲〕25 D▼−21.6゜（Ｃ＝0.69、CHCl3） 元素分析値:C129H133NO26＝2113.488として 計算値 C;73.31 H;6.34 N;0.66 測定値 C;73.42 H;6.38 N;0.701 H−NMR（400MHz、CDCl3）δ； 7.52-7.00（m,69H,アロマチックＨ） 5.400（d,1H,H-1c,J＝8.5Hz） 1.087（d,3H,H-6e,J＝6.4Hz）13 C−NMR（CDCl3）δ； 167.683（Ｃ＝０）,102.454（C-1a,C-1b）， 101.804（C-1d）,99.961（C-1c）,97.742（C-1e）， 57.052（C-2c）,16.904（C-6e） 〔実施例１〕 化合物〔17〕及び〔18〕の合成 アルゴンガス雰囲気下、事前に十分乾燥したM.S.（A.W.
400）500mgの入った二径褐色フラスコに化合物〔15〕
211mg（0.1mM）及び〔16〕182mg（0.14mM）をジクロロ
エタン7mlに溶解し加えた。−23℃（四塩化炭素／ドラ
イアイス）下、BF3・Et2O 12μ（0.1mM）を加え、１
時間撹拌した。トリエチルアミンを加え、反応を終了
後、クロロホルムで希釈し、不溶物をセライトよりろ去
し、ろ液を飽和重ソウ水、飽和食塩水にて順次洗浄後、
硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をゲ
ルろ過法（Bio-boads S-X2、日本バイオラッドラボラト
リーズ、ベンゼン展開）及びカラムクロマトグラフィー
（トルエン／酢酸エチル＝4/1展開）にて精製し、化合
物〔17〕252mg（収率、77.8％）化合物〔18〕20.0mg
（収率、12.0％）及び化合物〔15〕14mg（収率、6.6
％）を回収した。 化合物〔17〕 Rf＝0.72（トルエン／酢酸エチル） 〔α▲〕26 D▼27.4゜（Ｃ＝0.92、CHCl3） 元素分析値:C191H198N2O45・H2O＝3259.707として 計算値 C;70.38 H;6.18 N;0.86 測定値 C;70.07 H;6.09 N;0.961 H−NMR（400MHz、CDCl3）δ； 7.41-6.79（m,93H,アロマチックＨ） 5.316（d,1H,H-1f,J＝8.3Hz）， 5.236（d,1H,H-4h,J＝2.7Hz） 5.148（d,1H,H-1c,J＝8.3Hz）， 5.008（dd,1H,H-2h,j＝8.3,10.3Hz） 1.999,1.982,1.947,1.824（４×S,12H,COCH3）， 1.194（d,3H,H-6g,J＝6.4Hz）， 0.999（d,3H,H-6e,J＝6.4Hz）13 C−NMR（CDCl3）δ； 169.851,169.634,168.446,167.849（Ｃ＝０） 102.402,101.643,99.961,99.584,98.934,97.469（C-1a-
h） 57.106,56.510（C-2c,f） 21.347,20.371（COＣH3）,16.687（C-6e,g） 化合物の〔18〕 Rf＝0.40（トルエン／酢酸エチル） 〔α▲〕24 D▼−36.9゜（Ｃ＝0.51,CHCl3） 元素分析値;C62H65NO19:1/2H2O＝1137,212 計算値 C;65.48 H;5.85 N;1.23 測定値 C;65.10 H;5.79 N;1.231 H−NMR（400MHz、CDCl3）δ； 7.73-7.04（m,24H,アロマチックＨ） 6.686（s,1H,H-1a）,5.372（d,1H,H-4b,J＝2.4Hz） 5.259（dd,1H,H-2b,J＝8.2,10.7Hz） 4.984（dd,1H,H-3b,J＝3.3,10.7Hz） 4.824（d,1H,H-1c,J＝3.0Hz） 4.713,（d,1H,H-1b,J＝7.9Hz）,3.747（q,1H,H-5c,J＝
6.1Hz） 3.390（d,1H,H-4c,J＝1.5Hz） 2.163,2.064,1.988,1.924,（４×S,12H,COCH3） 0.843（d,3H,H-6c,J＝6.4Hz） 〔実施例２〕 化合物〔19〕の合成 化合物〔17〕252mg（0.077mM）を２％ヒドラジン−エタ
