JP2854203B2 - Process for the preparation of liposomes - Google Patents

Process for the preparation of liposomes

Info

Publication number
JP2854203B2
JP2854203B2 JP26089392A JP26089392A JP2854203B2 JP 2854203 B2 JP2854203 B2 JP 2854203B2 JP 26089392 A JP26089392 A JP 26089392A JP 26089392 A JP26089392 A JP 26089392A JP 2854203 B2 JP2854203 B2 JP 2854203B2
Authority
JP
Japan
Prior art keywords
1h
compound
dd
hz
3h
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
Application number
JP26089392A
Other languages
Japanese (ja)
Other versions
JPH0680560A (en
Inventor
詩郎 三好
暁 中林
淳 佐々木
仁史 山内
治民 山田
直一 村橋
邦雄 東
安理 森川
宏 渡辺
英雄 金子
勝利 青野
Original Assignee
株式会社ディ・ディ・エス研究所
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 株式会社ディ・ディ・エス研究所 filed Critical 株式会社ディ・ディ・エス研究所
Priority to JP26089392A priority Critical patent/JP2854203B2/en
Publication of JPH0680560A publication Critical patent/JPH0680560A/en
Application granted granted Critical
Publication of JP2854203B2 publication Critical patent/JP2854203B2/en
Anticipated expiration legal-status Critical
Application status is Expired - Lifetime legal-status Critical

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • A61K9/1271Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【産業上の利用分野】本発明は、いわゆる薬物送達システム(Drug Delivery System)としての薬物保持リポソームの製造法に関し、更に詳しくは、臓器指向性センサーを担い易くしたリポソームの製造法にする。 BACKGROUND OF THE INVENTION The present invention relates to a method for producing drug-retaining liposomes as a so-called drug delivery system (Drug Delivery System), and more particularly, to a method for producing liposomes easily play the organ directional sensor.

【0002】 [0002]

【従来の技術と問題点】生体に投与される薬物を必要な組織に必要な時に必要な量だけ送達し、有効な薬物治療を行なうドラッグデリバリーシステムの1つの手段として、リポソームやリピッドマイクロスフェアーなどの微粒子キャリヤーを利用することは公知である。 Delivered amount when needed to the prior art and problems Tissues required drug to be administered to a living body, as a means of drug delivery system for effective drug treatment, liposomes and lipid microspheres it is known to use a particulate carrier such as. しかしながら、これら微粒子キャリヤーが血管内に投与された場合には、肝臓、ひ臓等に代表される細網内皮系組織に捕捉され易く、従って薬物放出をコントロールする徐放性製剤や標的組織への薬物送達を目指すターゲティング型製剤への利用においてはなお問題があることもよく知られているところである。 However, if these fine particles carrier is administered intravascularly, liver, trapped in reticuloendothelial system tissue typified spleen, etc. easy, therefore the drug to the sustained release formulation or target tissues to control the drug release it is also a place that is well-known that there is still a problem in the use of the targeting type formulation that aims to delivery.

【0003】そこで、この問題を解決するために、リポソームに糖、抗体等の臓器指向性センサーを担わせることが試みられている。 [0003] To solve this problem, sugar liposomes, be borne organ directional sensor, such as an antibody has been attempted. 即ち、臓器指向性センサーの脂質誘導体によりリポソームを被覆して、リポソーム表層に臓器指向性センサーを露出させる。 That is, to cover the liposome lipid derivatives organ directional sensor to expose the organ directional sensor liposome surface. しかるにこの従来の方法によれば、ある場合には臓器指向性センサーが正しくあるいは高い頻度で臓器を認識せず、ある場合には、 However, according to this conventional method, not recognize the organ correctly or high frequency organ directivity sensor when there, in some cases,
臓器指向性センサーの脂質誘導体がリポソームを効率よく被覆せず、更にある場合には、リポソームの粒径が一定でなく、加えて他の場合には、リポソームの安定性が低い等の問題があった。 Uncoated efficient liposomal lipid derivatives organ directional sensor, if further there is not a particle size of the liposome is constant, in addition to other cases and is a problem of low stability of the liposomes It was.

【0004】 [0004]

【発明が解決しようとする課題】本発明は、安定性に優れ、細毛内皮系組織の回避性に優れ、特定の臓器への指向に優れ、そして薬物保持機能に優れたリポソームを提供することを目的とする。 [SUMMARY OF THE INVENTION The present invention is excellent in stability, excellent avoidance of cilia endothelial system tissues, superior directivity to a specific organ, and to provide excellent liposomal drug holding function for the purpose.

【0005】 [0005]

【課題を解決するための手段】本発明者は、上記課題を解決すべく鋭意研究の結果、本発明をなすに至った。 SUMMARY OF THE INVENTION The present inventors have, as a result of intensive studies to solve the above problems, the present invention has been accomplished.

【0006】以下、本発明を逐次説明する。 [0006] In the following, the present invention will be described sequentially.

【0007】 本発明は、原材料として、少なくとも、 [0007] The present invention is, as raw materials, at least,
極性脂質1モル、正電荷または負電荷を与える化合物0. Compounds giving polar mole lipid, a positive or negative charge 0.
05〜0.5 モル、コレステロール 0.3〜1.5モル、分子中に臓器指向性センサー、重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物0.02〜0.5 モル並びに水性溶媒50〜10 05 to 0.5 mol, cholesterol 0.3-1.5 mol, organ directional sensor in the molecule, polyethylene glycol having a degree of polymerization of 3-6 and Compound 0.02 mole and an aqueous solvent having at least two alkyl groups having a carbon number of 5-20 50 to 10
0 lをこの割合で使用することを特徴とするリポソームの製造法に関する。 The 0 l relates to a process for the preparation of liposomes, characterized by using at this ratio.

【0008】極性脂質は、リポソームの膜を形成する主成分である。 [0008] polar lipids, which is a main component for forming a film of the liposome. このような極性脂質としては、ジホスファチジルグリセロール、ホスファチジルイノシトール、ホスファチジルエタノールアミン、ホスファチジルコリン等の極性脂質並びにこれら極性脂質の混合物が挙げられるが、ホスファチジルコリン等の燐脂質が特に好適である。 Examples of such polar lipids, diphosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, mixtures polar lipids and their polar lipids, such as phosphatidylcholine, phospholipids, such as phosphatidylcholine is particularly preferred. ホスファチジルコリンとしては、ジミリストイルホスファチジルコリン、ジパルミトイルホスファチジルコリン、ジステアロイルフォスファチジルコリン、卵黄レシチン、大豆レシチン等が好ましい。 The phosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, egg yolk lecithin, soybean lecithin and the like are preferable.

【0009】正電荷を与える化合物としては、例えば、 [0009] As the compound giving a positive charge, for example,
ステアリルアミン等の脂肪族アミンが、そして負電荷を与える化合物としては、例えば、ジセチル燐酸が挙げられる。 Aliphatic amines stearylamine etc., and as the compound providing a negative charge, for example, dicetyl phosphate. これらの化合物は、極性脂質1モルに対し、0.05 These compounds, compared polar lipids 1 mol, 0.05
〜0.5 モルの割合で使用される。 0.5 is used in a proportion of mol.

【0010】コレステロールは、安定剤として使用するもので、この使用量が多すぎるとリポソームの形成が阻害されるかリポソームが形成されたとしても物理化学的に不安定であり、一方、少なすぎても安定なリポソームができない。 [0010] Cholesterol is for use as a stabilizer, is also physicochemically unstable as liposomes or the if the amount is too much formation of liposomes is inhibited is formed, whereas, with too little It can not be a stable liposomes. 従って、極性脂質1モルに対し 0.3〜1.5 Thus, polar lipids relative to 1 mol of 0.3 to 1.5
モルの割合での使用が好ましい。 Using a ratio of moles are preferred.

【0011】分子中に臓器指向性センサー、重合度3〜 [0011] organ directional sensor in the molecule, the degree of polymerization 3
6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物(以下、「脂質誘導体」ということがある)は、リポソームを被覆して臓器指向性センサーを担わせるものである。 6 Polyethylene glycol and at least two compounds having an alkyl group having 5 to 20 carbon atoms (hereinafter sometimes referred to as "lipid derivative") is for covering the liposome to play a organ directional sensor.

【0012】ポリエチレングリコールとしては、エチレングリコールの重合度3〜6のものを用いなければならない。 [0012] The polyethylene glycol must be used those having a polymerization degree of 3-6 ethylene glycol. これ以外の重合度のものを用いても望ましい結果は得られない。 No results are obtained preferably also be used as other degree of polymerization.

【0013】脂質誘導体の分子中に少なくとも2個炭<br/>素数5〜20のアルキル基を有する化合物とポリエチレン The compounds having at least two alkyl groups of carbon <br/> prime 5-20 in the molecule of the lipid derivative and polyethylene
グリコールとの結合様式に関して説明すると、脂質誘導体分子内において、ポリエチレングリコールその水酸基に直接結合しうる官能基例えばカルボキシル基を有する化合物が結合している場合と、該水酸基に結合しうる官能基を有するリンカー例えばグルタミン酸に化合物が結合している場合とがある。 To explain with respect to the binding mode of glycol, in the lipid derivative molecule, and if the compound having a functional group such as carboxyl group polyethylene glycol may engage directly stitched to the hydroxyl group is bonded, it may engage binding to the hydroxyl group and a case where the compound to a linker such as glutamic acid having a functional group is attached. 後者では、リンカーに2個の化合物が結合しうるようにできる故に都合がよい。 In the latter, it is convenient because it can be as may combine two compounds to the linker. Or
た、ポリエチレンレグリコールの水酸基がアミノ基また And a hydroxyl group of the polyethylene les glycol are also amino groups
はその他の反応性官能基に置き代わっている場合にも、 Even if the are replaced every other reactive functional groups,
上記と同様に、アルキル基が直接該反応性官能基と結合 Similar to the above, bonded directly to the reactive functional group is an alkyl group
している場合と、リンカーを介して結合している場合と And if you are, if they were attached through a linker
がある。 There is.

【0014】アルキル基の供与体として、脂肪酸、脂肪族アルコール及び脂肪族一級アミンを挙げることができる。 [0014] donor alkyl group include a fatty acid, fatty alcohols and aliphatic primary amines. これらの脂肪酸、脂肪族アルコール、脂肪族アミン等は、直鎖型及び分枝鎖型のいずれでもよい。 These fatty acids, fatty alcohols, fatty amines, etc. may be any of straight chain and branched chain.

【0015】炭素数5〜20のアルキル基を少なくとも2 [0015] The alkyl group having 5 to 20 carbon atoms at least 2
個有する化合物は、エチレングリコール、グルタミン酸等のリンカーを介して2個以上の炭素数5〜20のアルキ<br/>ル基がつながっているようなものでもよく、また2つ以 Compounds that individual chromatic include ethylene glycol, rather good even like alkyl <br/> Le group having 2 or more carbon atoms 5-20 via a linker glutamic acid is connected, also two or more
上に分岐しそれぞれの分岐が炭素数5〜20である分岐ア Branch A respective branches 5 to 20 carbon atoms branched on
ルキル基を有するようなものでもよい。 Alkyl group may be those having a.

【0016】本発明の脂質誘導体に含まれるべき少くと [0016] at least to be included in the lipid derivatives of the present invention
も2個のアルキル基を有する化合物のアルキル基の炭素数は、直鎖及び分枝鎖いずれのアルキル基においても5 The number of carbon atoms in the alkyl group of the compound also having two alkyl groups, 5 also in the straight and branched one alkyl group
〜20、好ましくは12〜18である To 20, preferably 12 to 18.

【0017】脂質誘導体において、アルキル基の一端の炭素原子は上記のようにポリエチレングリコールまたはリンカーと結合しうる官能基を有するが、他端の炭素原子は水素原子以外のものと結合していないでメチル基となっている(すなわち、官能基化されていない)。 [0017] In a lipid derivative, carbon atoms at one end of the alkyl group has a functional group capable of bonding to polyethylene glycol or a linker as described above, the carbon atoms at the other end is not bound to the other than hydrogen atoms has a methyl group (i.e., non-functionalized).

【0018】脂質誘導体のポリエチレングリコールの一端の水酸基は、上記のようにそのまままたはアミノ基等の他の官能基と置換してアルキル基の官能基と直接にまたはリンカーを介して結合しているが、他端は、抗体、 The hydroxyl group at one end of polyethylene glycol of lipid derivative is attached directly or via a linker and the functional groups of the alkyl groups be substituted with other functional groups such as an amino group as described above and the other end, antibody,
抗原、レクチン、細胞接着因子などのリガンド;細胞接着因子、抗体、イムノグロブリン等のタンパク質;糖類;アミノ酸;核酸及び核酸系化合物;その他種々の極性を有する化合物等の臓器指向性センサーを担っている。 It plays other organs directional sensors such as compounds with different polarity; antigens, lectins, ligands, cell adhesion factors; cell adhesion factor, an antibody, a protein of the immunoglobulin and the like; saccharides; amino; nucleic acids and nucleic acid-based compounds .

【0019】脂質誘導体の極性脂質に対する割合は、得られるリポソームの品質に大きな影響を与える。 [0019] The ratio of the polar lipids of the lipid derivative has a significant effect on the quality of the resulting liposomes. 即ち、 In other words,
多過ぎるときは、安定なリポソームが製造できず、少な過ぎるときは、得られるリポソームの膜に何らの変化も与えず、脂質誘導体を配合する効果が発揮されない。 When too much can not stable liposome preparation, when too little is not provide any change in the film of the obtained liposomes, the effect of compounding the lipid derivatives not be exhibited. このような理由から、脂質誘導体は極性脂質1モルに対し For this reason, a lipid derivative to polar lipid 1 mole
0.02〜0.5 モル、好ましくは 0.1〜0.5 モルの割合いで使用される。 0.02 to 0.5 mol, preferably used in medicine the rate of 0.1 to 0.5 mol.

【0020】リポソームに包含させるべき薬剤は、例えば抗癌剤、抗真菌剤等の種々の治療薬のほか、検査薬も含まれる。 The agents to be included in liposomes, for example anti-cancer agents, in addition to various therapeutic agents, such as antifungal agents, also include diagnostic agents. これらには、タンパク質、糖類、核酸及び核酸系化合物、ペプチド、種々の合成化合物が含まれる。 These include proteins, sugars, nucleic acids and nucleic acid-based compounds, peptides, various synthetic compounds.
これらの薬剤は、通常、水性溶媒に溶解して使用されるが、有機溶媒に添加して使用されることもある。 These agents are usually used by dissolving in an aqueous solvent, there may be used by adding to an organic solvent.

【0021】これら薬剤の水性溶媒中の濃度には、特別の制限はなく、リポソームの使用方法、用途などにより適宜定められる。 [0021] The concentration of the aqueous solvent of these agents is not particular limited, the use of liposomes, suitably determined by the intended use. 水性溶媒は、生理食塩水等の等張液が望ましく、pHも極端な酸性またはアルカリ性であってはならないことはもちろんである。 Aqueous solvents, isotonic solution is desirable, such as physiological saline, the pH should not be extremely acidic or alkaline, of course.

【0022】薬剤が有機溶媒に加えられる場合には、水性溶媒には薬剤は加えられないが、リポソームの調製方法は水性溶媒に薬剤を添加する場合と同じである。 [0022] When the drug is added to the organic solvent is the aqueous solvent agent is not added, a process for the preparation of liposomes is the same as the case of adding the agent to an aqueous solvent.

【0023】薬剤の水性溶液は、極性脂質1モルに対し [0023] The aqueous solution of the drug, the polar lipid 1 mole
50〜100 lの割合で用いられる。 Used in a proportion of 50~100 l.

【0024】極性脂質、正電荷または負電荷を与える化合物、コレステロール、脂質誘導体及び薬剤の水性溶液を上述の割合で原材料として使用して薬物保持リポソームを製造するための製法自体は、特別の方法である必要はない。 The polar lipid compounds provide a positive or negative charge, cholesterol, an aqueous solution of lipid derivatives and pharmaceutical preparation itself for the manufacture of a medicament holding liposomes using as a raw material at the rate described above, in a special way there is no need. 例えば、野島他編「リポソーム」(南江堂1989 For example, Nojima other ed., "Liposome" (Nankodo 1989
年9月15日発行)にはリポソームの調製法が多数収載されていて、これらのいずれの方法も本発明において使用することができる。 The annual September 15 published) have been listed a number of preparation of liposomes, any of these methods can be used in the present invention. 多重膜リポソームの調製方法としてバンガムの方法(ADBangham et al.,J.Mol.Biol., 13 , Bangamu way a process of preparing the multilamellar liposomes (ADBangham et al., J.Mol.Biol. , 13,
238(1965) が知られているが、この方法では、リポソームの原材料の有機溶媒溶液より窒素ガス気流あるいは減圧留去により溶媒を除去して容器壁にリピッドフィルムを形成させ、これに水性溶媒を加えて暫時静置してリピッドフィルムを水和させ、ついで超音波に曝すか、ボルテクシングを行ってリポソームを調製するもので、得られる多重膜リポソームは粒径も大きく、封入物(薬剤) 238 (1965) are known, in this method, the solvent was removed by nitrogen gas flow or distilled off under reduced pressure from the organic solvent solution of the liposome raw materials to form a lipid film on the container wall, which in an aqueous solvent in addition briefly standing to hydrate the lipid film, then either exposed to ultrasonic waves, those preparing liposomes performing Borutekushingu, multilamellar liposomes obtained the particle size is large, inclusions (drug)
の保持能も高い。 Also ability to hold high. 一方、小さな一枚膜リポソームは、超音波処理法、エタノール注入法、フレンチプレス法等で調製できるが、一般に水溶性薬剤に対する保持容積が低い。 On the other hand, small unilamellar liposomes, ultrasonication method, ethanol injection method, can be prepared by the French press method or the like, generally less holding volume to the water-soluble drug. しかしながら薬物の種類によっては、良い結果が得られる事がある。 However depending on the type of drug, which it may give good results. これに対し、エーテル注入法、コール酸(界面活性剤)法、カルシウムイオン融合法、凍結− In contrast, ether injection method, cholic acid (surfactant) method, the calcium ion fusion method, freeze -
融解法、逆相蒸発法等の大きな一枚膜リポソームを調製する方法は、比較的安定なリポソームが得られ、水溶性薬剤の保持量も多いので好ましい。 Fusion method, a method of preparing large unilamellar vesicles such as reverse-phase evaporation method, a relatively stable liposomes can be obtained and the holding amount of the water-soluble drug often.