ノール20mlに溶解し、終夜還流撹拌した。溶媒を留去
し、残渣を無水酢酸／ピリジン/4−ジメチルアミノピリ
ジン（2ml/2ml/触媒量）に溶解し、室温にて６時間撹拌
した。反応終了後、反応溶液を酢酸エチルで抽出し、
水、飽和重ソウ水、希塩酸、飽和食塩水で順次洗浄後、
硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をカ
ラムクロマトグラフィー（酢酸エチル／トルエン＝1/1
展開）にて精製し、油状物208mg（収率、86.3％）を得
た。 Rf＝0.43（酢酸エチル／トルエン＝1/1） 〔α▲〕25 D▼−30.9゜（Ｃ＝1.1、CHCl3） 元素分析値:C181H198N2O44・H2O＝3123.597として 計算値 C;69.60 H;6.45 N;0.89 測定値 C;69.27 H;6.43 N;0.841 H−NMR（400MHz、CDCl3）δ； 7.42-7.06（m,85H,アロマチックＨ） 5.501（d,1H,NH）,5.447（d,1H,H-4d,J＝3.3Hz） 5.419（d,1H,NH）,5.278（d,1H,H-4h,J＝3.0Hz） 2.019,1.947,1.934,1.862,1.832,1.469,1.266（７×S,2
1H,COCH3） 1.170（d,3H,H-H-6ｅorｇ,J＝6.4Hz） 1.114（d,3H8,H-6ｇorｅ,J＝6.4Hz）13 C−NMR（CDCl3）δ； 169.747,169.366,168.828（Ｃ＝０） 102.454,101.102,99.745,97.469,96.819（C-1a-h） 59.111,56.889（C-2c,f）,22.972,21.401,20.859,20.53
4（COＣH3）,17.121,16.741（C-6e,g） 〔実施例３〕 化合物〔20〕の合成 水素ガス雰囲気下、化合物〔19〕203mg（0.065mM）及び
10％Pd-C 50mgのメタノール酢酸（3ml/3ml）溶液を室温
にて終夜撹拌した。反応終了後、触媒をろ去し、溶媒を
留去後、残渣を無水酢酸／ピリジン/4−DMAP（2ml/2ml/
触媒量）に溶媒し、室温にて終夜撹拌した。反応溶液を
酢酸エチルで抽出し、水、飽和重ソウ水、希塩酸、飽和
食塩水にて順次洗浄後、硫酸マグネシウムで乾燥し、溶
媒を留去した。残渣をカラムクロマトグラフィー（アセ
トン／トルエン＝1/1展開）にて精製し、油状物117mg
（収率、78.0％）を得た。 Rf＝0.43 （アセトン／トルエン＝2/1） 元素分析値:C96H132N2O61＝2290.098 計算値 C;50.35 H;5.81 N;1.22 測定値 C;49.98 H;5.75 N;1.281 H−NMR（400MHz、CDCl3）δ； 6.254（d,1H,H-1aα,J＝3.7Hz） 2.191-1.966（mS,72H,COCH3） 1.203,1.156,（２×d,2×3H,H-6e,g J＝6.4Hz） 〔実施例４〕 化合物〔21〕の合成 化合物〔20〕103mg（0.045mM）をDMF2mlに溶解し、これ
にヒドラジン・酢酸塩9.2mg（0.1mM）を加え、室温にて
１時間撹拌した。反応溶液を酢酸エチルで抽出し、水洗
後、硫酸マグネシウムで乾燥し、溶媒を留去した。残渣
をジクロロエタン1mlに溶解し、これにトリクロアセト
ニトリル72mg（0.5mM）を加えた。アルゴンガス雰囲
気、氷冷下、これにDBU ７μ（0.045mM）を注入し、
１時間撹拌した。反応溶液を直接カラムクロマトグラフ
ィー（アセトン／トルエン＝1/1展開）にて精製し、化
合物〔21〕78mg（収率、72.5％）を得た。 Rf＝0.50 （アセトン／トルエン＝3/2） 〔α▲〕25 D▼−25.0゜（Ｃ＝1.00、CHCl3）1 H−NMR（400MHz、CDCl3）δ； 8.651（s,1H,＝NH） 6.482（d,1H,H-1a,J＝3.7Hz） 2.189-1.901（ms,69H,COCH3） 1.200,1.153,（２×d,2×3H,H-6e,g,J＝6.6Hz） 〔実施例５〕 化合物〔23〕及び〔24〕の合成 アルゴンガス雰囲気下、事前に十分乾燥したM.S.（A.W.
300）300mgの入った二径褐色フラスコに化合物〔21〕
24.0mg（0.1mM）及び〔22〕9.0mg（0.01mM）をクロロホ
ルム2mlに溶解し加えた。−23℃（CC l4−ドライアイ
ス）下、BF3・Et2O ２μ（0.015mM）を注入し、１時
間撹拌した。トリエチルアミンを加え、反応を終了後、
クロロホルムで希釈し、不溶物をセライトよりろ去し、
ろ液を飽和重ソウ水、飽和食塩水にて順次洗浄し、硫酸
マグネシウムで乾燥後、溶媒を留去した。残渣をカラム
クロマトグラフィー（トルエン／アセトン＝3/1展開）
及びゲルろ過法（Bio-boads S-X2、日本バイオラッドラ
ボラトリーズ、ベンゼン展開）にて精製し、化合物〔2
3〕1.5mg（収率、4.8％）及び〔24〕6.5mg（収率、27.2
％）を得た。 化合物〔23〕 Rf＝0.65 （トルエン／アセトン＝1/1） 〔α▲〕24 D▼−29.3゜（Ｃ＝0.058、CHCl3）1 H−NMR（400MHz、CDCl3）δ； 7.67-7.30（m,10H,アロマチックＨ） 2.188-1.900（ms,69H,COCH3） 1.202（d,3H,H-6ｅorｇ,J＝6.7Hz） 1.155（d,3H,H-6ｇorｅ,J＝6.4Hz） 1.004（s,9H,−tBu） 0.881（２×t,6H,2×CH3（Cer）,J＝5.5Hz） 化合物〔24〕 Rf＝0.36 （アセトン／トルエン＝1/1） 〔α▲〕25 D▼−47.0゜（Ｃ＝0.67、CHCl3） 元素分析値 C96H134N2O60・2H2O＝2312.146として 計算値 C;49.87 H;6.01 N;1.21 測定値 C;49.55 H;5.79 N;1.231 H−NMR（400MHz、CDCl3）δ； 2.192-1.902（ms,69H,COCH3） 1.203,1.154,（２×d,2×3H,H-6e,g,J＝6.7Hz） 〔実施例６〕 化合物〔１〕の合成 化号物〔23〕1.2mg（3.8×10-4mM）をTHF0.5mlに溶解
し、これにテトラｎ−ブチルアンモニウムフルオライド
のTHF1M溶液５μを加え、室温にて終夜撹拌した。反
応溶液を減圧下留去し、残渣をメタノール/THF（0.5ml/
0.5ml）に溶解し、これに、0.2N NaOMe/メタノール溶
液0.1mlを加え、室温にて４時間撹拌した。反応終了
後、アンバーリスト15を加え反応溶液を中和後、不溶物
をセライトよりろ去した。ろ液を濃縮後、残渣をゲルろ
過法（LH−20、クロロホルム／メタノール／水＝60/40/
4.6）にて精製し、化合物〔１〕0.5mg（収率、4.8％）
を得た。 Rf＝0.43 （ｎ−ブタノール／エタノール／水＝2/1/
1）1 H−NMR（400MHz、d6-DMSO）δ； 5.544（df,1H,H-5Cer,J＝6.1,14.6Hz） 5.357（dd,1H,H-4Cer,J＝7.3,15.1Hz） 4.858（d,2H,H-1d,g,J＝3.4Hz） 4.730（d,1H,H-1c,J＝7.6Hz） 4.714（d,1H,H-1f） 4.624（q,2H,H-5d,g,J＝6.1Hz） 4.337（d,1H,H-1e,J＝6.8Hz） 4.291（d,1H,H-1h,J＝6.8Hz） 4.267（d,1H,H-1b） 4.168（d,1H,H-1a,J＝7.8Hz） 3.065（t,1H,H-2a,J＝7.8Hz） 2.026（t,1H,H-2′Cer,J＝7.5Hz） 1.907（s,6H,2×NAc） 1.007（d,6H,H-6 d,g,J＝6.3Hz） 0.853（t,6H,2×CH3 Cer,J＝6.3Hz）[9] 405 mg (0.316 mM), palladium chloride 265 mg
(1.5 mM) and 123 mg of sodium acetate (1.5 mM), 90%
It was dissolved in acetic acid and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, the insoluble matter was filtered off from Celite, the filtrate was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Column chromatography of the residue (toluene / ethyl acetate = 5/1
(Development) to obtain an oily substance (278 mg, yield, 70.9%). Rf = 0.58 (toluene / ethyl acetate = 2/1) [α ▲] 27 D ▼ + 1.6 ° (C = 0.84, CHCl3) Elemental analysis: C 72 H 75 NO 18 = 1242.396 Calculated C; 69.61 H ; 6.08 N; 1.13 measured value C; 69.40 H; 6.09 N; 1.04 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.71-6.89 (m, 34H, aromatic H) 5.324 (d, 1H, H-4b, J = 2.7Hz) 4.830 (d, 1H, H-1c, J = 3.6Hz) 3.877 (dd, 1H, H-3c, J = 2.7,10.1Hz) 3.784 (dd, 1H, H-2c, J = 3.6 , 10.4Hz) 1.917,1.745 (2 × s, 6H, COCH 3 ) 1.135 (d, 3H, H-6c, J = 6.4Hz) [Reference Example 7] Synthesis of compound [11] Compound [11] under argon gas atmosphere 10] 232mg (0.186mM)
And 288 mg (2 mM) of trichloroacetonitrile are dissolved in 5 ml of dichloromethane, and DBU 30μ (0.2 m