【0025】本発明の薬物保持リポソームの粒径は、安定性、体内動態上の観点から50〜1000nm、より好ましくは50〜300nm である。 The particle size of the drug-retaining liposomes of the present invention, stability, 50-1000 nm from the viewpoint of pharmacokinetics, and more preferably from 50 to 300 nm. リポソームの粒径を調整するには、例えば、加圧濾過によることができる。 To adjust the particle size of the liposome can be, for example, by pressure filtration. なお、上記範囲の粒径のリポソームのものを選別する必要があるときは、ゲル濾過法、膜分離法等の通常の方法を必要があれば適宜改善して用いればよい。 Incidentally, when it is necessary to select those liposomes having a particle diameter of above range, gel filtration may be used as appropriate improvement if necessary a conventional method such as membrane separation.

【0026】本発明のより望ましい実施態様として、以下の3つを例示する。 [0026] As a more preferred embodiment of the present invention, illustrating the following three. 第1は極性脂質1モル、正電荷または負電荷を与える化合物0.05〜0.5 モル、コレステロール0.3〜1.5 モル及び分子中に臓器指向性センサー、 The first polar lipid 1 mol, compounds 0.05 to 0.5 mol of providing a positive or negative charge, organ directional sensor cholesterol 0.3-1.5 mol and molecular,
重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物0.02〜 Compound 0.02 with polyethylene glycol and at least two alkyl groups of carbon number 5-20 of polymerization degree 3-6
0.5 モルをこの割合で含有する有機溶媒より溶媒を除去してリピッドフィルムを生成させ、ついでリポソームに包含させるべき薬剤の水性溶液を燐脂質1モルに対し50 0.5 mol to produce a lipid film by removing the solvent from the organic solvent containing at this rate, then 50 to phospholipids 1 molar aqueous solution of the agent to be included in the liposome
〜100 lを該リピッドフィルムに加えてリポソームを形成させ、更に粒径50〜1000nmのリポソームを選択採取するものである。 The to 100 l to form a liposome in addition to the lipid film, and further selects collected liposome particle size 50-1000 nm.

【0027】有機溶媒には特別の制限はないが、極性脂質、コレステロール及び脂質誘導体を溶解しかつ除去の容易なものがよく、例えば、クロロホルム、エーテル、 [0027] Although there is no particular restriction on the organic solvent, polar lipid, often made easy cholesterol and dissolving the lipid derivative and removed, for example, chloroform, ether,
クロロホルム−メタノール混液等が挙げられる。 Chloroform - methanol mixture, and the like.

【0028】有機溶媒溶液の濃度にも特別の制限はなく、有機溶媒が極性脂質を溶解させることのできる量であればよい。 [0028] Also particular restriction on the concentration of the organic solvent solution is not, it may be an amount that can be organic solvent to dissolve the polar lipids.

【0029】有機溶媒溶液からのリピッドフィルムの作成は、例えば、窒素ガス気流により有機溶媒を除去して容器壁にリピッドフィルムを形成させたり、減圧により有機溶媒を留去することによることができる。 The creation of lipid film from an organic solvent solution, for example, or to form a lipid film on the vessel wall by removing the organic solvent by nitrogen gas stream can be by distilling off the organic solvent under reduced pressure.

【0030】リピッドフィルムに薬剤の水性溶液を加えて薬剤保持リポソームを調製する方法にも特別の制限はなく、例えば、リピッドフィルムに水性溶液を加えて暫時静置してリピッドフィルムを水和させ、ついで超音波に曝すかボルテキシングを行なうことによることができる。 The lipid film was added with an aqueous solution of the drug drug holding liposome no particular limitation on the method for preparing, for example, an aqueous solution to hydrate the lipid film and briefly left in addition to the lipid film, then it is possible by performing the vortexing or exposure to ultrasound.

【0031】このようにして調製したリポソームから粒径50〜1000nmの大きさのものを選択採取する。 [0031] selecting collected having a size of particle diameter 50~1000nm from liposomes prepared in this way. 選別の方法自体は、ゲル濾過法、分子篩膜法等の通常の方法によることができる。 The method itself of the sorting can be gel filtration, by conventional methods such as molecular sieve membrane method.

【0032】第2の実施態様としては、極性脂質1モル、正電荷または負電荷を与える化合物0.05〜0.5 モル、コレステロール 0.3〜1.5 モル及び分子中に臓器指 [0032] As the second embodiment, the polar lipid 1 mol, compounds 0.05 to 0.5 mol of providing a positive or negative charge, organ fingers cholesterol 0.3-1.5 mol and molecular
向性センサー、重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物0.02〜0.5 モルをこの割合で含有する有機溶媒にリポソームに包含させるべき薬剤の水性溶液を燐脂質1モルに対し50〜100 lを加え、ついでこの混合溶液を超音波処理してw/o型エマルジョンとした後減圧下に有機溶媒を除去し、更にボルテキシングを行ってo/w Tropism sensor, an aqueous solution of the agent to be included in the liposome in an organic solvent containing the compound from 0.02 to 0.5 mole of an alkyl group having polyethylene glycol and at least two carbon number 5-20 of polymerization degree 3-6 at this ratio the phospholipid 1 mole of 50 to 100 l was added to, then the organic solvent was removed under reduced pressure after the w / o emulsion was sonicated this mixed solution, further performs vortexed o / w
型エマルジョンとした後に必要により再び有機溶媒を減圧下に除去する、いわゆる逆蒸発法によるものである。 Again to remove the organic solvent under reduced pressure, if necessary after the mold emulsion is by so-called reverse evaporation method.

【0033】有機溶媒溶液と薬剤の水性溶液との混合溶液を超音波処理に付す目的はw/oエマルジョンの作成にあり、従って、この超音波処理は具体的には公知の通常の条件で行なうことができる。 The purpose of subjecting the mixed solution of an aqueous solution of an organic solvent solution and drug sonication is in the creation of w / o emulsions, thus, the ultrasonic treatment is specifically conducted by a known usual conditions be able to. 有機溶媒の除去についても、本発明については、格別に通常の方法とかえる必要はない。 For removal of the organic solvents, the present invention need not be exceptionally varied the usual manner.

【0034】ボルテキシングは、w/oエマルジョンをo/wエマルジョンに転換する目的で行なうものである。 [0034] vortexing are those carried out in order to convert the w / o emulsion o / w emulsion. 得られたo/wエマルジョンから減圧下で有機溶媒を除去すると目的の薬剤保持リポソームが得られる。 The purpose of the drug holding liposomes obtained when the resulting o / w emulsion to remove the organic solvent under reduced pressure.

【0035】第3の実施態様は、上述の2つの実施態様が薬剤を水性溶媒溶液として使用するのに対して、有機溶媒溶液として使用するものである。 [0035] The third embodiment, two embodiments described above with respect to use of agents as an aqueous solvent solution is to use as an organic solvent solution.

【0036】本発明の方法により調製される薬剤保持リポソーム、即ち少なくとも2個のアルキル基を有する脂質誘導体を含有するリポソームは、1個のアルキル基を有する化合物を使用した以外は本発明の方法と同じ方法で製造したリポソームに比べ、エチレングリコールの一端に臓器指向性センサーを担わしたときリポソームの臓器認識性の向上がみられ、該臓器または組織へのリポソームの集積性が高まる。 The drug holding liposomes prepared by the method of the present invention, i.e., liposomes containing lipid derivative having at least two alkyl groups, except for using the compound having one alkyl group and the method of the present invention compared to liposomes prepared in the same way, improved organ recognition of the liposomes when Ninawashi organ directional sensor at one end of the ethylene glycol is observed, increase the integration of the liposomes to organ or tissue.

【0037】 [0037]

【実施例】 【Example】

実施例1(合成例(その1)) 分子中に重合度3〜6のポリエチレングリコール及び少なくとも2個の、炭素数5〜20のアルキル基を有する4 Example 1 (Synthesis Example (1)) of polyethylene glycol and at least two degrees of polymerization 3-6 in a molecule, 4 having an alkyl group having 5 to 20 carbon atoms
種の化合物(本発明)256 、852 、331 及び531 を各々次のようにして合成した。 Class of compounds (present invention) in the 256, 852, each following the 331 and 531 as synthesized.

【0038】これらの合成反応における反応を図1〜4 [0038] Figure 1-4 The reactions in these synthetic reaction
に示す。 To show.

【0039】 (a) 化合物256 の合成(図1) 1)化合物254 の合成 ガラクトースパーアセテート(10.0g,25.62mmol )及びモノクロトリエチレングリコール(5.616 g,33.3mm [0039] (a) Synthesis galactose peracetate (10.0 g Synthesis of Compound 256 (FIG. 1) 1) Compound 254, 25.62mmol) and the monochrome triethylene glycol (5.616 g, 33.3 mm
ol,1.3 eq)の塩化メチレン(150ml )溶液にボロントリフルオライドエーテル錯体(12.6ml,4.0 eq)の塩化メチレン(30ml)溶液を氷冷下加え、一晩室温にて攪拌した。 ol, 1.3 eq) in methylene (150ml) was added boron trifluoride ether complex chloride (12.6 ml, 4.0 eq) in methylene chloride (30ml) solution under ice cooling was added a, and stirred overnight at room temperature. 得られた溶液を氷水に加え、クロロフォルム(150ml )に加えて抽出した。 The resulting solution was added to ice water and extracted by adding the chloroform (150 ml). 有機槽を2回水洗し、無水硫酸ナトリウムにて乾燥した。 The organic tank was washed with water twice and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、 The solvent was evaporated under reduced pressure,
残渣を1000mlのシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1:1)、 The residue was separated by silica gel column chromatography 1000 ml (hexane: ethyl acetate = 2: 1-1: 1),
目的物を得た(6.51g、50.9%)。 To give the desired product (6.51g, 50.9%).

【0040】 [α] D 20 =-0.4 ゜(c 1.098 ,クロロフォルム)。 [0040] [α] D 20 = -0.4 ° (c 1.098, chloroform).

【0041】 1 H-NMR(CDCl 3 ,δ) ;1.986 ,2.051 , [0041] 1 H-NMR (CDCl 3, δ); 1.986, 2.051,
2.063 ,2.152(4s,3H ×4),3.63-3.78(m,11H),3.95- 2.063, 2.152 (4s, 3H × 4), 3.63-3.78 (m, 11H), 3.95-
3.98(m,1H) ,3.917(brt,1H) ,4.131(dd,1H,J=6.8Hz,1 3.98 (m, 1H), 3.917 (brt, 1H), 4.131 (dd, 1H, J = 6.8Hz, 1
1.2Hz) ,4.178(dd,1H,J=6.6Hz),4.576(d,1H,J=8.1Hz) 1.2Hz), 4.178 (dd, 1H, J = 6.6Hz), 4.576 (d, 1H, J = 8.1Hz)
,5.023(dd,1H,J=3.4Hz),5.212(dd,1H,J=10.5Hz) , , 5.023 (dd, 1H, J = 3.4Hz), 5.212 (dd, 1H, J = 10.5Hz),
5.390(brd,1H) 。 5.390 (brd, 1H).

【0042】2)化合物225 の合成 化合物254 (3.445 g,12.91mmol )及びナトリウムアジド(1.26g,19.4mmol,1.5 eq)にDMF(50ml) [0042] 2) Compound 254 (3.445 g of compound 225, 12.91mmol) and sodium azide (1.26g, 19.4mmol, 1.5 eq) in DMF (50 ml)
を加え、60℃にて17時間加熱攪拌した。 It was added and heating for 17 hours stirring at 60 ° C.. 得られた溶液に水(100ml )を加え、酢酸エチルで抽出した。 To the resulting solution was washed with water (100ml) was added and extracted with ethyl acetate. 有機層を水洗し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed with water and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を 500mlのシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1.5 The solvent was distilled off under reduced pressure, the residue was separated by silica gel column chromatography 500 ml (hexane: ethyl acetate = 2: 1.5
−1:1)目的物を得た(5.30g、81.2%)。 -1: 1) to give the desired product (5.30g, 81.2%).

【0043】[α] D 17 =-3.2 ゜(c 1.04,CHCl 3 )。 [0043] [α] D 17 = -3.2 DEG (c 1.04, CHCl 3).

【0044】 1 H-NMR(CDCl 3 ,δ) ;1.984 ,2.048 , [0044] 1 H-NMR (CDCl 3, δ); 1.984, 2.048,
2.060 ,2.148(4s,3H ×4),3.398(t,2H,J=5.0Hz) ,3. 2.060, 2.148 (4s, 3H × 4), 3.398 (t, 2H, J = 5.0Hz), 3.
63-3.69(m,8H) ,3.73-3.78(m,1H) ,3.95-3.98(m,1H) 63-3.69 (m, 8H), 3.73-3.78 (m, 1H), 3.95-3.98 (m, 1H)
,3.910(brt,1H) ,4.131(dd,1H,J=6.8Hz,11.2Hz) , , 3.910 (brt, 1H), 4.131 (dd, 1H, J = 6.8Hz, 11.2Hz),
4.176(dd,1H,J=6.3Hz),4.571(d,1H,J=7.8Hz) ,5.023 4.176 (dd, 1H, J = 6.3Hz), 4.571 (d, 1H, J = 7.8Hz), 5.023
(dd,1H,J=3.4Hz),5.210(dd,1H,J=10.5Hz) ,5.387(dd, (Dd, 1H, J = 3.4Hz), 5.210 (dd, 1H, J = 10.5Hz), 5.387 (dd,
1H,J=1.0Hz)。 1H, J = 1.0Hz).

【0045】3)化合物225 (0.417 g)及びパラトルスルホン酸1水和物(0.190 g)にメタノール(20ml) [0045] 3) Compound 225 (0.417 g) and para Torr acid monohydrate (0.190 g) in methanol (20ml)
及び酢酸エチル(40ml)を加えて溶解した。 And it was dissolved by adding ethyl acetate (40 ml). 溶液にリンドラー触媒(0.2 g)を加え、50psiの水素雰囲気下で8時間攪拌した。 It added Lindlar catalyst (0.2 g) to the solution and stirred for 8 hours under a hydrogen atmosphere of 50 psi. 触媒を濾去し、減圧下溶媒を留去した。 The catalyst was filtered off, the solvent was evaporated under reduced pressure. 残渣を塩化メチレン(20ml)及びヘキサン(10ml) Residue was dissolved in methylene chloride (20ml) and hexane (10ml)
に溶解し、2−パルミチルステアリン酸(0.662 g)、 It was dissolved in 2-palmityl stearic acid (0.662 g),
N−ヒドロキシコハク酸(0.150 g)、トリエチルアミン(0.181ml )及びジシクロヘキシルカルボジイミド N- hydroxysuccinimide (0.150 g), triethylamine (0.181ml) and dicyclohexylcarbodiimide
(0.268g)を加え、一晩攪拌した。 The (0.268 g) was added and stirred overnight. 溶液を減圧下濃縮し、残渣に酢酸エチルを加え、不溶物を濾去した。 The solution was concentrated under reduced pressure, the residue added ethyl acetate, and the insoluble material was removed by filtration. 濾液を濃縮し、シリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1)、目的物を得た(0.504 g、57.1%)。 The filtrate was concentrated and separated by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (0.504 g, 57.1%).

【0046】 [α] D 18 =-0.4 ゜(c 1.04,クロロフォルム)。 [0046] [α] D 18 = -0.4 DEG (c 1.04, chloroform).

【0047】 1 H-NMR(CDCl 3 ,δ) ;0.88(t,6H,J=7.0H [0047] 1 H-NMR (CDCl 3, δ); 0.88 (t, 6H, J = 7.0H
z),1.18-1.26(m,56H),1.34-1.43(m,2H) ,1.52-1.62 z), 1.18-1.26 (m, 56H), 1.34-1.43 (m, 2H), 1.52-1.62
(m,2H) ,1.99(bs,4H) ,2.05(s,3H),2.06(s,3H),2.1 (M, 2H), 1.99 (bs, 4H), 2.05 (s, 3H), 2.06 (s, 3H), 2.1
5(s,3H),3.46-3.49(m,2H) ,3.54(t,2H,J=5.0Hz),3.5 5 (s, 3H), 3.46-3.49 (m, 2H), 3.54 (t, 2H, J = 5.0Hz), 3.5
9-3.67(m,6H) ,3.74(ddd,1H,J=3.6Hz,7.2Hz,10.8Hz) 9-3.67 (m, 6H), 3.74 (ddd, 1H, J = 3.6Hz, 7.2Hz, 10.8Hz)
,3.90-3.93(m,1H) ,3.98(dt,1H,J=4.4Hz) ,4.13(d , 3.90-3.93 (m, 1H), 3.98 (dt, 1H, J = 4.4Hz), 4.13 (d
d,1H,J=6.8Hz,11.2Hz),4.18(dd,1H,J=6.6Hz,11.2Hz), d, 1H, J = 6.8Hz, 11.2Hz), 4.18 (dd, 1H, J = 6.6Hz, 11.2Hz),
4.55(d,1H,J=7.9Hz),5.02(dd,1H,J=3.4Hz,10.5Hz),5. 4.55 (d, 1H, J = 7.9Hz), 5.02 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.
21(dd,1H,J=7.9Hz,10.5Hz),5.39(dd,1H,J=3.4Hz,1.0H 21 (dd, 1H, J = 7.9Hz, 10.5Hz), 5.39 (dd, 1H, J = 3.4Hz, 1.0H
z) ,5.92(t,1H,J=5.6Hz)。 z), 5.92 (t, 1H, J = 5.6Hz).

【0048】4)化合物256 の合成 化合物225 (341mg )をベンゼン(10ml)に溶解し、5 [0048] 4) Synthesis Compound 225 Compound 256 (341 mg) was dissolved in benzene (10 ml), 5
M/1のナトリウムメチラートメタノール溶液を8滴加え、一晩攪拌した。 M / 1 of sodium methylate methanol solution and 8 drops of stirred overnight. 溶液に強酸性イオン交換樹脂「Do Solution a strongly acidic ion exchange resin "Do
wex 50w×8」のH型を加えて中和した。 It was neutralized with H type of wex 50 w × 8 ". 溶液を濾過し、減圧下濃縮し、残渣を「セファデックスLH−2 The solution was filtered and concentrated under reduced pressure, the residue "Sephadex LH-2
0」(クロロフォルム:メタノール=9:1、22mmφ×4 0 "(chloroform: methanol = 9: 1,22mmφ × 4
5cm)にて精製し、目的化合物を得た(252mg 、90 Was purified by 5 cm), to obtain the desired compound (252 mg, 90
%)。 %).