M) was injected and stirred for 1 hour. The reaction solution was directly purified by column chromatography (toluene / ethyl acetate = 5/1 development) to obtain 208 mg of an oil (yield, 81.2%). Rf = 0.46 (toluene / ethyl acetate = 5/1) [α ▲] 27 D ▼ + 6.5 ° (C = 1.0, CHCl 3 ) 1 H-NMR (400 MHz, CDCl 3 ) δ; 8.528 (s, 1H, NH) 7.69-6.99 (m, 34H, aromatic H) 6.394 (d, 1H, H-1a, J = 8.8Hz) 5.328 (d, 1H, H-4b, J = 2.9Hz) 4.828 (d, 1H, H-1c, J = 3.6Hz) 4.627 (d, 1H, H-1b, J = 8.0Hz) 3.885 (d, d, 1H, H-3c, J = 2.4,10.2Hz) 3.786 (dd, 1H, H -2c, J = 3.6,10.2Hz) 1.915,1.759 (2 × S, 6H, COCH 3 ) 1.300 (d, 3H, H-6c, J = 6.6Hz) [Reference Example 8] Compounds [13] and [14] ] Synthesis of MS (AW
400) Compound [11] 578 in a 2 diameter brown flask containing 1.5 g
mg (0.42 mM) and [12] 605 mg (0.62 mM) were dissolved in 15 ml of dichloroethane and added. Under −23 ° C. (CCl 4 -dry ice), BF 3 · Et 2 O 50 μ (0.42 mM) was added, and the mixture was stirred for 1 hour. Triethylamine was added, and after the reaction was completed, the mixture was diluted with chloroform, the insoluble matter was filtered off from Celite, and the filtrate was washed successively with water, saturated sodium bicarbonate solution and saturated saline, dried over magnesium sulfate, and then the solvent was added. Distilled off. The residue was subjected to column chromatography (n-hexane / ethyl acetate = 5 /
1 development), compound [13] 472 mg (yield, 51.1
%) And compound [14] 90 mg (yield, 17.5%), and compound [12] 372 mg (yield, 61.5%) was recovered. Compound [13] Rf = 0.40 (n-hexane / ethyl acetate = 2/1) [α ▲] 27 D ▼ -23.5 ° (C = 0.52, CHCl 3 ) Elemental analysis value: C 133 H 137 NO 28 = 2197.564 Calculation Value C; 72.69 H; 6.28 N; 0.64 Measurement value C; 72.22 H; 6.24 N; 0.70 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.38-6.84 (m, 69H, aromatic H) 5.351 (d, 1H , H-4d, J = 3.6Hz) 5.345 (d, 1H, H-1c, J = 8.2Hz) 1.926,1.740 (2 × S, 6H, COC H 3 ) 1.131 (d, 3H, H-6e, J = 6.7 Hz) 13 C-NMR (CDCl 3 ) δ; 169.695,169.478,167.632 (C = 0), 102.454 (C-1a, C-
1b), 102.020 (C-1d), 99.961 (C-1c), 97.577 (C-1
e), 57.106 (C-2c ), 20.534 (CO C H 3), 16.958 (C-6e) Compound (14) Rf = 0.29 (n-hexane / ethyl acetate) [alpha ▲] 24 D ▼ -41.4 ° ( C = 0.69, CHCl 3 ) Elemental analysis value: calculated value as C 72 H 74 NO 17 = 1225.389 C; 70.57 H; 6.09 N; 1.14 measurement value C; 70.63 H; 6.03 N; 1.08 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.72-7.04 (m, 34H, aromatic H) 6.714 (s, 1H, H-1a) 5.439 (d, 1H, H-4b, J = 2.7Hz) 4.955 (dd, 1H, H-3b) , J = 3.6,10.4Hz) 4.797 (d, 1H, H-1c, J = 3.4Hz) 3.380 (d, 1H, H-4c, J = 1.5Hz) 2.039,1.952 (2 × S, 6H, COCH 3 ) 0.836 (d, 3H, H-6c, J = 6.7Hz) 13 C-NMR (CDCl 3 ) δ; 170.015,169.851,168.013 (C = 0) 107.655 (C-1a), 102.779 (C-1b), 98.661 (C-1c) 20.642 ( CO C H 3), 16.525 (C-6c) reference example 9 synthesis of compound [15] [13] 446 mg (0.203 mm) in methanol / THF (10 ml