【0049】[α] D 20 =-1.1 ゜(c 1.12,クロロフォルム:メタノール=9:1)。 [0049] [α] D 20 = -1.1 ° (c 1.12, chloroform: methanol = 9: 1).

【0050】 1 H-NMR(pyridine-d 5 -D 2 O,δ) ;0.88(t, [0050] 1 H-NMR (pyridine-d 5 -D 2 O, δ); 0.88 (t,
6H,J=7.0Hz),1.21-1.39(m,52H),1.43-1.62(m,6H) , 6H, J = 7.0Hz), 1.21-1.39 (m, 52H), 1.43-1.62 (m, 6H),
1.91-1.99(m,6H) ,2.51-2.57(m,1H) ,3.61-3.66(4H, 1.91-1.99 (m, 6H), 2.51-2.57 (m, 1H), 3.61-3.66 (4H,
m) ,3.70-3.78(6H,m) ,3.93(dt,1H,J=5.3Hz,10.7H m), 3.70-3.78 (6H, m), 3.93 (dt, 1H, J = 5.3Hz, 10.7H
z),4.02-4.04(m,1H) ,4.13(dd,J=3.3Hz,9.4Hz),4.26 z), 4.02-4.04 (m, 1H), 4.13 (dd, J = 3.3Hz, 9.4Hz), 4.26
(dt,1H,J=10.7Hz,4.8Hz),4.40-4.44(m,3H) ,4.54(bd, (Dt, 1H, J = 10.7Hz, 4.8Hz), 4.40-4.44 (m, 3H), 4.54 (bd,
1H) ,4.78(d,1H,J=7.8Hz),8.76(bt,1H) 。 1H), 4.78 (d, 1H, J = 7.8Hz), 8.76 (bt, 1H).

【0051】 (b) 化合物852 の合成(図2)カルボン酸828 (180mg )およびN−ヒドロキシスクシンイミド(41mg)の塩化メチレン溶液(10ml)にN, [0051] (b) Synthesis of Compound 852 in methylene chloride solution (10ml) of (2) carboxylic acid 828 (180 mg) and N- hydroxysuccinimide (41 mg) N,
N′−ジシクロヘキシルカルボジイミド(74mg)を加え、室温にて1時間撹拌した。 N'- dicyclohexylcarbodiimide (74 mg) and the mixture was stirred for 1 hour at room temperature. この溶液にアミノ体のパラトルエンスルホン酸塩818 (190mg )およびトリエチルアミン(90μl)の塩化メチレン(5ml)溶液を加え、室温にて終夜撹拌した。 The solution in methylene chloride (5ml) solution of p-toluenesulfonic acid salt 818 amino compound (190 mg) and triethylamine (90 [mu] l) was added, and the mixture was stirred overnight at room temperature. 不溶物を濾去した後、濾液を水及び半飽和食塩水にて洗浄し、硫酸マグネシウムにて乾燥した。 After the insoluble material was removed by filtration, the filtrate was washed with water and half saturated brine, and dried over magnesium sulfate. 溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(シリカゲル40g、クロロホルム:メタノール=98:2)にて精製してアミド体(310mg ,77 The residue was purified by silica gel column chromatography (silica gel 40 g, chloroform: methanol = 98: 2) purified to amide by (310 mg, 77
%)を得た。 %) Was obtained.

【0052】IR(KBr) :3700,3600,1745,1710,151 [0052] IR (KBr): 3700,3600,1745,1710,151
0,1480,1420cm -1 0,1480,1420cm -1.

【0053】 1 H-NMR(CD 3 OD) :0.90(3H,t,J=7Hz),1.9 [0053] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.9
3(3H,s),1.95(3H,s),2.03(3H,s),2.14(3H,s),4.65 3 (3H, s), 1.95 (3H, s), 2.03 (3H, s), 2.14 (3H, s), 4.65
(1H,d,J=8.5Hz),5.07(1H,dd,J=3.5,11.5Hz),5.33(1H, (1H, d, J = 8.5Hz), 5.07 (1H, dd, J = 3.5,11.5Hz), 5.33 (1H,
d,J=3.5Hz)。 d, J = 3.5Hz).

【0054】 R f =0.6(クロロホルム:メタノール=93:7 )。 [0054] R f = 0.6 (chloroform: methanol = 93: 7).

【0055】上記で得たアミド体(270mg )のメタノール(20ml)溶液にナトリウムメトキシド(28%メタノール溶液55μl)を加え、室温にて5.5 時間撹拌した。 [0055] amide obtained above in methanol (20ml) was added sodium methoxide (28% methanol solution 55 [mu] l) of (270 mg) was added, and stirred for 5.5 hours at room temperature.
「アンバーリスト15E」を液性が中性になるまで加えた後樹脂を濾去して、濾液を濃縮し、目的化合物852 (21 By filtering off the resin after liquid the "Amberlyst 15E" was added until neutral, the filtrate was concentrated, the target compound 852 (21
5mg )を得た。 5mg) was obtained.

【0056】 [α] D 26 +43.9 ゜(c 1.0 ,メタノール)。 [0056] [α] D 26 +43.9 DEG (c 1.0, methanol).

【0057】 IR(KBr) :3340,3330,1655,1555,1470cm -1 [0057] IR (KBr): 3340,3330,1655,1555,1470cm -1.

【0058】 1 H-NMR(CD 3 OD) :0.90(3H,t,J=7Hz),2.0 [0058] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 2.0
0(3H,s),3.84(1H,d,J=3Hz),4.45(1H,dJ=8.3H)。 0 (3H, s), 3.84 (1H, d, J = 3Hz), 4.45 (1H, dJ = 8.3H).

【0059】 R f =0.37 (クロロホルム:メタノール=9:1)。 [0059] R f = 0.37 (chloroform: methanol = 9: 1).

【0060】 (c) 化合物331 の合成(図3) 1)化合物327 の合成 α−D−マンノースペンタアセテート(化合物302 ) [0060] (c) Synthesis of Compound 331 (FIG. 3) 1) Synthesis alpha-D-mannose pentaacetate Compound 327 (Compound 302)
(3.90g)と2−[2−(2−クロロエトキシ)エトキシ]エタノール(3.37g)を塩化メチレン(200ml )に溶解し、BF 3・Et 2 O(5.68g)を加え、室温で5 (3.90 g) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (3.37 g) was dissolved in methylene chloride (200ml), BF 3 · Et 2 O a (5.68 g) was added, 5 at room temperature
日間攪拌した。 Days and the mixture was stirred. 反応液を塩化メチレンで希釈し、水、5 The reaction was diluted with methylene chloride, water, 5
%NaHCO 3水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 % NaHCO 3 and washed with water and then water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(200 g)を用いるカラムクロマトグラフィー(クロロホルム)で精製し、α The residue was purified on silica gel (200 g) column chromatography (chloroform) using, alpha
−グリコシド化合物327 (4.13g)を無色油状物として得た。 - give glycoside compound 327 (4.13 g) as a colorless oil.

【0061】[α] D +38.7 °(c 1.51,CHCl 3 )。 [0061] [α] D +38.7 ° (c 1.51, CHCl 3).

【0062】 1 H-NMR(CDCl 3 ) δ:2.04(3H,s),2.05(3 [0062] 1 H-NMR (CDCl 3) δ: 2.04 (3H, s), 2.05 (3
H,s),2.10(3H,s),2.16(3H,s),3.63-3.70(9H,m) ,3. H, s), 2.10 (3H, s), 2.16 (3H, s), 3.63-3.70 (9H, m), 3.
75-3.85(3H,m) ,4.07(1H,ddd,J=2.4Hz,5.1Hz,10.0Hz) 75-3.85 (3H, m), 4.07 (1H, ddd, J = 2.4Hz, 5.1Hz, 10.0Hz)
,4.11(1H,dd,J=2.4Hz,12.2Hz),4.29(1H,dd,J=4.9Hz, , 4.11 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9Hz,
12.2Hz),4.88(1H,d,J=1.5Hz),5.27(1H,dd,J=1.5Hz,3. 12.2Hz), 4.88 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz, 3.
4Hz) ,5.29(1H,t,J=10.0Hz) ,5.36(1H,dd,J=3.4Hz,1 4Hz), 5.29 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 1
0.0Hz)。 0.0Hz).

【0063】2)化合物328 の合成 クロル体化合物327 (3.68g)をDMF(50ml)に溶解し、アジ化ナトリウム(0.72g)を加え、60℃で24時間撹拌した。 [0063] 2) was dissolved synthesized chloro body of Compound 328 327 (3.68 g) in DMF (50 ml), sodium azide (0.72 g) was added and stirred at 60 ° C. 24 hours. 反応液を酢酸エチルで希釈し、水洗し、乾燥後溶媒を減圧下留去した。 The reaction solution was diluted with ethyl acetate, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(150 g) The residue on silica gel (0.99 g)
を用いるカラムクロマトグラフィー(クロロホルム−アセトン 10:1)で精製し、アジド体化合物328 (3.05 Column chromatography using (chloroform - acetone 10: 1) to give azide compound 328 (3.05
g)を無色油状物として得た。 g) as a colorless oil.

【0064】[α] D +35.6 °(c 2.54,CHCl 3 )。 [0064] [α] D +35.6 ° (c 2.54, CHCl 3).

【0065】 1 H-NMR(CDCl 3 ) δ:1.99(3H,s),2.04(3 [0065] 1 H-NMR (CDCl 3) δ: 1.99 (3H, s), 2.04 (3
H,s),2.11(3H,s),2.16(3H,s),3.40(2H,t,J=5.1Hz), H, s), 2.11 (3H, s), 2.16 (3H, s), 3.40 (2H, t, J = 5.1Hz),
3.62-3.86(10H,m),4.06(1H,ddd,J=2.4Hz,4.9Hz,10.0H 3.62-3.86 (10H, m), 4.06 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0H
z) ,4.10(1H,dd,J=2.4Hz,12.2Hz),4.29(1H,dd,J=4.9H z), 4.10 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9H
z,12.2Hz),4.88(1H,d,J=1.5Hz),5.27(1H,dd,J=1.5Hz, z, 12.2Hz), 4.88 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz,
3.4Hz) ,5.29(1H,t,J=10.0Hz) ,5.36(1H,dd,J=3.4Hz, 3.4Hz), 5.29 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz,
10.0Hz)。 10.0Hz).

【0066】3)化合物329 の合成 アジド体化合物328 (386mg )とp−トルエンスルホン酸(145mg )をエタノール(20ml)に溶解し、リンドラー触媒(770mg )を加え、室温50psiで 7.5時間接触還元を行った。 [0066] 3) Synthesis azide compound 328 Compound 329 (386 mg) and p- toluenesulfonic acid (145 mg) was dissolved in ethanol (20 ml), was added Lindlar catalyst (770 mg), 7.5 hours catalytic reduction at room temperature 50psi went. 触媒を濾去後、濾液を減圧下濃縮し、アミン体化合物329 を得た。 After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give the amine compound compound 329.

【0067】4)化合物330 の合成 2−(1−ヘキサデシル)オクタデカン酸(153mg )をヘキサン(15ml)と塩化メチレン(20ml)の混合溶媒に溶解し、N−ヒドロキシスクシンイミド(35mg)とN, [0067] 4) Synthesis of 2- (1-hexadecyl) octadecanoate compound 330 (153 mg) was dissolved in a mixed solvent of methylene chloride (20ml) and hexane (15 ml), N-hydroxysuccinimide and (35 mg) N,
N′−ジンクロヘキシルカルボジイミド(62mg)を加え、室温で24時間攪拌した。 N'- Jinkuro hexyl carbodiimide (62 mg) was added and stirred for 24 hours at room temperature. 反応混合物にアセトニトリル(15ml)に溶解したアミン体化合物329(235mg )を加え、ついでトルエチルアミン(67mg)を加えた後、室温で23時間攪拌した。 The reaction mixture acetonitrile amine was dissolved in (15ml) Compounds 329 (235 mg) was added, followed after adding torr ethylamine (67 mg), and stirred at room temperature for 23 hours. 不溶物を濾去し、濾液をクロロホルムで希釈し、水洗し、乾燥後溶媒を減圧下留去した。 The insoluble material was removed and the filtrate was diluted with chloroform, washed with water, dried and then the solvent was distilled off under reduced pressure.
残渣をシリカゲル(60g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 150:1)で精製した。 The residue was purified by column chromatography using silica gel (60 g) (chloroform - methanol 150: 1). 再度、シリカゲル(60g)を用いるカラムクロマトグラフィー(ヘキサン−酢酸エチル 5:4)で精製し、目的化合物(130mg)を無色油状物として得た。 Again, silica gel column chromatography using (60 g) (hexane - ethyl acetate 5: 4) to give the desired compound (130 mg) as a colorless oil.

【0068】[α] D +18.2 °(c 1.02,CHCl 3 )。 [0068] [α] D +18.2 ° (c 1.02, CHCl 3).

【0069】 1 H-NMR(CDCl 3 ) δ;0.88(6H,t,J=6.8H [0069] 1 H-NMR (CDCl 3) δ; 0.88 (6H, t, J = 6.8H
z),1.20-1.33(56H,m),1.34-1.43(2H,m) ,1.53-1.62 z), 1.20-1.33 (56H, m), 1.34-1.43 (2H, m), 1.53-1.62
(2H,m) ,2.00(3H,s),2.04(3H,s),2.11(3H,s),2.16 (2H, m), 2.00 (3H, s), 2.04 (3H, s), 2.11 (3H, s), 2.16
(3H,s),3.47(2H,q),3.55(2H,t),3.60-3.73(7H,m) , (3H, s), 3.47 (2H, q), 3.55 (2H, t), 3.60-3.73 (7H, m),
3.80-3.85(1H,m) ,4.07(1H,ddd,J=2.4Hz,4.9Hz,10.0H 3.80-3.85 (1H, m), 4.07 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0H
z) ,4.12(1H,dd,J=2.4Hz,12.2Hz),4.29(1H,dd,J=4.9H z), 4.12 (1H, dd, J = 2.4Hz, 12.2Hz), 4.29 (1H, dd, J = 4.9H
z),4.89(1H,d,J=1.7Hz),5.27(1H,dd,J=1.7Hz,3.4Hz) z), 4.89 (1H, d, J = 1.7Hz), 5.27 (1H, dd, J = 1.7Hz, 3.4Hz)
,5.30(1H,t,J=10.0Hz) ,5.36(1H,dd,J=3.4Hz,10.0H , 5.30 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 10.0H
z),6.00(1H,m)。 z), 6.00 (1H, m).

【0070】5)化合物331 の合成 化合物330 (123mg )をメタノール(10ml)に溶解し、 [0070] 5) Compound 330 Compound 331 (123 mg) was dissolved in methanol (10 ml),
28%NaOME inMeOH(20μl)を加え、室温で4時間攪拌した。 28% NaOME inMeOH a (20 [mu] l) was added, followed by stirring at room temperature for 4 hours. 反応液に「アンバーライトIRC− "Amber light to the reaction solution IRC-
50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固した。 50 "was added, insoluble material the filtrate after filtration was concentrated to dryness under reduced pressure to. 残渣にクロロホルムを加え、不溶物を濾去後濾液を減圧下濃縮乾固し、残渣を氷冷下ヘキサンで洗浄して目的化合物231 (101mg )を無色粉末として得た。 Chloroform was added to the residue, insoluble material the filtrate after filtration concentrated to dryness under reduced pressure, to give the desired compound 231 (101 mg) as a colorless powder residue was washed with ice-cooling hexane.

【0071】[α] D +19.5 °(c 0.59,CHCl 3 )。 [0071] [α] D +19.5 ° (c 0.59, CHCl 3).

【0072】 1 H-NMR(CDCl 3 ) δ:0.88(6H,t,J=6.8H [0072] 1 H-NMR (CDCl 3) δ: 0.88 (6H, t, J = 6.8H
z),1.20-1.33(56H,m),1.34-1.44(2H,m) ,1.52-1.61 z), 1.20-1.33 (56H, m), 1.34-1.44 (2H, m), 1.52-1.61
(2H,m) ,2.00(1H,m),3.42-3.96(18H,m),4.89(1H, (2H, m), 2.00 (1H, m), 3.42-3.96 (18H, m), 4.89 (1H,
s(,6.10(1H,m)。 s (, 6.10 (1H, m).

【0073】 (d) 化合物531 の合成(図4) 1)化合物530 の合成 2−(1−ヘキサデシル)オクタデカン酸(153mg )をヘキサン(15ml)と塩化メチレン(20ml)の混合溶液に溶解し、N−ヒドロキシスクシンイミド(35mg)とN, [0073 (d) The synthesis of compound 531 (FIG. 4) 1) Synthesis of 2- (1-hexadecyl) octadecanoate compound 530 (153 mg) was dissolved in a mixed solution of hexane (15ml) and methylene chloride (20 ml), N- hydroxysuccinimide (35 mg) and N,
N′−ジシクロヘキシルカルボジイミド(62mg)を加え、室温で24時間攪拌した。 N'- dicyclohexylcarbodiimide (62 mg) was added and stirred for 24 hours at room temperature. 反応混合物にアセトニトリル(15ml)を溶解したアミン体化合物527(214mg )を加え、ついでトリエチルアミン(67mg)を加えた後、室温で24時間攪拌した。 The reaction mixture acetonitrile (15ml) amine Compounds were dissolved 527 (214 mg) was added, followed after addition of triethylamine (67 mg), and stirred at room temperature for 24 hours. 不溶物を濾去し、濾液をクロロホルムで希釈し、水洗し、乾燥後溶媒を減圧下留去した。 The insoluble material was removed and the filtrate was diluted with chloroform, washed with water, dried and then the solvent was distilled off under reduced pressure.
残渣をシリカゲル(60g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 150:1)で精製した。 The residue was purified by column chromatography using silica gel (60 g) (chloroform - methanol 150: 1). 再度、シリカゲル(60g)を用いるカラムクロマトグラフィー(ヘキサン−酢酸エチル 2:1)で精製し、目的化合物530(165mg )を無色油状物として得た。 Again, silica gel (60 g) column chromatography using (hexane - ethyl acetate 2: 1) to give the target compound 530 (165 mg) as a colorless oil.

【0074】[α] D -51.4 °(c 0.84,CHCl 3 )。 [0074] [α] D -51.4 ° (c 0.84, CHCl 3).

【0075】 1 H-NMR(CDCl 3 ) δ:0.88(6H,t,J=6.8H [0075] 1 H-NMR (CDCl 3) δ: 0.88 (6H, t, J = 6.8H
z),1.14(3H,d,J=6.4Hz),1.20-1.33(56H,m),1.34-1.4 z), 1.14 (3H, d, J = 6.4Hz), 1.20-1.33 (56H, m), 1.34-1.4
3(2H,m) ,1.56-1.62(2H,m) ,1.99(3H,s),2.07(3H, 3 (2H, m), 1.56-1.62 (2H, m), 1.99 (3H, s), 2.07 (3H,
s),2.17(3H,s),3.47(2H,m),3.54(2H,m),3.58-3.70 s), 2.17 (3H, s), 3.47 (2H, m), 3.54 (2H, m), 3.58-3.70
(7H,m) ,3.76-3.83(1H,m) ,4.22(1H,dq,J=1.2Hz,6.4 (7H, m), 3.76-3.83 (1H, m), 4.22 (1H, dq, J = 1.2Hz, 6.4
Hz),5.12(1H,dd,J=3.7Hz,10.0Hz),5.13(1H,d,J=3.7H Hz), 5.12 (1H, dd, J = 3.7Hz, 10.0Hz), 5.13 (1H, d, J = 3.7H
z),5.29(1H,dd,J=1.2Hz,3.4Hz),5.37(1H,dd,J=3.4Hz,1 z), 5.29 (1H, dd, J = 1.2Hz, 3.4Hz), 5.37 (1H, dd, J = 3.4Hz, 1
0.0Hz),6.02(1H,m)。 0.0Hz), 6.02 (1H, m).

【0076】2)化合物531 の合成 化合物530 (138mg )をメタノール(10ml)に溶解し、 [0076] 2) Synthesis of Compound 531 530 (138 mg) was dissolved in methanol (10 ml),
28%NaOMe inMeOH(20μl)を加え、室温で 2.5時間攪拌した。 28% NaOMe inMeOH a (20 [mu] l) was added, followed by stirring at room temperature for 2.5 hours. 反応液に「アンバーライトIRC "Amberlite IRC to the reaction solution
−50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固した。 -50 "was added, insoluble material the filtrate after filtration was concentrated to dryness under reduced pressure to. 残渣にクロロホルムに加え、不溶物を濾去後濾液を減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合物(101mg )を無色粉末として得た。 The residue was added chloroform, insoluble material the filtrate after filtration concentrated to dryness under reduced pressure, to give the desired compound (101 mg) as a colorless powder by washing the residue with ether.

【0077】[α] D -36.7 ゜(c 0.69,CHCl 3 )。 [0077] [α] D -36.7 ° (c 0.69, CHCl 3).

【0078】 1 H-NMR(CDCl 3 ) δ:0.88(6H,t,J=6.8H [0078] 1 H-NMR (CDCl 3) δ: 0.88 (6H, t, J = 6.8H
z),1.20-1.30(56H,m),1.30(3H,d,J=6.8Hz),1.34-1.4 z), 1.20-1.30 (56H, m), 1.30 (3H, d, J = 6.8Hz), 1.34-1.4
3(2H,m) ,3.37-3.72(11H,m),3.74-3.85(3H,m) ,3.88 3 (2H, m), 3.37-3.72 (11H, m), 3.74-3.85 (3H, m), 3.88
-3.94(1H,m) ,4.03(1H,q,J=6.8Hz),4.92(1H,d,J=3.4H -3.94 (1H, m), 4.03 (1H, q, J = 6.8Hz), 4.92 (1H, d, J = 3.4H
z),6.37(1H,m)。 z), 6.37 (1H, m).

【0079】対照として、上記化合物256 、852 、331 [0079] As a control, the compound 256, 852, 331
及び531 にそれぞれ対応する、炭素数5〜20のアルキル基を1個有する4種の化合物(コントロール化合物)22 And corresponding respectively to 531, four compounds that one have a alkyl group having 5 to 20 carbon atoms (Control Compound) 22
8 、851 、333 及び529 を次のようにして合成した。 8, 851, 333 and 529 were synthesized as follows.

【0080】これらの合成反応における反応を図5〜8 [0080] Figures 5-8 The reactions in these synthetic reaction
に示す。 To show.

【0081】 (a′) 化合物228 の合成(図5) 1)化合物225 の合成 β−D−ガラクトースペンタアセテート化合物201 、5. [0081] (a ') Synthesis of Compound 228 (FIG. 5) 1) Synthesis beta-D-galactose pentaacetate of Compound 225 201, 5.
254 g及び2−[2−(2−アジドエトキシ)エトキシ]エタノール3.066 gを塩化メチレン50mlに溶かし、 The 254 g and 2- [2- (2-azido-ethoxy) ethoxy] ethanol 3.066 g was dissolved in methylene chloride 50 ml,
氷冷下撹拌した。 And the mixture was stirred under ice-cooling. ここに三フッ化硼素ジエチルエーテル錯体6.62mlを塩化メチレン10mlに溶かして10分間で滴下した。 It was added dropwise over 10 minutes here boron trifluoride diethyl ether complex 6.62ml dissolved in methylene chloride 10 ml. 室温で14時間撹拌した後、氷水にあけ、有機層を分離した。 After stirring at room temperature for 14 hours, poured into ice water, and the organic layer was separated. 3回水洗した後(水層は中性となった)、飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Washed with water 3 times (aqueous layer became neutral), washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1:1)、目的物を無色油状物として2.62g得た。 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1: 1) to obtain 2.62g of the desired product as a colorless oil.

【0082】 1 H-NMR(δ,CDCl 3 ) :1.99(s,3H),2.05 [0082] 1 H-NMR (δ, CDCl 3): 1.99 (s, 3H), 2.05
(s,3H),2.06(s,3H),2.15(s,3H),3.40(t,2H,J=5.0H (S, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 3.40 (t, 2H, J = 5.0H
z),3.64-3.69(m,8H) ,3.73-3.78(m,1H) ,3.90-3.93 z), 3.64-3.69 (m, 8H), 3.73-3.78 (m, 1H), 3.90-3.93
(m,1H),3.94-3.98(m,1H) ,4.12(dd,1H,J=6.8Hz,11.2H (M, 1H), 3.94-3.98 (m, 1H), 4.12 (dd, 1H, J = 6.8Hz, 11.2H
z),4.18(dd,1H,J=6.3Hz,11.2Hz),4.57(d,1H,J=8.1H z), 4.18 (dd, 1H, J = 6.3Hz, 11.2Hz), 4.57 (d, 1H, J = 8.1H
z),5.02(dd,1H,J=3.4Hz,10.5Hz),5.21(dd,1H,J=8.1H z), 5.02 (dd, 1H, J = 3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1H
z,10.5Hz),5.39(dd,1H,J=1.0Hz,3.4Hz) 。 z, 10.5Hz), 5.39 (dd, 1H, J = 1.0Hz, 3.4Hz).

【0083】[α] D 20 = -8.1゜(c=1.03,CHCl 3 )。 [0083] [α] D 20 = -8.1 DEG (c = 1.03, CHCl 3) .

【0084】2)化合物226 の合成 化合物225 、0.928 gに酢酸エチル70mlを加えて溶かした。 [0084] 2) Synthesis Compound 225 Compound 226 was dissolved by adding ethyl acetate 70ml to 0.928 g. ここにp−トルエンスルホン酸1水和物0.350 g及びリンドラー触媒0.506 gを加え、50psiで4時間接触還元した。 Here p- toluenesulfonic acid monohydrate 0.350 g and Lindlar catalyst 0.506 g was added, and 4 hours catalytic reduction at 50 psi. さらにリンドラー触媒0.509 gを加え、50 Further added Lindlar catalyst 0.509 g, 50
psiで6時間接触還元した。 It was subjected to catalytic reduction for 6 hours at psi. 触媒を濾去し、目的物を淡褐色油状物として1.001 g得た。 The catalyst was filtered off, to obtain 1.001 g of the desired product as a pale brown oil. これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0085】3)化合物227 の合成 化合物226 、1.001 gに塩化メチレン20mlを加え、ここにトリエチルアミン214 μlを加えて均一溶液とし、氷冷下撹拌した。 [0085] 3) Compound 226 Compound 227, a 1.001 g of methylene chloride 20ml addition, where added triethylamine 214 [mu] l to give a homogeneous solution, which was stirred under ice-cooling. ここに(N−パルミトイルオキシ)スクシンイミド0.815 gを塩化メチレン6mlに溶かして加え、室温まで昇温させながら3日間撹拌した。 Here (N- palmitoyl) succinimide 0.815 g was added dissolved in methylene chloride 6 ml, was stirred for 3 days while warming to room temperature. 減圧下溶媒を留去し、残渣をシリカゲルクロマトグラフィーで精製して(溶出溶媒:n−ヘキサン−酢酸エチル 1: The solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: n-hexane - ethyl acetate 1:
1)、目的物を0.38g得た。 1), to give 0.38g of the desired product.

【0086】 1 H-NMR(δ,CDCl 3 ) :0.87(t,3H,J=7.0H [0086] 1 H-NMR (δ, CDCl 3): 0.87 (t, 3H, J = 7.0H
z),1.16-1.32(m,24H),1.59-1.65(m,2H) ,1.99(s,3 z), 1.16-1.32 (m, 24H), 1.59-1.65 (m, 2H), 1.99 (s, 3
H),2.05(s,3H) 2.06(s,3H) ,2.15(s,3H),2.18(t,2H, H), 2.05 (s, 3H) 2.06 (s, 3H), 2.15 (s, 3H), 2.18 (t, 2H,
J=7.6Hz),3.44-3.48(m,2H) ,3.55(t,2H,J=5.3Hz),3. J = 7.6Hz), 3.44-3.48 (m, 2H), 3.55 (t, 2H, J = 5.3Hz), 3.
59-3.67(m,6H) ,3.72-3.76(m,1H) ,3.90-3.93(m,1H) 59-3.67 (m, 6H), 3.72-3.76 (m, 1H), 3.90-3.93 (m, 1H)
,3.97-4.00(m,1H) ,4.13(dd,1H,J=6.8Hz,11.2Hz), , 3.97-4.00 (m, 1H), 4.13 (dd, 1H, J = 6.8Hz, 11.2Hz),
4.18(dd,1H,J=6.3Hz,11.2Hz),4.55(d,1H,J=7.8Hz),5. 4.18 (dd, 1H, J = 6.3Hz, 11.2Hz), 4.55 (d, 1H, J = 7.8Hz), 5.
02(dd,1H,J=3.3Hz,10.3Hz),5.21(dd,1H,J=7.8Hz,10.3H 02 (dd, 1H, J = 3.3Hz, 10.3Hz), 5.21 (dd, 1H, J = 7.8Hz, 10.3H
z),5.39(dd,1H,J=0.5Hz,3.3Hz) ,6.04(bs,1H) 。 z), 5.39 (dd, 1H, J = 0.5Hz, 3.3Hz), 6.04 (bs, 1H).

【0087】[α] D 23 =-7.1 ゜(c=1.02,CHCl 3 )。 [0087] [α] D 23 = -7.1 DEG (c = 1.02, CHCl 3) .

【0088】4)化合物228 の合成 化合物227 、1.42gにメタノール20mlを加えて、氷冷下撹拌した。 [0088] 4) Synthesis Compound 227 Compound 228, was added methanol 20ml to 1.42 g, which was stirred under ice-cooling. ここに28%ナトリウムメトキシドメタノール溶液を6滴加えてpH=12とし、室温で12.5時間撹拌した。 And pH = 12 by adding 6 drops of here 28% sodium methoxide methanol solution was stirred for 12.5 hours at room temperature. ここに「ダウエックス50X−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 Here was neutralized by adding "Dowex 50X-8" ion exchange resin (H-type), it was filtered off the resin. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:クロロホルム−メタノール 1:1)、目的化合物を1.11g得た。 The solvent was evaporated under reduced pressure, the residue was purified by "Sephadex LH-20" (elution solvent: chloroform - methanol 1: 1) to obtain 1.11g of the desired compound.

【0089】 1 H-NMR(δ,pyridine-d 5 -D 2 O):0.87(t, [0089] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.87 (t,
3H,J=7.0Hz),1.23-1.38(m,24H),1.80(quintet,2H,J= 3H, J = 7.0Hz), 1.23-1.38 (m, 24H), 1.80 (quintet, 2H, J =
7.6Hz),2.40(t,1H,J=7.6Hz),3.55-3.57(m,2H) ,3.58 7.6Hz), 2.40 (t, 1H, J = 7.6Hz), 3.55-3.57 (m, 2H), 3.58
-3.60(m,6H) ,3.63-3.71(m,6H) ,3.89(dt,1H,J=5.3H -3.60 (m, 6H), 3.63-3.71 (m, 6H), 3.89 (dt, 1H, J = 5.3H
z,10.6Hz),4.02-4.05(m,1H),4.13(dd,1H,J=3.4Hz,9.5 z, 10.6Hz), 4.02-4.05 (m, 1H), 4.13 (dd, 1H, J = 3.4Hz, 9.5
Hz) ,4.25(dt,1H,J=5.3Hz,10.6Hz),4.41-4.44(m,3H) Hz), 4.25 (dt, 1H, J = 5.3Hz, 10.6Hz), 4.41-4.44 (m, 3H)
,4.54(bd,1H) ,4.78(d,1H,J=7.6Hz),8.54(bt,1H) , 4.54 (bd, 1H), 4.78 (d, 1H, J = 7.6Hz), 8.54 (bt, 1H)
.

【0090】 [α] D 25 =-1.7 ゜(c=1.00,CHCl 3 -MeOH 1:1 )。 [0090] [α] D 25 = -1.7 DEG (c = 1.00, CHCl 3 -MeOH 1: 1).

【0091】FAB-MS:[M+H] + ;m/z=550 。 [0091] FAB-MS: [M + H ] +; m / z = 550.

【0092】 (b′) 化合物851 の合成(図6)アミノ体のパラトルエンスルホン酸塩818 (167mg )の塩化メチレン(10ml)溶液にN−パルミトイルオキシスクシンイミド(115mg )のトルエン(5ml)溶液にトリエチルアミン(90μl)を加えたもの加え、終夜撹拌した。 [0092] (b ') Synthesis of Compound 851 in toluene (5ml) solution of (6) in methylene chloride (10ml) was added N- palmitoyloxy succinimide paratoluenesulfonate 818 amino compound (167 mg) (115 mg) In addition those triethylamine was added (90 [mu] l), and stirred overnight. 反応液を水及び半飽和食塩水にて洗浄し、硫酸マグネシクムにて乾燥した。 The reaction mixture was washed with water and half saturated brine, and dried over sulfate Maguneshikumu. 溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィーにて精製し、パルミトイル体(181mg )を得た。 The solvent was distilled off and the residue was purified by silica gel column chromatography to give palmitoyl member (181 mg).

【0093】 [α] D 23 -20.6 ゜(c 1.2 ,クロロホルム)。 [0093] [α] D 23 -20.6 ° (c 1.2, chloroform).

【0094】IR(KBr) :3700,3600,2980,2435,152 [0094] IR (KBr): 3700,3600,2980,2435,152
0,1480,1420cm -1 0,1480,1420cm -1.

【0095】 1 H-NMR(CD 3 OD) :0.90(3H,t,J=7Hz),1.9 [0095] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.9
3(3H,s),1.95(3H,s),2.02(3H,s),2.14(3H,s),4.46 3 (3H, s), 1.95 (3H, s), 2.02 (3H, s), 2.14 (3H, s), 4.46
(1H,d,J=4.6Hz),5.06(1H,dd,J=3.5,11.5Hz),5.33(1H, (1H, d, J = 4.6Hz), 5.06 (1H, dd, J = 3.5,11.5Hz), 5.33 (1H,
brs)。 brs).

【0096】 R f =0.4(クロロホルム:メタノール=93:7)。 [0096] R f = 0.4 (chloroform: methanol = 93: 7).

【0097】上記で得たパルミトイル体(141mg )のメタノール(15ml)溶液にナトリウムメトキシド(28%メタノール溶液40μl)を加え、室温にて5.5 時間撹拌した。 [0097] obtained above palmitoyl body (141 mg) in methanol (15ml) solution of sodium methoxide (28% methanol solution 40 [mu] l) was added, and stirred for 5.5 hours at room temperature. 陽イオン交換樹脂「アンバーリスト15E」(ローム・アンド・ハース社製)を液性が中性になるまで加えた後樹脂を濾去して、濾液を濃縮し、目的化合物851 (10 By filtering off the resin after liquid cation-exchange resin "Amberlyst 15E" (produced by Rohm and Haas) was added until neutral, the filtrate was concentrated, the target compound 851 (10
4mg ,90%)を得た。 4 mg, 90%) was obtained.

【0098】 [α] D 26 +43.9 ゜(c 1.0 ,メタノール)。 [0098] [α] D 26 +43.9 DEG (c 1.0, methanol).

【0099】 IR(KBr) :3340,3330,1640,1560,1470 -1 cm。 [0099] IR (KBr): 3340,3330,1640,1560,1470 -1 cm .

【0100】 1 H-NMR(CD 3 OD) :0.90(3H,t,J=7Hz),1.9 [0100] 1 H-NMR (CD 3 OD ): 0.90 (3H, t, J = 7Hz), 1.9
8(3H,s),2.19(2Ht,J=7Hz,),3.83(1H,d,J=3Hz),3.90 8 (3H, s), 2.19 (2Ht, J = 7Hz,), 3.83 (1H, d, J = 3Hz), 3.90
(1H,t,J=8.5Hz),4.44(1H,d,J=8.5Hz)。 (1H, t, J = 8.5Hz), 4.44 (1H, d, J = 8.5Hz).

【0101】 R f =0.26 (クロロホルム:メタノール=9:1)。 [0102] R f = 0.26 (chloroform: methanol = 9: 1).