/ 4ml) and add 0.2m NaOMe methanol solution 2m
l was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, Amberlyst 15 was added to neutralize the reaction solution, which was then filtered off, and the filtrate was evaporated. The residue was purified by column chromatography (toluene / ethyl acetate = 5/1 development), oil 374mg
(Yield, 87.2%) was obtained. Rf = 0.46 (toluene / ethyl acetate = 3/1) [α ▲] 25 D ▼ -21.6 ° (C = 0.69, CHCl 3 ) Elemental analysis: C 129 H 133 NO 26 ＝ 2113.488 Calculated C; 73.31 H ; 6.34 N; 0.66 measured value C; 73.42 H; 6.38 N; 0.70 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.52-7.00 (m, 69H, aromatic H) 5.400 (d, 1H, H-1c, J = 8.5Hz) 1.087 (d, 3H, H-6e, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 167.683 (C = 0), 102.454 (C-1a, C-1b), 101.804 ( C-1d), 99.961 (C-1c), 97.742 (C-1e), 57.052 (C-2c), 16.904 (C-6e) [Example 1] Synthesis of compounds [17] and [18] Argon gas atmosphere Bottom, fully dried MS (AW
400) Compound [15] in a 2 diameter brown flask containing 500 mg
211 mg (0.1 mM) and [16] 182 mg (0.14 mM) were dissolved in 7 ml of dichloroethane and added. Add BF 3 · Et 2 O 12 μm (0.1 mM) at −23 ° C. (carbon tetrachloride / dry ice), and add 1
Stir for hours. Triethylamine was added, and after the reaction was completed, the reaction mixture was diluted with chloroform, the insoluble matter was filtered off from Celite, and the filtrate was washed successively with saturated sodium bicarbonate water and saturated saline,
It was dried over magnesium sulfate and the solvent was distilled off. The residue was purified by gel filtration (Bio-boads S-X2, Nippon Bio-Rad Laboratories, benzene development) and column chromatography (toluene / ethyl acetate = 4/1 development), and compound [17] 252 mg (yield, 77.8%) Compound [18] 20.0 mg
(Yield, 12.0%) and Compound [15] 14 mg (Yield, 6.6
%) Was recovered. Compound [17] Rf = 0.72 (toluene / ethyl acetate) [α ▲] 26 D ▼ 27.4 ° (C = 0.92, CHCl 3 ) Elemental analysis value: Calculated as C 191 H 198 N 2 O 45・ H 2 O = 3259.707 Value C; 70.38 H; 6.18 N; 0.86 Measured value C; 70.07 H; 6.09 N; 0.96 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.41-6.79 (m, 93H, aromatic H) 5.316 (d, 1H , H-1f, J = 8.3Hz), 5.236 (d, 1H, H-4h, J = 2.7Hz) 5.148 (d, 1H, H-1c, J = 8.3Hz), 5.008 (dd, 1H, H- 2h, j = 8.3,10.3Hz) 1.999,1.982,1.947,1.824 (4 × S, 12H, COCH 3 ), 1.194 (d, 3H, H-6g, J = 6.4Hz), 0.999 (d, 3H, H -6e, J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ; 169.851,169.634,168.446,167.849 (C = 0) 102.402,101.643,99.961,99.584,98.934,97.469 (C-1a-