【0102】 (c′) 化合物333 の合成(図7) 1)化合物332 の合成 アミン体化合物329 (210mg )とパルミチン酸N−ヒドロキシスクシンイミドエステル(113mg )を塩化メチレン(20ml)に溶解し、トリエチルアミン(65mg)を加え、室温で4時間攪拌した。 [0102] (c ') Synthesis of Compound 333 (Figure 7) 1) Synthesis amine Compounds 329 Compound 332 (210 mg) and palmitic acid N- hydroxysuccinimide ester (113 mg) was dissolved in methylene chloride (20 ml), triethylamine the (65 mg) was added, followed by stirring at room temperature for 4 hours. 反応液を塩化メチレンで希釈し、水、10%クエン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 The reaction was diluted with methylene chloride, washed successively with water, 10% citric acid solution and water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(50g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 100:1)で精製し、目的化合物332 (194mg )を得た。 Column chromatography of the residue on silica gel (50 g) (chloroform - methanol 100: 1) to give the target compound 332 (194 mg).

【0103】[α] D +23.7 °(c 1.07,CHCl 3 )。 [0103] [α] D +23.7 ° (c 1.07, CHCl 3).

【0104】 1 H-NMR(CDCl 3 ) δ:0.88(3H,t,J=6.8H [0104] 1 H-NMR (CDCl 3) δ: 0.88 (3H, t, J = 6.8H
z),1.23-1.33(24H,m),1.63(2H,m),2.00(3H,s),2.04 z), 1.23-1.33 (24H, m), 1.63 (2H, m), 2.00 (3H, s), 2.04
(3H,s),2.11(3H,s),2.16(3H,s),2.17(2H,t,J=7.8H (3H, s), 2.11 (3H, s), 2.16 (3H, s), 2.17 (2H, t, J = 7.8H
z),3.45(2H,q),3.56(2H,t),3.60-3.73(7H,m) ,3.80 z), 3.45 (2H, q), 3.56 (2H, t), 3.60-3.73 (7H, m), 3.80
-3.85(1H,m) ,4.07(1H,ddd,J=2.4Hz,4.9Hz,10.0Hz) , -3.85 (1H, m), 4.07 (1H, ddd, J = 2.4Hz, 4.9Hz, 10.0Hz),
4.11(1H,dd,J=2.4Hz,12.2Hz),4.28(1H,dd,J=4.9Hz,12. 4.11 (1H, dd, J = 2.4Hz, 12.2Hz), 4.28 (1H, dd, J = 4.9Hz, 12.
2Hz),4.89(1H,d,J=1.5Hz),5.27(1H,dd,J=1.5Hz,3.4H 2Hz), 4.89 (1H, d, J = 1.5Hz), 5.27 (1H, dd, J = 1.5Hz, 3.4H
z) ,5.30(1H,t,J=10.0Hz),5.36(1H,dd,J=3.4Hz,10.0H z), 5.30 (1H, t, J = 10.0Hz), 5.36 (1H, dd, J = 3.4Hz, 10.0H
z),6.06(1H,m)。 z), 6.06 (1H, m).

【0105】2)化合物333 の合成 化合物332 (185mg )をメタノール(5ml)に溶解し、 [0105] 2) Synthesis of Compound 333 332 (185 mg) was dissolved in methanol (5 ml),
28%NaOMe inMeOH(20μl)を加え、室温で4時間攪拌した。 28% NaOMe inMeOH a (20 [mu] l) was added, followed by stirring at room temperature for 4 hours. 反応液に「アンバーライトIRC− "Amber light to the reaction solution IRC-
50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固した。 50 "was added, insoluble material the filtrate after filtration was concentrated to dryness under reduced pressure to. 残渣にクロロホルムを加え、不溶物を濾去後濾液を減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合物333 (128mg )を無色粉末として得た。 Chloroform was added to the residue, insoluble material the filtrate after filtration concentrated to dryness under reduced pressure, the residue was washed with ether to give the desired compound 333 (128 mg) as a colorless powder.

【0106】[α] D +28.2 °(c 1.02,CHCl 3 )。 [0106] [α] D +28.2 ° (c 1.02, CHCl 3).

【0107】 1 H-NMR(CDCl 3 ) δ:0.88(3H,t,J=6.6H [0107] 1 H-NMR (CDCl 3) δ: 0.88 (3H, t, J = 6.6H
z),1.20-1.34(24H,m),1.62(2H,m),2.18(2H,t,J=7.6H z), 1.20-1.34 (24H, m), 1.62 (2H, m), 2.18 (2H, t, J = 7.6H
z),3.42-3.93(18H,m),4.88(1H,s),6.31(1H,m)。 z), 3.42-3.93 (18H, m), 4.88 (1H, s), 6.31 (1H, m).

【0108】 (d′) 化合物529 の合成(図8) 1)化合物524 の合成 L−フコーステトラアセテート(化合物523 )(10.16 [0108] (d ') Synthesis of Compound 529 (FIG. 8) 1) Synthesis L- fucose tetraacetate compound 524 (Compound 523) (10.16
g)と2−[2−(2−クロロエトキシ)エトキシ]エタノール(10.31 g)を塩化メチレン(300ml)に溶解し、BF 3・Et 2 O(17.36 g)を加え、室温で25時間攪拌した。 g) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (10.31 g) was dissolved in methylene chloride (300ml), BF 3 · Et 2 O a (17.36 g) was added, followed by stirring at room temperature for 25 hours . 反応液を塩化メチレンで希釈し、水、5% The reaction was diluted with methylene chloride, water, 5%
NaHCO 3水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 NaHCO 3 was washed sequentially with water and water, dried and then the solvent was distilled off under reduced pressure. 残渣をピリジン(26ml)に溶解し、無水酢酸(20ml)を加え、室温で15時間攪拌した。 The residue was dissolved in pyridine (26 ml), was added acetic anhydride (20 ml), and stirred at room temperature for 15 hours. 反応混合物を酢酸エチルで希釈し、水、5%NaHCO 3水、水、 The reaction mixture was diluted with ethyl acetate, water, 5% NaHCO 3 water, water,
10%クエン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 Successively washed with 10% citric acid solution and water, dried and then the solvent was distilled off under reduced pressure. 残渣シリカゲル(250 g)を用いるカラムクロマトグラフィー(クロロホルム)で精製し、α−グリコシド体化合物524 (4.40g,33%)とβ−グリコシド体化合物525 (1.79g)を無色油状物として得た。 The residue was purified on silica gel (250 g) column chromatography (chloroform) using, alpha-glycoside Compounds 524 (4.40 g, 33%) and β- glycoside Compounds 525 (1.79 g) as a colorless oil.

【0109】α−グリコシド体化合物524 : [α] D -112.3°(c 0.96,CHCl 3 )。 [0109] α- glycoside Compounds 524: [α] D -112.3 ° (c 0.96, CHCl 3).

【0110】 1 H-NMR(CDCl 3 ) δ:1.14(3H,d,J=6.6H [0110] 1 H-NMR (CDCl 3) δ: 1.14 (3H, d, J = 6.6H
z),1.99(3H,s),2.08(3H,s),2.17(3H,s),3.62-3.84 z), 1.99 (3H, s), 2.08 (3H, s), 2.17 (3H, s), 3.62-3.84
(12H,m),4.23(1H,q,J=6.6Hz),5.11(1H,d,J=3.7Hz), (12H, m), 4.23 (1H, q, J = 6.6Hz), 5.11 (1H, d, J = 3.7Hz),
5.12(1H,dd,J=3.7Hz,10.0Hz),5.30(1H,d,J=3.4Hz),5. 5.12 (1H, dd, J = 3.7Hz, 10.0Hz), 5.30 (1H, d, J = 3.4Hz), 5.
37(1H,dd,J=3.4Hz,10.0Hz)。 37 (1H, dd, J = 3.4Hz, 10.0Hz).

【0111】2)化合物526 の合成 クロル体化合物524 (3.56g)をDMF(50ml)に溶解し、アジ化ナトリウム(1.05g)を加え、70℃で2日間攪拌した。 [0111] 2) was dissolved synthetic chlorinated Compounds 524 compound 526 (3.56 g) in DMF (50 ml), was added sodium azide (1.05 g), and stirred for 2 days at 70 ° C.. 反応液を酢酸エチルで希釈し、水洗し、乾燥後溶媒を減圧下留去した。 The reaction solution was diluted with ethyl acetate, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(100 g) The residue on silica gel (100 g)
を用いるカラムクロマトグラフィー(クロロホルム)で精製し、アジド体化合物526 (2.98g)を無色油状物として得た。 Purification by column chromatography (chloroform) to use, to give azide compound 526 (2.98 g) as a colorless oil.

【0112】[α] D -113.7°(c 0.96,CHCl 3 )。 [0112] [α] D -113.7 ° (c 0.96, CHCl 3).

【0113】 1 H-NMR(CDCl 3 ) δ:1.14(3H,d,J=6.6H [0113] 1 H-NMR (CDCl 3) δ: 1.14 (3H, d, J = 6.6H
z),1.99(3H,s),2.07(3H,s),2.16(3H,s),3.40(2H,t, z), 1.99 (3H, s), 2.07 (3H, s), 2.16 (3H, s), 3.40 (2H, t,
J=5.0Hz),3.62-3.70(9H,m) ,3.78-3.84(1H,m) ,4.23 J = 5.0Hz), 3.62-3.70 (9H, m), 3.78-3.84 (1H, m), 4.23
(1H,dq,J=1.2Hz,6.6Hz) ,5.10(1H,d,J=3.7Hz),5.12(1 (1H, dq, J = 1.2Hz, 6.6Hz), 5.10 (1H, d, J = 3.7Hz), 5.12 (1
H,dd,J=3.7Hz,10.3Hz),5.30(1H,dd,J=1.2Hz,3.4Hz) , H, dd, J = 3.7Hz, 10.3Hz), 5.30 (1H, dd, J = 1.2Hz, 3.4Hz),
5.37(1H,dd,J=3.4Hz,10.3Hz)。 5.37 (1H, dd, J = 3.4Hz, 10.3Hz).

【0114】3)化合物527 の合成 アジド体化合物526 (2.21g)とp−トルエンスルホン酸(0.94g)をエタノール(100ml )に溶解し、リンドラー触媒(4.40g)を加え、室温50psiで7時間接触還元を行った。 [0114] 3) Synthesis azide compound compound 527 526 (2.21 g) and p- toluenesulfonic acid (0.94 g) was dissolved in ethanol (100 ml), added Lindlar catalyst (4.40 g), 7 hours at room temperature 50psi the catalytic reduction was carried out. 触媒を濾去後、濾液を減圧下濃縮し、アミン体化合物527 (2.84g)を無色油状物質として得た。 After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give amine compound compound 527 (2.84 g) as a colorless oil.

【0115】4)化合物528 の合成 アミン体化合物527 (240mg )とパルチミン酸N−ヒドロキシスクシンイミドエステル(143mg)を塩化メチレン(20ml)に溶解し、トリエチルアミン(82mg)を加え、 [0115] 4) Synthesis amine Compounds 527 compound 528 (240 mg) and palmitic acid N- hydroxysuccinimide ester (143 mg) was dissolved in methylene chloride (20 ml), triethylamine (82 mg) was added,
室温で3時間攪拌した。 The mixture was stirred for 3 hours at room temperature. 反応液を塩化メチレンで希釈し、水、10%クエン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 The reaction was diluted with methylene chloride, washed successively with water, 10% citric acid solution and water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリガゲル(50g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 100:1)で精製し、目的化合物(241mg )を得た。 The residue was purified by column chromatography using Shirigageru (50 g) (chloroform - methanol 100: 1) to give the desired compound (241 mg).

【0116】[α] D -65.0 °(c 1.01,CHCl 3 )。 [0116] [α] D -65.0 ° (c 1.01, CHCl 3).

【0117】1H-NMR(CDCl 3 ) δ:0.88(3H,t,J=6.8H [0117] 1H-NMR (CDCl 3) δ : 0.88 (3H, t, J = 6.8H
z),1.14(3H,d,J=6.6Hz),1.20-1.34(24H,m),1.63(2H, z), 1.14 (3H, d, J = 6.6Hz), 1.20-1.34 (24H, m), 1.63 (2H,
m),1.99(3H,s),2.07(3H,s),2.17(3H,s),2.18(2H, m), 1.99 (3H, s), 2.07 (3H, s), 2.17 (3H, s), 2.18 (2H,
m),3.46(2H,m),3.56(2H,m),3.58-3.68(7H,m) ,3.80 m), 3.46 (2H, m), 3.56 (2H, m), 3.58-3.68 (7H, m), 3.80
(1H,m),4.23(1H,dq,J=1.2Hz,6.6Hz) ,5.12(1H,dd,J= (1H, m), 4.23 (1H, dq, J = 1.2Hz, 6.6Hz), 5.12 (1H, dd, J =
3.7Hz,10.3Hz),5.13(1H,d,J=3.7Hz),5.29(1H,dd,J=1. 3.7Hz, 10.3Hz), 5.13 (1H, d, J = 3.7Hz), 5.29 (1H, dd, J = 1.
2Hz,3.4Hz) ,5.37(1H,dd,J=3.4Hz,0.3Hz) ,6.10(1H, 2Hz, 3.4Hz), 5.37 (1H, dd, J = 3.4Hz, 0.3Hz), 6.10 (1H,
m)。 m).

【0118】5)化合物529 の合成 化合物528 (208mg )をメタノール(5ml)に溶解し、 [0118] 5) Compound 528 Compound 529 (208 mg) was dissolved in methanol (5 ml),
28%NaOMe inMeOH(20μl)を加え、室温で 2.5時間攪拌した。 28% NaOMe inMeOH a (20 [mu] l) was added, followed by stirring at room temperature for 2.5 hours. 反応液に「アンバーライトIRC "Amberlite IRC to the reaction solution
−50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固した。 -50 "was added, insoluble material the filtrate after filtration was concentrated to dryness under reduced pressure to. 残渣にクロロホルムを加え、不溶物を濾去後濾液を減圧下濃縮乾固し、残渣をエーテルで洗浄して目的化合物529 (151mg )を無色粉末として得た。 Chloroform was added to the residue, insoluble material the filtrate after filtration concentrated to dryness under reduced pressure, the residue was washed with ether to give the desired compound 529 (151 mg) as a colorless powder.

【0119】[α] D -55.2 °(c 0.56,CHCl 3 )。 [0119] [α] D -55.2 ° (c 0.56, CHCl 3).

【0120】 1 H-NMR(CDCl 3 ) δ:0.88(3H,t,J=6.8H [0120] 1 H-NMR (CDCl 3) δ: 0.88 (3H, t, J = 6.8H
z),1.20-1.34(24H,m),1.30(3H,d,J=6.6Hz),1.62(2H, z), 1.20-1.34 (24H, m), 1.30 (3H, d, J = 6.6Hz), 1.62 (2H,
m),2.18(2H,m),3.40-3.72(11H,m),3.74-3.84(3H,m) m), 2.18 (2H, m), 3.40-3.72 (11H, m), 3.74-3.84 (3H, m)
,3.90-3.94(1H,m) ,4.04(1H,q,J=3.3Hz),4.92(1H, , 3.90-3.94 (1H, m), 4.04 (1H, q, J = 3.3Hz), 4.92 (1H,
d,J=3.4Hz),6.43(1H,m)。 d, J = 3.4Hz), 6.43 (1H, m).

【0121】実施例2(合成例(その2)) 分子中に重合度3〜6のポリエチレングリコール及び少なくとも2個の、炭素数5〜20のアルキル基を有する14 [0121] Example 2 (Synthesis example (2)) of polyethylene glycol and at least two degrees of polymerization 3-6 in the molecule, 14 having an alkyl group having 5 to 20 carbon atoms
種の化合物(本発明)243 、251 、830 、833、856 、7 Class of compounds (present invention) 243, 251, 830, 833,856, 7
18 、1105、1205、4−3、8−2、12−8、15−2、2 18, 1105,1205,4-3,8-2,12-8,15-2,2
8−2及び18−2を各々次のようにして合成した。 8-2 and 18-2 were each synthesized in the following manner.

【0122】これらの合成反応における反応を図9〜22 [0122] The reaction in these synthetic reaction Figure 9-22
に示す。 To show.

【0123】 (e) 化合物243 の合成(図9) 1)化合物240 の合成 J. [0123] (e) Synthesis of Compound 243 (FIG. 9) 1) Synthesis of Compound 240 J. Org,Chem. Org, Chem. 56 ,4326(1991)に記載の方法で合成した2−{2−[2−(2−アジドエキトキ)エトキシ]エトキシ}エタノール 1,980g及びβ−D−ガラクト−スペンタアセート 3.525gを塩化メチレン50ml , 56, 4326 synthesized 2 by the method described in (1991) {2- [2- (2-Ajidoekitoki) ethoxy] ethoxy} ethanol 1,980g and beta-D-galacto - Supentaaseto 3.525g of methylene chloride 50ml
に溶かし、氷冷下攪拌した。 Dissolved, and the mixture was stirred under ice-cooling. ここに三フッ化硼素ジエチルエーテル錯体4.44mlを滴下した。 It was added dropwise boron trifluoride-diethyl ether complex 4.44ml here. 室温で17.5時間攪拌した後、氷水にあけ、有機層を分離した。 After stirring at room temperature for 17.5 hours, poured into ice water, and the organic layer was separated. 飽和食塩水で5回洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 It washed 5 times with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1: The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1:
5)、目的物を無色油状物として 1.238g得た。 5), to give 1.238g of the desired product as a colorless oil.

【0124】 1 H-MNR(δ,CDCl 3 ) :1.99(s,3H),2.05 [0124] 1 H-MNR (δ, CDCl 3): 1.99 (s, 3H), 2.05
(s,3H),2.06(s,3H),2.15(s,3H),3.40(t,2H,J=5.0H (S, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 3.40 (t, 2H, J = 5.0H
z),3.62-3.69(m,12H),3.75(ddd,1H,J=3.7Hz,7.4Hz,1 z), 3.62-3.69 (m, 12H), 3.75 (ddd, 1H, J = 3.7Hz, 7.4Hz, 1
1.1Hz),3.90-3.93(m,1H) ,3.94-9.98(dt,1H,J=4.3Hz, 1.1Hz), 3.90-3.93 (m, 1H), 3.94-9.98 (dt, 1H, J = 4.3Hz,
11.1Hz) ,4.13(dd,1H,J=6.8Hz,11.2Hz),4.18(dd,1H,J 11.1Hz), 4.13 (dd, 1H, J = 6.8Hz, 11.2Hz), 4.18 (dd, 1H, J
=6.6Hz,11.2Hz),4.57(d,1H,J=8.1Hz),5.02(dd,1H,J= = 6.6Hz, 11.2Hz), 4.57 (d, 1H, J = 8.1Hz), 5.02 (dd, 1H, J =
3.4Hz,10.5Hz),5.21(dd,1H,J=8.1Hz,10.5Hz),5.39(d 3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.39 (d
d,1H,J=1.0Hz,3.4Hz) 。 d, 1H, J = 1.0Hz, 3.4Hz).