h) 57.106,56.510 (C-2c, f) 21.347,20.371 (CO C H 3 ), 16.687 (C-6e, g) Compound [18] Rf = 0.40 (toluene / ethyl acetate) [α ▲] 24 D ▼ -36.9 ° (C = 0.51, CHCl 3 ) Elemental analysis value; C 62 H 65 NO 19 : 1 / 2H 2 O = 1137,212 Calculated value C; 65.48 H; 5.85 N; 1.23 Measured value C; 65.10 H; 5.79 N; 1.23 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.73-7.04 (m, 24H, aromatic H) 6.686 (s, 1H, H-1a), 5.372 (d, 1H, H-4b, J = 2.4Hz) 5.259 (dd, 1H, H-2b, J = 8.2,10.7Hz) 4.984 (dd, 1H, H-3b, J = 3.3,10.7Hz) 4.824 (d, 1H, H-1c, J = 3.0Hz) 4.713, (d, 1H, H-1b, J = 7.9Hz), 3.747 (q, 1H, H-5c, J =
6.1Hz) 3.390 (d, 1H, H-4c, J = 1.5Hz) 2.163,2.064,1.988,1.924, (4 × S, 12H, COCH 3 ) 0.843 (d, 3H, H-6c, J = 6.4Hz Example 2 Synthesis of Compound [19] 252 mg (0.077 mM) of compound [17] was dissolved in 20 ml of 2% hydrazine-ethanol, and the mixture was stirred under reflux overnight. The solvent was evaporated, the residue was dissolved in acetic anhydride / pyridine / 4-dimethylaminopyridine (2 ml / 2 ml / catalytic amount), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate,
After washing sequentially with water, saturated heavy sour water, diluted hydrochloric acid, and saturated saline,
It was dried over magnesium sulfate and the solvent was distilled off. Column chromatography of the residue (ethyl acetate / toluene = 1/1
After purification, the oily substance was obtained in an amount of 208 mg (yield, 86.3%). Rf = 0.43 (ethyl acetate / toluene = 1/1) [α ▲] 25 D ▼ -30.9 ° (C = 1.1, CHCl 3 ) Elemental analysis value: C 181 H 198 N 2 O 44・ H 2 O = 3123.597 Calculated value C; 69.60 H; 6.45 N; 0.89 Measured value C; 69.27 H; 6.43 N; 0.84 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.42-7.06 (m, 85 H, aromatic H) 5.501 (d, 1H, NH), 5.447 (d, 1H, H-4d, J = 3.3Hz) 5.419 (d, 1H, NH), 5.278 (d, 1H, H-4h, J = 3.0Hz) 2.019,1.947,1.934, 1.862,1.832,1.469,1.266 (7 × S, 2
1H, COCH 3 ) 1.170 (d, 3H, HH-6 e or g , J = 6.4Hz) 1.114 (d, 3H8, H-6 g or e , J = 6.4Hz) 13 C-NMR (CDCl 3 ) δ 169.747,169.366,168.828 (C = 0) 102.454,101.102,99.745,97.469,96.819 (C-1a-h) 59.111,56.889 (C-2c, f), 22.972,21.401,20.859,20.53
4 (CO C H 3), 17.121,16.741 (C-6e, g) Synthesis of hydrogen gas atmosphere EXAMPLE 3 Compound [20], compound [19] 203 mg (0.065 mm) and
A solution of 50 mg of 10% Pd-C in methanol acetic acid (3 ml / 3 ml) was stirred overnight at room temperature. After completion of the reaction, the catalyst was filtered off, the solvent was distilled off, and the residue was mixed with acetic anhydride / pyridine / 4-DMAP (2 ml / 2 ml /
(Catalyst amount), and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate, washed successively with water, saturated aqueous sodium hydrogen carbonate, diluted hydrochloric acid and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography (developed with acetone / toluene = 1/1) and the oil was 117 mg.