【0125】[α] D 23 =-5.4 ゜(c=1.02,CHCl 3 )。 [0125] [α] D 23 = -5.4 DEG (c = 1.02, CHCl 3) .

【0126】2)化合物241 の合成 化合物240 、1.129 gに酢酸エチル120ml を加えて溶かした。 [0126] 2) Synthesis Compound 240 Compound 241 was dissolved by adding ethyl acetate 120ml to 1.129 g. ここにp−トルエンスルホン酸1水和物 0.391g Here p- toluenesulfonic acid monohydrate 0.391g
及びリンドラー触媒 0.570gを加え、50psiで 5.5時間触媒還元した。 And Lindlar catalyst 0.570g was added and 5.5 hours catalytic reduction at 50 psi. さらにリンドラー触媒 0.564gを加え、50psiで5時間触媒還元した。 Further Lindlar catalyst 0.564g added, and 5 hours the catalyst reduced at 50 psi. 触媒を濾去し、目的物を淡褐色油状物として 1.172g得た。 The catalyst was filtered off to give 1.172g of the desired product as a pale brown oil. これ以上の精製はせず、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0127】3)化合物1103の合成 2−(n−ヘキサデシル)オクタデカン酸 0.525gに塩化チオニル2mlを加え、6時間熱還流させた。 [0127] 3) Synthesis of Compound 1103 2-(n-hexadecyl) of thionyl chloride 2ml addition to octadecanoic acid 0.525 g, was refluxed for 6 hours heat. 塩化チオニルを減圧下留去した。 It was evaporated under reduced pressure thionyl chloride. 残渣にベンゼンを加えて溶かし、減圧下濾去した(3回)。 Residue was dissolved by addition of benzene and filtered off under reduced pressure (3 times). これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0128】4)化合物242 の合成 化合物241 、0.618 gに塩化メチレン10mlを加えて溶かし、氷冷下攪拌した。 [0128] 4) Synthesis Compound 241 Compound 242 was dissolved by adding methylene chloride 10ml to 0.618 g, and stirred under ice-cooling. ここにトリエチルアミン 268μl Here in triethylamine 268μl
を加え、さらに上記反応で得た化合物1103全量を塩化メチレン4mlに溶かして加え、室温に昇温させつつ14時間攪拌した。 Was added, it was added dissolved further compounds 1103 the total amount obtained in the above reaction in methylene chloride 4 ml, was stirred for 14 hours while allowed to warm to room temperature. 塩化メチレンで希釈し、水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Diluted with methylene chloride, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル2:3)、 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 2: 3),
目的物を 0.550g得た。 The desired product was obtained 0.550g.

【0129】 1 H-NMR(δ,CDCl 3 ) :0.88(t,6H,J=7.0H [0129] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z),1.19-1.33(m,56H),1.35-1.42(m,2H) ,1.53-1.62 z), 1.19-1.33 (m, 56H), 1.35-1.42 (m, 2H), 1.53-1.62
(m,2H) ,1.97-2.03(m,1H) ,1.99(s,3H),2.05(s,3 (M, 2H), 1.97-2.03 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3
H),2.06(s,3H),2.15(s,3H),3.45-3.48(m,1H) ,3.48 H), 2.06 (s, 3H), 2.15 (s, 3H), 3.45-3.48 (m, 1H), 3.48
-3.54(t,2H,J=5.0Hz) ,3.61-3.68(m,10H),3.75(ddd,1 -3.54 (t, 2H, J = 5.0Hz), 3.61-3.68 (m, 10H), 3.75 (ddd, 1
H,J=3.7Hz,7.3Hz,11.0Hz) ,3.90-3.94(m,1H) ,3.96(d H, J = 3.7Hz, 7.3Hz, 11.0Hz), 3.90-3.94 (m, 1H), 3.96 (d
t,1H,J=4.4Hz) ,4.13(dd,1H,J=7.1Hz,11.2Hz),4.17(d t, 1H, J = 4.4Hz), 4.13 (dd, 1H, J = 7.1Hz, 11.2Hz), 4.17 (d
d,1H,J=6.6Hz,11.2Hz),4.56(d,1H,J=8.1Hz),5.02(dd, d, 1H, J = 6.6Hz, 11.2Hz), 4.56 (d, 1H, J = 8.1Hz), 5.02 (dd,
1H,J=3.5Hz,10.5Hz),5.21(dd,1H,J=8.1Hz,10.5Hz),5. 1H, J = 3.5Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.1Hz, 10.5Hz), 5.
39(dd,1H,J=1.0Hz,3.5Hz),5.96(t,1H,J=5.6Hz)。 39 (dd, 1H, J = 1.0Hz, 3.5Hz), 5.96 (t, 1H, J = 5.6Hz).

【0130】 [α] D 23 =-2.5 ゜(c=1.00,CHCl 3 -MeOH 1:1 )。 [0130] [α] D 23 = -2.5 DEG (c = 1.00, CHCl 3 -MeOH 1: 1).

【0131】5)化合物243 の合成 化合物242 、0.518 gにメタノール5ml及びベンゼン10 [0131] 5) Compound 242 Compound 243, methanol 5ml and benzene 10 to 0.518 g
mlを加えて溶かした。 It was dissolved by the addition of ml. ここに28%ナトリウムメトキシドメタノール溶液を6滴加えてpH=10とし、室温で19時間攪拌した。 And pH = 10 by adding 6 drops of here 28% sodium methoxide methanol solution, followed by stirring at room temperature for 19 hours. ここに「ダウエックス50X−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 Here was neutralized by adding "Dowex 50X-8" ion exchange resin (H-type), it was filtered off the resin. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:クロロホルム−メタノール 1: The solvent was evaporated under reduced pressure, the residue is purified by "Sephadex LH-20" (elution solvent: chloroform - methanol 1:
1)、目的化合物を 0.403g得た。 1), to give 0.403g of the desired compound.

【0132】 1 H-NMR(δ, pyridine-d 5 -D 2 O):0.88(t, [0132] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.88 (t,
6H,J=7.0Hz),1.02-1.39(m,52H),1.44-1.62(m,6H) , 6H, J = 7.0Hz), 1.02-1.39 (m, 52H), 1.44-1.62 (m, 6H),
1.92-2.00(m,2H) ,2.51-2.57(m,1H) ,3.63-3.77(m,14 1.92-2.00 (m, 2H), 2.51-2.57 (m, 1H), 3.63-3.77 (m, 14
H),3.93(dt,1H,J=5.3Hz,10.7Hz),4.02-4.05(m,1H) , H), 3.93 (dt, 1H, J = 5.3Hz, 10.7Hz), 4.02-4.05 (m, 1H),
4.14(dd,1H,J=3.4Hz,9.5Hz),4.26(dt,1H,J=4.9Hz,10.7 4.14 (dd, 1H, J = 3.4Hz, 9.5Hz), 4.26 (dt, 1H, J = 4.9Hz, 10.7
Hz),4.40-4.44(m,3H) ,4.54(bd,1H) ,4.78(d,1H,J Hz), 4.40-4.44 (m, 3H), 4.54 (bd, 1H), 4.78 (d, 1H, J
1 , 2 =7.6Hz) , 8.776(bt,1H) 。 1, 2 = 7.6Hz), 8.776 (bt, 1H).

【0133】 [α] D 28 =-3.6 ゜(c=1.00,CHCl 3 -MeOH 1:1 )。 [0133] [α] D 28 = -3.6 DEG (c = 1.00, CHCl 3 -MeOH 1: 1).

【0134】FAB-MS:[M+H] + ;m/z=846 。 [0134] FAB-MS: [M + H ] +; m / z = 846.

【0135】 (f) 化合物251 の合成(図10) 1)化合物HHHの合成 水素化ナトリウム1.55g(60%分散液)をn−ヘキサンで洗い、N,N−ジメチルホルムアミド40mlに懸濁させ、氷冷下攪拌した。 [0135] (f) Synthesis of Compound 251 (Figure 10) 1) washing compound HHH synthetic sodium hydride 1.55g (60% dispersion) in n- hexane, N, suspended in N- dimethylformamide 40 ml, under ice-cooling and the mixture was stirred. ここにマロン酸ジベンジルエステル4.47mlをN,N−ジメチルホルムアミド10mlに溶かして滴下し、室温で30分間攪拌した。 Here malonic acid dibenzyl ester 4.47ml of N, was added dropwise dissolved in N- dimethylformamide 10 ml, and stirred at room temperature for 30 minutes. 再び氷冷してn−オクチルブロミド7.29mlを加え、60℃で18時間攪拌した。 Chilled n- octyl bromide 7.29ml was added again ice and stirred for 18 hours at 60 ° C..
溶媒を減圧下濾去した。 The solvent was filtered off under reduced pressure. 残渣に酢酸エチルと水を加え、 The residue were added ethyl acetate and water,
有機層を分離した。 The organic layer was separated. 飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Washed with saturated brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n− The residue was purified by silica gel column chromatography (elution solvent: n-
ヘキサン−酢酸エチル 20:1)、目的物を無色油状物として 7.227g得た。 Hexane - ethyl acetate 20: 1) to afford 7.227g of the desired product as a colorless oil.

【0136】 1 H-NMR(δ,CDCl 3 ) :0.87(t,6H,J=7.1H [0136] 1 H-NMR (δ, CDCl 3): 0.87 (t, 6H, J = 7.1H
z),1.02-1.09(m,4H) ,1.15-1.30(m,20H),1.86-1.89 z), 1.02-1.09 (m, 4H), 1.15-1.30 (m, 20H), 1.86-1.89
(m,4H) ,5.10(s,4H),5.10(s,4H),7.25-7.32(m,10 (M, 4H), 5.10 (s, 4H), 5.10 (s, 4H), 7.25-7.32 (m, 10
H)。 H).

【0137】2)化合物JJJの合成 化合物HHH 6.967gに酢酸エチル70mlを加えて溶かし、10%Pd-C 0.105g(乾物)を加え、11.5時間常圧接触還元した。 [0137] 2) Synthesis Compound HHH 6.967G compound JJJ dissolved by adding ethyl acetate 70ml, 10% Pd-C 0.105g of (dry) was added and catalytic reduction for 11.5 hours under normal pressure. 触媒を濾去し、溶媒を減圧下留去した。 The catalyst was filtered off, the solvent was evaporated under reduced pressure. 化<br/>合物IIIを無色粉末として得た。 The reduction <br/> compound III was obtained as a colorless powder. これをアルゴン雰囲気下 140℃で 2.5時間加熱した。 This was heated for 2.5 hours at 140 ° C. under an argon atmosphere. 放冷して化合物JJJ Allowed to cool to compound JJJ
を無色結晶として 3.824g得た。 It was obtained 3.824g as colorless crystals.

【0138】化合物III1 H-NMR(δ,CDCl 3 ) :0. [0138] Compound III: 1 H-NMR (δ , CDCl 3): 0.
87(t,6H,J=7.1Hz),1.20-1.32(m,24H),1.94-1.97(m,4 87 (t, 6H, J = 7.1Hz), 1.20-1.32 (m, 24H), 1.94-1.97 (m, 4
H) 。 H).

【0139】化合物JJJ1 H-NMR(δ,CDCl 3 ) :0. [0139] Compound JJJ: 1 H-NMR (δ , CDCl 3): 0.
88(t,6H,J=7.0Hz),1.21-1.34(m,24H),1.43-1.51(m,2 88 (t, 6H, J = 7.0Hz), 1.21-1.34 (m, 24H), 1.43-1.51 (m, 2
H) ,1.58-1.64(m,2H) ,2.33-2.38(m,1H) 。 H), 1.58-1.64 (m, 2H), 2.33-2.38 (m, 1H).

【0140】3)化合物KKKの合成 化合物JJJ 0.336gに塩化チオニル 1.5mlを加え、80 [0140] 3) of thionyl chloride 1.5ml added to Compound JJJ 0.336 g of compound KKK, 80
℃で 2.5時間加熱した。 It was heated ℃ for 2.5 hours. 塩化チオニルを減圧下留去した。 It was evaporated under reduced pressure thionyl chloride. 残渣にベンゼンを加えて溶かし、減圧下留去した(3回)。 Residue was dissolved by addition of benzene and evaporated under reduced pressure (3 times). これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0141】4)化合物250 の合成 化合物226 、 0.442gに塩化メチレン5mlを加えて溶かし、氷冷下攪拌した。 [0141] 4) Synthesis Compound 226 Compound 250 was dissolved by adding methylene chloride to 0.442 g 5 ml, followed by stirring under ice cooling. ここにトリエチルアミン 259μl Here in triethylamine 259μl
を加え、さらに上記反応で得た化合物KKK全量を塩化メチレン5mlを溶かして加え、室温に昇温させつつ12時間攪拌した。 Was added, added further dissolved in methylene chloride 5ml compounds KKK total amount obtained in the above reaction, and stirred for 12 hours while allowed to warm to room temperature. クロロホルムで希釈し、水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Diluted with chloroform, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1:2)、目的物を無色非晶質として 0.357g得た。 The residue was purified by silica gel chromatography (elution solvent: n-hexane - ethyl acetate 1: 2) to give 0.357g of the desired product as a colorless amorphous.

【0142】 1 H-NMR(δ,CDCl 3 ) :0.88 (t,6H,J=7.0H [0142] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z),1.17-1.32(m,24H),1.36-1.43(m,2H) ,1.53-1.62 z), 1.17-1.32 (m, 24H), 1.36-1.43 (m, 2H), 1.53-1.62
(m,2H) ,1.97-2.03(m,1H) ,1.99(s,3H),2.05(s,3 (M, 2H), 1.97-2.03 (m, 1H), 1.99 (s, 3H), 2.05 (s, 3
H),2.06(s,3H),2.15(s,3H),3.46-3.49(m,2H) ,3.54 H), 2.06 (s, 3H), 2.15 (s, 3H), 3.46-3.49 (m, 2H), 3.54
(t,2H,J=5.0Hz),3.58-3.69(m,6H) ,3.74(ddd,1H,J=4. (T, 2H, J = 5.0Hz), 3.58-3.69 (m, 6H), 3.74 (ddd, 1H, J = 4.
0Hz,6.7Hz,10.7Hz) ,3.91(brt,1H),3.98(dt,1H,J=4.4 0Hz, 6.7Hz, 10.7Hz), 3.91 (brt, 1H), 3.98 (dt, 1H, J = 4.4
Hz,10.7Hz),4.13(dd,1H,J=7.0Hz,11.3Hz),4.18(dd,1 Hz, 10.7Hz), 4.13 (dd, 1H, J = 7.0Hz, 11.3Hz), 4.18 (dd, 1
H,J=6.6Hz,11.3Hz),4.55(d,1H,J=8.0Hz),5.02(dd,1H, H, J = 6.6Hz, 11.3Hz), 4.55 (d, 1H, J = 8.0Hz), 5.02 (dd, 1H,
J=3.4Hz,10.5Hz),5.21(dd,1H,J=8.0Hz,10.5Hz),5.39 J = 3.4Hz, 10.5Hz), 5.21 (dd, 1H, J = 8.0Hz, 10.5Hz), 5.39
(dd,1H,J=1.0Hz) ,5.96(t,1H,J=5.5Hz)。 (Dd, 1H, J = 1.0Hz), 5.96 (t, 1H, J = 5.5Hz).

【0143】[α] D 25 =-5.6 ゜(c=0.98,CHCl 3 )。 [0143] [α] D 25 = -5.6 DEG (c = 0.98, CHCl 3) .

【0144】5)化合物251 の合成 化合物250 、 0.325gにメタノール10ml及びベンゼン5 [0144] 5) Compound 250 Compound 251, methanol 10ml and benzene in 0.325 g 5
mlを加えて溶かした。 It was dissolved by the addition of ml. ここに28%ナトリウムメトキシドメタノール溶液を4滴加えてpH=11とし、室温で14時間攪拌した。 And pH = 11 by adding 4 drops of here 28% sodium methoxide methanol solution, followed by stirring at room temperature for 14 hours. ここに「ダウエックス50X−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 Here was neutralized by adding "Dowex 50X-8" ion exchange resin (H-type), it was filtered off the resin. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:クロロホルム−メタノール 1: The solvent was evaporated under reduced pressure, the residue is purified by "Sephadex LH-20" (elution solvent: chloroform - methanol 1:
1)、目的化合物を無色非晶質として 0.235g得た。 1), to give 0.235g of the desired compound as a colorless amorphous.

【0145】 1 H-NMR(δ,pyridine-d 5 -D 2 O):0.85(t, [0145] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.85 (t,
6H,J=7.0Hz),1.16-1.38(m,20H),1.40-1.58(m,6H) , 6H, J = 7.0Hz), 1.16-1.38 (m, 20H), 1.40-1.58 (m, 6H),
1.89-1.98(m,2H) ,2.49-2.55(m,1H) ,3.60-3.65(m,4 1.89-1.98 (m, 2H), 2.49-2.55 (m, 1H), 3.60-3.65 (m, 4
H) ,3.69-3.77(m,6H) ,3.93(dt,1H,J=5.3Hz,10.7H H), 3.69-3.77 (m, 6H), 3.93 (dt, 1H, J = 5.3Hz, 10.7H
z),405(brt,1H) ,4.15(dd,1H,J=3.4Hz) ,4.27(dt,1 z), 405 (brt, 1H), 4.15 (dd, 1H, J = 3.4Hz), 4.27 (dt, 1
H,J=5.0Hz,10.7Hz),4.42(d,2H,J=6.1Hz),4.44(dd,1H, H, J = 5.0Hz, 10.7Hz), 4.42 (d, 2H, J = 6.1Hz), 4.44 (dd, 1H,
J=7.6Hz,9.5Hz) ,4.55(br d,1H) ,4.79(d,1H,J=7.6H J = 7.6Hz, 9.5Hz), 4.55 (br d, 1H), 4.79 (d, 1H, J = 7.6H
z),8.75(brt,1H)。 z), 8.75 (brt, 1H).

【0146】 [α] D 25 =-2.0 ゜(c=0.98,CHCl 3 -MeOH 1:1 )。 [0146] [α] D 25 = -2.0 DEG (c = 0.98, CHCl 3 -MeOH 1: 1).

【0147】FAB-MS: [M+H] + ;m/z=578 。 [0147] FAB-MS: [M + H ] +; m / z = 578.

【0148】 (g) 化合物830 の合成(図11)アミド体化合物829 (87mg)のメタノール(4ml)溶液にナトリウムメトキシド(8μl 、28%メタノール溶液)を加え、室温下 1.5時間撹拌して反応させた。 [0148] (g) Synthesis of Compound 830 (FIG. 11) amide compounds 829 (87 mg) in methanol (4 ml) solution of sodium methoxide (8 [mu] l, 28% methanol solution) was added and the reaction was stirred at room temperature for 1.5 hours It was.

【0149】反応液を遠心分離に付し、得られた不溶物にメタノールを加えて再び遠心分離に付し、GalNA [0149] subjected the reaction mixture to centrifugation, subjected to centrifugation again by adding methanol to the resulting insoluble matter, GalNA
c誘導体化合物830 を49mg(収率67%)得た。 The c derivative compound 830 was obtained 49 mg (67% yield).

【0150】 R F 0.37(クロロホルム−メタノール−水 10:6:1)。 [0150] R F 0.37 (chloroform - methanol - water 10: 6: 1).

【0151】 1 H-NMR(CD 3 OD+CDCl 3 ) δ (ppm) in 500 [0151] 1 H-NMR (CD 3 OD + CDCl 3) δ (ppm) in 500
MHz:0.89(s,6H),2.01(brs,9H),4.45-4.50(m,3H) 。 MHz: 0.89 (s, 6H), 2.01 (brs, 9H), 4.45-4.50 (m, 3H).

【0152】IR(KBr) :3400,3300,1650,1560cm -1 [0152] IR (KBr): 3400,3300,1650,1560cm -1.

【0153】 (h) 化合物833 の合成(図12)アミド体化合物832 (69mg)のメタノール(3ml)溶液にナトリウムメトキシド(6μl 、28%メタノール溶液)を加え、室温下3時間撹拌して反応させた。 [0153] (h) in methanol (3 ml) was added sodium methoxide synthesis of compound 833 (FIG. 12) amide compound 832 (69 mg) (6 [mu] l, 28% methanol solution) was added and the reaction was stirred at room temperature for 3 hours It was.

【0154】反応液を遠心分離に付し、得られた不溶物にメタノールを加えて再び遠心分離に付し、GalNA [0154] subjected the reaction mixture to centrifugation, subjected to centrifugation again by adding methanol to the resulting insoluble matter, GalNA
c誘導体化合物833 を42mg(収率73%)得た。 The c derivative compound 833 was obtained 42 mg (73% yield).

【0155】 R F 0.35(クロロホルム−メタノール−水 10:6:1)。 [0155] R F 0.35 (chloroform - methanol - water 10: 6: 1).

【0156】[α] D − 2.6°(c 0.58,クロロホルム−メタノール−水 10:10:3 )。 [0156] [α] D - 2.6 ° ( c 0.58, chloroform - methanol - water 10: 10: 3).

【0157】 1 H-NMR(CD 3 OD+CDCl 3 ) δ (ppm) in 500 [0157] 1 H-NMR (CD 3 OD + CDCl 3) δ (ppm) in 500
MHz:0.89(t,3H),2.02(s,9H),4.4-4.5(m,3H) 。 MHz: 0.89 (t, 3H), 2.02 (s, 9H), 4.4-4.5 (m, 3H).

【0158】IR(KBr) :3400,3300,1650,1550cm -1 [0158] IR (KBr): 3400,3300,1650,1550cm -1.

【0159】 (i) 化合物852 の合成(図13) 1)化合物1103の合成 2−(n−ヘキサデシル)オクタデカン酸 0.291gに塩化チオニル2mlを加え、6時間加熱還流した。 [0159] (i) Synthesis (13) of the compound 852 1) of thionyl chloride 2ml addition to synthesis 2-(n-hexadecyl) octadecanoic acid 0.291g of compound 1103, was heated under reflux for 6 hours. 塩化チオニルを減圧下留去した。 It was evaporated under reduced pressure thionyl chloride. 残渣にベンゼンを加えて溶かし、減圧下濾去した。 Residue was dissolved by the addition of benzene, it was filtered off under reduced pressure. (2回)。 (2 times). これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0160】2)化合物855 の合成 化合物818 、 0.278gに塩化メチレン5mlを加えて溶かし、氷冷下攪拌した。 [0160] 2) Synthesis Compound 818 Compound 855 was dissolved by adding methylene chloride to 0.278 g 5 ml, followed by stirring under ice cooling. ここにトリエチルアミン 139μl Here in triethylamine 139μl
を加え、さらに上記反応で得た化合物1103全量を塩化メチレン5mlに溶かして加え、室温に昇温させつつ3日間攪拌した。 Was added, it was added dissolved further compounds 1103 the total amount obtained in the above reaction in methylene chloride 5 ml, and stirred for 3 days while allowed to warm to room temperature. 塩化メチレンで希釈し、水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Diluted with methylene chloride, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:塩化メチレン−メタノール 70: The residue was purified by silica gel column chromatography (eluent: methylene chloride - methanol 70:
1)、目的物を無色非晶質として 0.318g得た。 1), to give 0.318g of the desired product as a colorless amorphous.

【0161】 1 H-NMR で2種のconformer の約1:1の混合物となっており、以下のNMRの水素数は、各々の [0161] 1 H-NMR about the two score conformer 1: has a mixture of 1, the number of hydrogen the following NMR, each
conformer の水素1つを1Hとして数えて示してある。 One hydrogen of the conformer is shown counted as 1H.

【0162】 1 H-NMR(δ,CD 3 OD) :0.90(t,12H,J=7.0H [0162] 1 H-NMR (δ, CD 3 OD): 0.90 (t, 12H, J = 7.0H
z) ,1.20-1.42(m,116H) ,1.51-1.59(m,4H) ,1.93(s, z), 1.20-1.42 (m, 116H), 1.51-1.59 (m, 4H), 1.93 (s,
3H),1.94(2,3H),1.95(s,6H),2.03(s,3H),2.14(s,3 3H), 1.94 (2,3H), 1.95 (s, 6H), 2.03 (s, 3H), 2.14 (s, 3
H),2.15-2.21(m,2H) ,3.34-3.41(m,4H) ,3.36(t,2H, H), 2.15-2.21 (m, 2H), 3.34-3.41 (m, 4H), 3.36 (t, 2H,
J=5.6Hz),3.57-5.76(m,10H),3.90-3.96(m,2H) ,4.02 J = 5.6Hz), 3.57-5.76 (m, 10H), 3.90-3.96 (m, 2H), 4.02
(brt,2H),4.07-4.19(m,6H) ,4.64(d,1H,J=8.5Hz),4. (Brt, 2H), 4.07-4.19 (m, 6H), 4.64 (d, 1H, J = 8.5Hz), 4.
65(d,1H,J=8.5Hz),5.05(dd,1H,J=9.5Hz,3.4Hz) ,5.08 65 (d, 1H, J = 8.5Hz), 5.05 (dd, 1H, J = 9.5Hz, 3.4Hz), 5.08
(dd,1H,J=9.4Hz,3.3Hz) ,5.33(brd,1H),5.34(brd,1H) (Dd, 1H, J = 9.4Hz, 3.3Hz), 5.33 (brd, 1H), 5.34 (brd, 1H)
.

【0163】 [α] D 26 =-12.2゜(c=1.00,CHCl 3 -MeOH 1:1 )。 [0163] [α] D 26 = -12.2 ° (c = 1.00, CHCl 3 -MeOH 1: 1).

【0164】3)化合物856 (GalNAc-t-pas) の合成 化合物855 、 0.300gにベンゼン4ml及びメタノール2 [0164] 3) Compound 856 (GalNAc-t-pas Compound of) 855, benzene 0.300 g 4 ml and methanol 2
mlを加えて溶かし、氷冷下攪拌した。 Dissolved by the addition of ml, and the mixture was stirred under ice-cooling. ここに28%ナトリウムメトキシドメタノール溶液を3滴加えてpH=12とし、室温で12時間攪拌した。 And pH = 12 by adding 3 drops of here 28% sodium methoxide methanol solution, followed by stirring at room temperature for 12 hours. ここに「ダウエックス50X Here "Dowex 50X
−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 -8 "ion exchange resin (H-type) was neutralized by adding to the resin was filtered off. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:クロロホルム−メタノール1:1)、目的化合物を無色粉末として 0.147g The solvent was evaporated under reduced pressure, the residue is purified by "Sephadex LH-20" (elution solvent: chloroform - methanol 1: 1), 0.147 g of the desired compound as a colorless powder
得た。 Obtained.

【0165】 1 H-NMR(δ,pyridine-d 5 -D 2 O):0.88(t, [0165] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.88 (t,
3H,J=7.0Hz),1.19-1.41(m,52H),1.43-1.62(m,6H) , 3H, J = 7.0Hz), 1.19-1.41 (m, 52H), 1.43-1.62 (m, 6H),
1.92-2.00(m,2H) ,2.13(s,3H),2.52-2.59(m,1H) ,3. 1.92-2.00 (m, 2H), 2.13 (s, 3H), 2.52-2.59 (m, 1H), 3.
63-3.80(m,10H),3.91(dt,1H,J=5.4Hz) ,3.99-4.01(br 63-3.80 (m, 10H), 3.91 (dt, 1H, J = 5.4Hz), 3.99-4.01 (br
t,1H),4.19(dt,1H,H=4.6Hz,11.0Hz),4.33(dd,1H,J= t, 1H), 4.19 (dt, 1H, H = 4.6Hz, 11.0Hz), 4.33 (dd, 1H, J =
3.2Hz,10.6Hz),4.37-4.42(m,3H) ,4.49(dm1H,J=3.2H 3.2Hz, 10.6Hz), 4.37-4.42 (m, 3H), 4.49 (dm1H, J = 3.2H
z),4.82(dd,1H,J=8.4Hz,10.6Hz),5.05(d,1H,J=8.4H z), 4.82 (dd, 1H, J = 8.4Hz, 10.6Hz), 5.05 (d, 1H, J = 8.4H
z),8.84(br t,1H) 。 z), 8.84 (br t, 1H).

【0166】 [α] D 25 =-5.9 ゜(c=0.99,CHCl 3 -MeOH 1:1 )。 [0166] [α] D 25 = -5.9 DEG (c = 0.99, CHCl 3 -MeOH 1: 1).

【0167】FAB-MS: [M+H] + ;m/z=843 。 [0167] FAB-MS: [M + H ] +; m / z = 843.

【0168】 (j) 化合物718 の合成(図14) 1)化合物715 の合成 β−D−ラクト−スオクタアセテート(化合物701 )6. [0168] (j) Synthesis of Compound 718 (Figure 14) 1) Synthesis beta-D-lacto compounds 715 - scan octaacetate (Compound 701) 6.
99g及び2−[2−(2−アジドエトキシ)エトキシ] 99g and 2- [2- (2-azido-ethoxy) ethoxy]
エタノール2.35gを塩化メチレン40mlに溶かし、氷冷下撹拌した。 Dissolved ethanol 2.35g of methylene chloride 40 ml, and stirred under ice-cooling. ここに三フッ化硼素ジエチルエーテル錯体5. Here boron trifluoride diethyl ether complex 5.
1ml を塩化メチレン15mlに溶かして15分間で滴下した。 1ml was added dropwise at 15 minutes was dissolved in methylene chloride 15 ml.
室温で15時間撹拌した後、氷水にあけ、有機層を分離した。 After stirring for 15 hours at room temperature, poured into ice water, and the organic layer was separated. 3回水洗した後(水層は中性となった)、飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Washed with water 3 times (aqueous layer became neutral), washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1: The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1:
2)、目的物を無色油状物として2.87g得た。 2) to give 2.87g of the desired product as a colorless oil.

【0169】 1 H-NMR(δ,CDCl 3 ) :1.97(s,3H),2.04 [0169] 1 H-NMR (δ, CDCl 3): 1.97 (s, 3H), 2.04
(s,9H),2.06(s,3H),2.12(s,3H),2.15(s,3H),3.40 (S, 9H), 2.06 (s, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.40
(t,2H,J=5.0Hz),3.58-3.75(m,10H),3.79(t,1H,J=9.4H (T, 2H, J = 5.0Hz), 3.58-3.75 (m, 10H), 3.79 (t, 1H, J = 9.4H
z),3.85-3.88(m,1H) ,3.89-3.93(m,1H) ,4.06-4.15 z), 3.85-3.88 (m, 1H), 3.89-3.93 (m, 1H), 4.06-4.15
(m,2H) ,4.47-4.50(m,2H) ,4.57(d,1H,J=8.0Hz),4.9 (M, 2H), 4.47-4.50 (m, 2H), 4.57 (d, 1H, J = 8.0Hz), 4.9
0(dd,1H,J=8.0Hz, 9.5Hz),4.95(dd,1H,J=3.5Hz,10.3H 0 (dd, 1H, J = 8.0Hz, 9.5Hz), 4.95 (dd, 1H, J = 3.5Hz, 10.3H
z),5.11(dd,1H,J=8.0Hz,10.3Hz),5.20(t,1H,J=9.4H z), 5.11 (dd, 1H, J = 8.0Hz, 10.3Hz), 5.20 (t, 1H, J = 9.4H
z),5.35(bd,1H,J=3.5Hz) 。 z), 5.35 (bd, 1H, J = 3.5Hz).

【0170】[α] D 24 = -9.8゜(c=1.03,CHCl 3 )。 [0170] [α] D 24 = -9.8 DEG (c = 1.03, CHCl 3) .

【0171】2)化合物716 の合成 化合物715 、2.69gに酢酸エチル150ml を加えて溶かした。 [0171] 2) Synthesis Compound 715 Compound 716 was dissolved by adding ethyl acetate 150ml to 2.69 g. ここにp−トルエンスルホン酸1水和物0.65g及びリンドラー触媒1.32gを加え、50psiで4.5時間接触還元した。 Here p- toluenesulfonic acid monohydrate 0.65g and Lindlar catalyst 1.32g was added and 4.5 hours catalytic reduction at 50 psi. さらにリンドラー触媒1.31gを加え、50ps Further added Lindlar catalyst 1.31 g, 50 ps
iで2.5 時間接触還元した。 For 2.5 hours catalytic reduction by i. 触媒を濾去し、目的物を淡褐色油状物として3.11g得た。 The catalyst was filtered off to give 3.11g of the desired product as a pale brown oil. これ以上の精製はせずに、以下の反応を用いた。 Without the further purification, it was used following reaction.

【0172】4)化合物717 の合成 化合物716 、1.51gに塩化メチレン20ml及びトリエチルアミン220 μlを加えて溶かし、ここに上記反応で得た化合物1103全量を塩化メチレン5mlに溶かして加え、さらに19.5時間撹拌した。 [0172] 4) Synthesis Compound 716 Compound 717 was dissolved by adding methylene 20ml and triethylamine 220 [mu] l chloride 1.51 g, here a compound 1103 the total amount obtained in the above reaction was added dissolved in methylene chloride 5 ml, further 19.5 hours with stirring did. 塩化メチレンで希釈し、10%クエン酸、水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Diluted with methylene chloride, 10% citric acid, washed with water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1:2)、目的物を無色油状物として1.62g得た。 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1: 2) to give 1.62g of the desired product as a colorless oil.

【0173】 1 H-NMR(δ,CDCl 3 ) :0.88(t,6H,J=7.0H [0173] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z),1.19-1.43(m,58H),1.54-1.61(m,2H) ,1.97(s,3 z), 1.19-1.43 (m, 58H), 1.54-1.61 (m, 2H), 1.97 (s, 3
H),1.97-2.11(m,1H) ,2.04(s,3H),2.05(s,6H),2.06 H), 1.97-2.11 (m, 1H), 2.04 (s, 3H), 2.05 (s, 6H), 2.06
(s,3H),2.12(s,3H),2.15(s,3H),3.44-3.73(m,12H), (S, 3H), 2.12 (s, 3H), 2.15 (s, 3H), 3.44-3.73 (m, 12H),
3.79(t,1H,J=9.4Hz)) ,3.86-3.89(m,1H) ,3.91-3.95 3.79 (t, 1H, J = 9.4Hz)), 3.86-3.89 (m, 1H), 3.91-3.95
(m,1H) ,4.06-4.15(m,3H) ,4.48-4.51(m,2H) ,4.55 (M, 1H), 4.06-4.15 (m, 3H), 4.48-4.51 (m, 2H), 4.55
(d,1H,J=8.0Hz),4.90(dd,1H,J=8.0Hz, 9.4Hz),4.96(d (D, 1H, J = 8.0Hz), 4.90 (dd, 1H, J = 8.0Hz, 9.4Hz), 4.96 (d
d,1H,J=3.4Hz,10.5Hz),5.11(dd,1H,J=8.1Hz,10.5Hz), d, 1H, J = 3.4Hz, 10.5Hz), 5.11 (dd, 1H, J = 8.1Hz, 10.5Hz),
5.20(t,1H,J=9.4Hz),5.34(dd,1H,J=0.9Hz,3.4Hz), 5. 5.20 (t, 1H, J = 9.4Hz), 5.34 (dd, 1H, J = 0.9Hz, 3.4Hz), 5.
95(t,1H,J=5.5Hz) 。 95 (t, 1H, J = 5.5Hz).

【0174】[α] D 24 =-6.6 ゜(c=1.05,CHCl 3 )。 [0174] [α] D 24 = -6.6 DEG (c = 1.05, CHCl 3) .

【0175】5)化合物718 の合成 化合物717 、0.79gにメタノール5ml及びベンゼン10ml [0175] 5) Compound 717 Compound 718, methanol 5ml and benzene 10ml into 0.79g
を加えて溶かし、氷冷下撹拌した。 Dissolved, and the mixture was stirred under ice-cooling. ここに28%ナトリウムメトキシドメタノール溶液を5滴加えてpH=12とし、室温で3時間撹拌した。 And pH = 12 by adding 5 drops of here 28% sodium methoxide methanol solution was stirred at room temperature for 3 hours. ここに「ダウエックス50X Here "Dowex 50X
−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 -8 "ion exchange resin (H-type) was neutralized by adding to the resin was filtered off. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:クロロホルム−メタノール 2:1)、目的化合物を0.60g得た。 The solvent was evaporated under reduced pressure, the residue was purified by "Sephadex LH-20" (elution solvent: chloroform - methanol 2: 1) to obtain 0.60g of the desired compound.