(Yield, 78.0%) was obtained. Rf = 0.43 (acetone / toluene = 2/1) Elemental analysis value: C 96 H 132 N 2 O 61 = 2290.098 Calculated value C; 50.35 H; 5.81 N; 1.22 Measured value C; 49.98 H; 5.75 N; 1.28 1 H -NMR (400MHz, CDCl 3) δ ; 6.254 (d, 1H, H-1aα, J = 3.7Hz) 2.191-1.966 (mS, 72H, COCH 3) 1.203,1.156, (2 × d, 2 × 3H, H -6e, g J = 6.4 Hz) [Example 4] Synthesis of compound [21] Compound [20] 103 mg (0.045 mM) was dissolved in DMF 2 ml, and hydrazine acetate 9.2 mg (0.1 mM) was added thereto. The mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 1 ml of dichloroethane, and 72 mg (0.5 mM) of trichloroacetonitrile was added thereto. DBU 7μ (0.045mM) was injected into this under argon gas atmosphere and ice cooling,
Stir for 1 hour. The reaction solution was directly purified by column chromatography (acetone / toluene = 1/1 development) to obtain 78 mg (yield, 72.5%) of compound [21]. Rf = 0.50 (acetone / toluene = 3/2) [α ▲] 25 D ▼ -25.0 ° (C = 1.00, CHCl 3 ) 1 H-NMR (400 MHz, CDCl 3 ) δ; 8.651 (s, 1H, = NH ) 6.482 (d, 1H, H-1a, J = 3.7Hz) 2.189-1.901 (ms, 69H, COCH 3 ) 1.200,1.153, (2 × d, 2 × 3H, H-6e, g, J = 6.6Hz Example 5 Synthesis of Compounds [23] and [24] MS (AW) which was sufficiently dried in advance under an argon gas atmosphere.
300) Compound [21] in a 2 diameter brown flask containing 300 mg
24.0 mg (0.1 mM) and [22] 9.0 mg (0.01 mM) were dissolved in 2 ml of chloroform and added. Under −23 ° C. (CCl 4 − dry ice), BF 3 · Et 2 O 2 μ (0.015 mM) was injected, and the mixture was stirred for 1 hour. After adding triethylamine to complete the reaction,
Dilute with chloroform, remove insoluble matter by filtration from Celite,
The filtrate was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. Column chromatography of the residue (toluene / acetone = 3/1 development)
And gel filtration (Bio-boads S-X2, Nippon Bio-Rad Laboratories, developed with benzene) to give compound [2
3] 1.5 mg (yield, 4.8%) and [24] 6.5 mg (yield, 27.2
%) Was obtained. Compound [23] Rf = 0.65 (toluene / acetone = 1/1) [α ▲] 24 D ▼ -29.3 ° (C = 0.58, CHCl 3 ) 1 H-NMR (400 MHz, CDCl 3 ) δ; 7.67-7.30 ( m, 10H, aromatic H) 2.188-1.900 (ms, 69H, COCH 3 ) 1.202 (d, 3H, H-6 e or g , J = 6.7Hz) 1.155 (d, 3H, H-6 g or e ,) J = 6.4Hz) 1.004 (s, 9H, -tBu) 0.881 (2 × t, 6H, 2 × CH 3 (Cer), J = 5.5Hz) compound [24] Rf = 0.36 (acetone / toluene = 1/1 ) [Α ▲] 25 D ▼ -47.0 ° (C = 0.67, CHCl 3 ) Elemental analysis value C 96 H 134 N 2 O 60・ 2H 2 O = 2312.146 Calculated value C; 49.87 H; 6.01 N; 1.21 Measured value C; 49.55 H; 5.79 N; 1.23 1 H-NMR (400 MHz, CDCl 3 ) δ; 2.192-1.902 (ms, 69H, COCH 3 ) 1.203,1.154, (2 × d, 2 × 3H, H-6e, g , J = 6.7 Hz) [Example 6] Synthesis of compound [1] 1.2 mg (3.8 x 10 -4 mM) of compound [23] was dissolved in 0.5 ml of THF, and tetra-n-butylammonium fluoride was added thereto. 5 μL of THF1M solution was added and stirred overnight at room temperature. I stirred. The reaction solution was evaporated under reduced pressure, and the residue was methanol / THF (0.5 ml /
0.5 ml), 0.2N NaOMe / methanol solution (0.1 ml) was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, Amberlyst 15 was added to neutralize the reaction solution, and the insoluble matter was removed by filtration from Celite. After concentrating the filtrate, the residue was subjected to gel filtration (LH-20, chloroform / methanol / water = 60/40 /
4.6), 0.5 mg of compound [1] (yield, 4.8%)
Got Rf = 0.43 (n-butanol / ethanol / water = 2/1 /
1) 1 H-NMR (400MHz, d 6 -DMSO) δ; 5.544 (df, 1H, H-5Cer, J = 6.1,14.6Hz) 5.357 (dd, 1H, H-4Cer, J = 7.3,15.1Hz) 4.858 (d, 2H, H-1d, g, J = 3.4Hz) 4.730 (d, 1H, H-1c, J = 7.6Hz) 4.714 (d, 1H, H-1f) 4.624 (q, 2H, H- 5d, g, J = 6.1Hz) 4.337 (d, 1H, H-1e, J = 6.8Hz) 4.291 (d, 1H, H-1h, J = 6.8Hz) 4.267 (d, 1H, H-1b) 4.168 (D, 1H, H-1a, J = 7.8Hz) 3.065 (t, 1H, H-2a, J = 7.8Hz) 2.026 (t, 1H, H-2′Cer, J = 7.5Hz) 1.907 (s, 6H, 2 × NAc) 1.007 (d, 6H, H-6 d, g, J = 6.3Hz) 0.853 (t, 6H, 2 × CH 3 Cer, J = 6.3Hz)
Claims (1)
を特徴とするスフィンゴ糖脂質関連化合物〔１〕の製造
法。 （ただしAcはアセチル基を表わす。） （ａ）化合物〔15〕及び化合物〔16〕を反応せしめて化
合物〔17〕を製造する工程。 （ただしAcはアセチル基、Bnはベンジル基、Phthはフタ
ロイル基を表わす。） （ｂ）化合物〔17〕をヒドラジン処理してフタロイル基
を脱離し、次いでアセチル化して化合物〔19〕を製造す
る工程。 （ｃ）化合物〔19〕を脱ベンジル化し、次いでアセチル
化して化合物〔20〕を製造する工程。 （ｄ）化合物〔20〕をヒドラジン／酢酸で処理した後、
トリクロロアセトニトリルで処理して化合物〔21〕を製
造する工程。 （ｅ）化合物〔21〕とセラミド化合物〔22〕を反応せし
め、化合物〔23〕を製造する工程。 （ただしPhはフェニル基を表す。） （ｆ）化合物〔23〕の保護基を脱離し、化合物〔１〕を
製造する工程。1. A process for producing a glycosphingolipid-related compound [1], which comprises the following steps (a) to (f): (However, Ac represents an acetyl group.) (A) A step of reacting the compound [15] and the compound [16] to produce the compound [17]. (However, Ac represents an acetyl group, Bn represents a benzyl group, and Phth represents a phthaloyl group.) (B) A step of treating the compound [17] with hydrazine to eliminate the phthaloyl group, and then acetylating to produce a compound [19]. . (C) A step of producing a compound [20] by debenzylating the compound [19] and then acetylating it. (D) After treating the compound [20] with hydrazine / acetic acid,
A step of producing compound [21] by treating with trichloroacetonitrile. (E) A step of producing a compound [23] by reacting the compound [21] with a ceramide compound [22]. (However, Ph represents a phenyl group.) (F) A step of removing the protecting group of the compound [23] to produce the compound [1].
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30743186A JPH0689042B2 (en) | 1986-12-23 | 1986-12-23 | Method for producing glycosphingolipid-related compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30743186A JPH0689042B2 (en) | 1986-12-23 | 1986-12-23 | Method for producing glycosphingolipid-related compound |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8643394A Division JPH0819161B2 (en) | 1994-04-25 | 1994-04-25 | Novel glycosphingolipid-related compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63159402A JPS63159402A (en) | 1988-07-02 |
| JPH0689042B2 true JPH0689042B2 (en) | 1994-11-09 |
Family
ID=17968983
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30743186A Expired - Lifetime JPH0689042B2 (en) | 1986-12-23 | 1986-12-23 | Method for producing glycosphingolipid-related compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0689042B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0508493A1 (en) * | 1986-08-06 | 1992-10-14 | Mect Corporation | Ganglioside related compounds and method of producing the same |
| JPH07126278A (en) * | 1993-09-10 | 1995-05-16 | Daikin Ind Ltd | Fluorinated ganglioside gm3 |
| JP2828391B2 (en) * | 1993-10-29 | 1998-11-25 | 東燃株式会社 | Liposomes with oligosaccharides on the surface |
| JPH0952902A (en) * | 1995-08-09 | 1997-02-25 | Daikin Ind Ltd | Fluorine-containing sialyl-lewis x derivative and its synthetic intermediate |
-
1986
- 1986-12-23 JP JP30743186A patent/JPH0689042B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63159402A (en) | 1988-07-02 |
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