【0176】 1 H-NMR(δ,pyridine-d 5 -D 2 O):0.88(t, [0176] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.88 (t,
6H,J=6.8Hz),1.20-1.61(m,58H),1.90-2.00(m,2H) , 6H, J = 6.8Hz), 1.20-1.61 (m, 58H), 1.90-2.00 (m, 2H),
2.50-2.58(m,1H) ,3.59-3.82(m,11H),3.84-3.91(m,2 2.50-2.58 (m, 1H), 3.59-3.82 (m, 11H), 3.84-3.91 (m, 2
H) ,3.99(bt,1H) ,4.10-4.14(m,2H) ,4.18-4.26(m,3 H), 3.99 (bt, 1H), 4.10-4.14 (m, 2H), 4.18-4.26 (m, 3
H) ,4.34(dd,1H,J=5.0Hz,11.0Hz),4.40-4.50(m,5H) H), 4.34 (dd, 1H, J = 5.0Hz, 11.0Hz), 4.40-4.50 (m, 5H)
,4.77(d,1H,J=7.5Hz),5.06(d,1H,J=8.0Hz),8.82(b , 4.77 (d, 1H, J = 7.5Hz), 5.06 (d, 1H, J = 8.0Hz), 8.82 (b
t,1H) 。 t, 1H).

【0177】 [α] D 22 = -3.0゜(c=1.01,CHCl 3 -MeOH 2:1 )。 [0177] [α] D 22 = -3.0 DEG (c = 1.01, CHCl 3 -MeOH 2: 1).

【0178】FAB-MS:[M+H] + ;m/z=964 。 [0178] FAB-MS: [M + H ] +; m / z = 964.

【0179】 (k) 化合物1105の合成(図15) 1)化合物1101の合成 β−D−グルコースペンタアセテート6.16g及び2− [0179] (k) synthesis (Figure 15) of Compound 1105 1) Synthesis beta-D-glucose pentaacetate 6.16g of compound 1101 and 2-
[2−(2−アジドエトキシ)エトキシ]エタノール6. [2- (2-azido-ethoxy) ethoxy] ethanol 6.
59gを塩化メチレン50mlに溶かし、氷冷下撹拌した。 It was dissolved 59g of methylene chloride 50 ml, and stirred under ice-cooling. ここに三フッ化硼素ジエチルエーテル錯体8.7ml を塩化メチエン10mlに溶かして5分間で滴下した。 It was added dropwise over 5 minutes by dissolving boron trifluoride diethyl ether complex 8.7ml chloride Mechien 10ml herein. 室温で19時間撹拌した後、氷水にあけ、有機層を分離した。 After stirring 19 hours at room temperature, poured into ice water, and the organic layer was separated. 4回水洗いした後(水層は中性となった)、飽和食塩水で洗い、 After washing 4 times (aqueous layer became neutral), washed with brine,
硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Dried over magnesium sulfate, and the solvent was removed under reduced pressure.
残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 2:1)、目的物を無色油状物として2.27g を得た。 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 2: 1) to give 2.27g of the desired product as a colorless oil.

【0180】 1 H-NMR(δ,CDCl 3 ) :2.01(s,3H),2.03 [0180] 1 H-NMR (δ, CDCl 3): 2.01 (s, 3H), 2.03
(s,3H),2.05(s,3H),2.09(s,3H),3.41(t,2H,J=5.0H (S, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 3.41 (t, 2H, J = 5.0H
z),3.63-3.78(m,10H),3.93-3.97(m,1H) ,4.14(dd,1 z), 3.63-3.78 (m, 10H), 3.93-3.97 (m, 1H), 4.14 (dd, 1
H,J=2.0Hz,12.5Hz),4.26(dd,1H,5.0Hz,12.5Hz),4.62 H, J = 2.0Hz, 12.5Hz), 4.26 (dd, 1H, 5.0Hz, 12.5Hz), 4.62
(d,1H,J=7.9Hz),5.00(dd,1H,J=7.9Hz,9.8Hz) ,5.09 (D, 1H, J = 7.9Hz), 5.00 (dd, 1H, J = 7.9Hz, 9.8Hz), 5.09
(t,J=9.8Hz) ,5.21(t,1H,J=9.8Hz)。 (T, J = 9.8Hz), 5.21 (t, 1H, J = 9.8Hz).

【0181】[α] D 20 =-12.1゜(c=1.01,CHCl 3 )。 [0181] [α] D 20 = -12.1 ° (c = 1.01, CHCl 3) .

【0182】2)化合物1102の合成 化合物1101、2.11gに酢酸エチル150ml を加えて溶かした。 [0182] 2) it was dissolved by adding ethyl acetate 150ml synthetic compounds 1101,2.11g compound 1102. ここにp−トルエンスルホン酸1水和物0.79g及びリンドラー触媒1.04gを加え、50psiで6.5時間接触還元した。 Here p- toluenesulfonic acid monohydrate 0.79g and Lindlar catalyst 1.04g was added, and 6.5 hours catalytic reduction at 50 psi. さらにリンドラー触媒1.04gを加え、50ps Further added Lindlar catalyst 1.04 g, 50 ps
iで3時間接触還元した。 For 3 hours catalytic reduction by i. 触媒を濾去し、目的物を淡褐色油状物として2.49g得た。 The catalyst was filtered off to give 2.49g of the desired product as a pale brown oil. これ以上の精製はせずに、 Without the further purification,
以下の反応に用いた。 It was used in the following reaction.

【0183】3)化合物1103の合成 2−(n−ヘキサデシル)オクタデカン酸0.91gに塩化チオニル5mlを加え、6時間加熱還流させた。 [0183] 3) Synthesis of Compound 1103 2-(n-hexadecyl) of thionyl chloride 5ml was added to octadecanoic acid 0.91 g, and heated to reflux for 6 hours. 塩化チオニルを減圧下留去した。 It was evaporated under reduced pressure thionyl chloride. 残渣にベンゼンを加えて溶かし、減圧下留去した(2回)。 Residue was dissolved by addition of benzene and evaporated under reduced pressure (twice). これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0184】4)化合物1104の合成 化合物1102、0.90gに塩化メチレン30ml及びトリエチルアミン190 μlを加えて溶かし、ここに上記反応で得た化合物1103全量を塩化メチレン5mlに溶かして加え、さらに2時間撹拌し、さらに室温で30分間撹拌した。 [0184] 4) Synthesis Compound 1102,0.90g compound 1104 was dissolved by adding methylene chloride 30ml and triethylamine 190 [mu] l, wherein the compound 1103 the total amount obtained in the above reaction was added dissolved in methylene chloride 5 ml, further stirred for 2 hours and it was stirred for a further 30 minutes at room temperature. 塩化メチレンで希釈し、1N塩酸、水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Diluted with methylene chloride, washed with 1N hydrochloric acid, water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1:1)、 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1: 1),
目的物を無色油状物として0.67g得た。 To give 0.67g of the desired product as a colorless oil.

【0185】 1 H-NMR(δ,CDCl 3 ) :0.88(t,6H,J=7.0H [0185] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z),1.22-1.43(m,58H),1.56-1.62(bs,2H),1.97-2.02 z), 1.22-1.43 (m, 58H), 1.56-1.62 (bs, 2H), 1.97-2.02
(m,1H) ,2.01(s,3H),2.03(s,3H),2.05(s,3H),2.09 (M, 1H), 2.01 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.09
(s,3H),3.44-3.76(m,12H),3.95-3.98(m,1H) ,4.10- (S, 3H), 3.44-3.76 (m, 12H), 3.95-3.98 (m, 1H), 4.10-
4.16(m,2H) ,4.26(dd,1H,J=4.8Hz,12.3Hz),4.60(d,1 4.16 (m, 2H), 4.26 (dd, 1H, J = 4.8Hz, 12.3Hz), 4.60 (d, 1
H,J=8.1Hz),5.00(dd,1H,J=8.1Hz,9.5Hz) ,5.09(t,1H, H, J = 8.1Hz), 5.00 (dd, 1H, J = 8.1Hz, 9.5Hz), 5.09 (t, 1H,
J=9.5Hz),5.21(t,1H,J=9.5Hz),5.99(t,1H,J=5.6Hz)。 J = 9.5Hz), 5.21 (t, 1H, J = 9.5Hz), 5.99 (t, 1H, J = 5.6Hz).

【0186】[α] D 21 = -8.3゜(c=1.02,CHCl 3 )。 [0186] [α] D 21 = -8.3 DEG (c = 1.02, CHCl 3) .

【0187】5)化合物1105の合成 化合物1104、0.62gにメタノール6ml及びベンゼン12ml [0187] 5) methanol 6ml, and benzene 12ml into synthetic compounds 1104,0.62g compound 1105
を加えて溶かし、氷冷下撹拌した。 Dissolved, and the mixture was stirred under ice-cooling. ここに28%ナトリウムメトキシドメタノール溶液を5滴加えてpH=12とし、室温で5時間撹拌した。 And pH = 12 by adding 5 drops of here 28% sodium methoxide methanol solution was stirred at room temperature for 5 hours. ここに「ダウエックス50X Here "Dowex 50X
−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 -8 "ion exchange resin (H-type) was neutralized by adding to the resin was filtered off. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」で精製し(溶出溶媒:塩化メチレン−メタノール1:1)、目的化合物を0.46g得た。 The solvent was evaporated under reduced pressure, the residue was purified by "Sephadex LH-20" (eluent: methylene chloride - methanol 1: 1), the desired compound was obtained 0.46 g.

【0188】 1 H-NMR(δ,pyridine-d 5 -D 2 O):0.88(t, [0188] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.88 (t,
6H,J=6.8Hz),1.22-1.60(m,58H),1.92-1.99(m,2H) , 6H, J = 6.8Hz), 1.22-1.60 (m, 58H), 1.92-1.99 (m, 2H),
2.51-2.58(m,1H) ,3.59-3.67(m,4H) ,3.68-3.78(m,6 2.51-2.58 (m, 1H), 3.59-3.67 (m, 4H), 3.68-3.78 (m, 6
H) ,3.90-3.95(m,2H) ,4.00(t,1H,J=7.8Hz),4.15-4. H), 3.90-3.95 (m, 2H), 4.00 (t, 1H, J = 7.8Hz), 4.15-4.
27(m,3H) ,4.32(dd,1H,J=5.5Hz,11.7Hz),4.51(d,1H,J 27 (m, 3H), 4.32 (dd, 1H, J = 5.5Hz, 11.7Hz), 4.51 (d, 1H, J
=11.7Hz) ,4.85(d,1H,J=7.8Hz),8.78(t,1H,J=5.0H = 11.7Hz), 4.85 (d, 1H, J = 7.8Hz), 8.78 (t, 1H, J = 5.0H
z)。 z).

【0189】[α] D 21 = -7.1゜(c=1.02,CHCl 3 )。 [0189] [α] D 21 = -7.1 DEG (c = 1.02, CHCl 3) .

【0190】FAB-MS:[M+H] + ;m/z=802 。 [0190] FAB-MS: [M + H ] +; m / z = 802.

【0191】 (l) 化合物1205の合成(図16) 1)化合物1202の合成 β−D−リボ−ステトラアセテート(化合物1201)4.29 [0191] (l) Synthesis of Compound 1205 (FIG. 16) 1) Synthesis beta-D-ribo compounds 1202 - scan tetraacetate (Compound 1201) 4.29
9 g及び2−[2−(2−アジドエトキシ)エトキシ] 9 g and 2- [2- (2-azido-ethoxy) ethoxy]
エタノール1.183 gを塩化メチレン40mlに溶かし、氷冷下撹拌した。 Dissolve ethanol 1.183 g of methylene chloride 40 ml, and stirred under ice-cooling. ここに三フッ化硼素ジエチルエーテル錯体 Here boron trifluoride-diethyl ether complex
3.32mlを塩化メチレン6ml に溶かして滴下した。 The 3.32ml was added dropwise dissolved in methylene chloride 6 ml. 室温で1時間撹拌した後、氷水にあけ、有機層を分離した。 After stirring for 1 hour at room temperature, poured into ice water, and the organic layer was separated. 6
回水洗した後(水層は中性となった)、飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 After times washed (aqueous layer became neutral), washed with brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン−酢酸エチル 1:1)、 The residue was purified by silica gel column chromatography (eluent: n-hexane - ethyl acetate 1: 1),
目的物を無色油状物として1.967 g得た。 The desired product was obtained 1.967 g as a colorless oil.

【0192】 1 H-NMR(δ,CDCl 3 ) :2.06(s,3H),2.09 [0192] 1 H-NMR (δ, CDCl 3): 2.06 (s, 3H), 2.09
(s,3H),2.11(s,3H),3.40(t,2H,J=5.0Hz),3.64-3.69 (S, 3H), 2.11 (s, 3H), 3.40 (t, 2H, J = 5.0Hz), 3.64-3.69
(m,9H) ,3.85(ddd,1H,J=3.1Hz,5.1Hz,10.3Hz) ,4.14 (M, 9H), 3.85 (ddd, 1H, J = 3.1Hz, 5.1Hz, 10.3Hz), 4.14
(dd,1H,J=6.0Hz,11.4Hz),4.28-4.32(m,1H) ,4.34(dd, (Dd, 1H, J = 6.0Hz, 11.4Hz), 4.28-4.32 (m, 1H), 4.34 (dd,
1H,J=3.8Hz,11.4Hz),5.06(s,1H),5.28(d,1H,J=4.8H 1H, J = 3.8Hz, 11.4Hz), 5.06 (s, 1H), 5.28 (d, 1H, J = 4.8H
z),5.35(dd,1H,J=4.8Hz,7.0Hz) 。 z), 5.35 (dd, 1H, J = 4.8Hz, 7.0Hz).

【0193】[α] D 20 =-14.5゜(c=1.04,CHCl 3 )。 [0193] [α] D 20 = -14.5 ° (c = 1.04, CHCl 3) .

【0194】2)化合物1203の合成 化合物1202、1.844 gに酢酸エチル100ml を加えて溶かした。 [0194] 2) it was dissolved by adding ethyl acetate 100ml synthetic compounds 1202,1.844 g of compound 1203. ここにp−トルエンスルホン酸1水和物0.809 g Here p- toluenesulfonic acid monohydrate 0.809 g
及びリンドラー触媒0.944 gを加え、50psiで4時間接触還元した。 And Lindlar catalyst 0.944 g was added thereto, followed by 4 hours catalytic reduction at 50 psi. さらにリンドラー触媒0.855 gを加え、 Further added Lindlar catalyst 0.855 g,
50psiで3時間接触還元した。 For 3 hours catalytic reduction at 50psi. 触媒を濾去し、目的物を淡褐色油状物として2.422 g得た。 The catalyst was filtered off, to obtain 2.422 g of the desired product as a pale brown oil. これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0195】3)化合物1103の合成 2−(n−ヘキサデシル)オクタデカン酸1.024 gに塩化チオニル5mlを加え、2.5 時間加熱還流させた。 [0195] 3) Synthesis of Compound 1103 2-(n-hexadecyl) of thionyl chloride 5ml addition octadecanoate 1.024 g, was heated under reflux for 2.5 hours. 塩化チオニルを減圧下留去した。 It was evaporated under reduced pressure thionyl chloride. 残渣にベンゼンを加えて溶かし、減圧下留去した(3回)。 Residue was dissolved by addition of benzene and evaporated under reduced pressure (3 times). これ以上の精製はせずに、以下の反応に用いた。 Without the further purification, it was used in the following reaction.

【0196】4)化合物1204の合成 化合物1203に塩化メチレン20ml及びトリエチルアミン23 [0196] 4) methylene chloride Compound 1203 Compound 1204 20 ml and triethylamine 23
6 μlを加えて溶かし、氷冷下撹拌した。 Dissolved by the addition of 6 μl, and the mixture was stirred under ice-cooling. ここにトリエチルアミン283 μlを加え、さらに上記反応で得た化合物1103全量を塩化メチレン5mlに溶かして加え、室温に昇温させつつ17時間撹拌した。 Here triethylamine 283 [mu] l was added, in addition dissolved further compounds 1103 the total amount obtained in the above reaction in methylene chloride 5 ml, was stirred for 17 h while allowed to warm to room temperature. 塩化メチレンで希釈し、 It was diluted with methylene chloride,
水及び飽和食塩水で洗い、硫酸マグネシウム上乾燥させ、溶媒を減圧下留去した。 Washed with water and brine, dried over magnesium sulfate, and the solvent was removed under reduced pressure. 残渣をシリカゲルカラムクロマトグラフィーで精製し(溶出溶媒:n−ヘキサン− The residue was purified by silica gel column chromatography (eluent: n-hexane -
酢酸エチル 3:2)、目的物を0.910 g得た。 Ethyl acetate 3: 2) to obtain the desired compound 0.910 g.

【0197】 1 H-NMR(δ,CDCl 3 ) :0.88(t,6H,J=7.0H [0197] 1 H-NMR (δ, CDCl 3): 0.88 (t, 6H, J = 7.0H
z),1.21-1.34(m,56H),1.35-1.44(m,2H) ,1.56-1.63 z), 1.21-1.34 (m, 56H), 1.35-1.44 (m, 2H), 1.56-1.63
(m,2H) ,1.96-2.02(m,1H) ,2.06(s,3H),2.09(s,3 (M, 2H), 1.96-2.02 (m, 1H), 2.06 (s, 3H), 2.09 (s, 3
H),2.11(s,3H),3.45-3.48(m,2H) ,3.54(t,2H,J=5.0H H), 2.11 (s, 3H), 3.45-3.48 (m, 2H), 3.54 (t, 2H, J = 5.0H
z),3.59-3.66(m,7H) ,3.84-3.88(m,1H) ,4.15(dd,1 z), 3.59-3.66 (m, 7H), 3.84-3.88 (m, 1H), 4.15 (dd, 1
H,J=5.3Hz,10.9Hz),4.29-4.32(m,1H) ,4.33(dd,1H,J= H, J = 5.3Hz, 10.9Hz), 4.29-4.32 (m, 1H), 4.33 (dd, 1H, J =
4.0Hz,10.9Hz),5.06(s,1H),5.28(d,1H ,J=5.0Hz), 4.0Hz, 10.9Hz), 5.06 (s, 1H), 5.28 (d, 1H, J = 5.0Hz),
5.35(dd,1H,J=5.0Hz,6.7Hz),6.01(t,1H,J=5.6Hz)。 5.35 (dd, 1H, J = 5.0Hz, 6.7Hz), 6.01 (t, 1H, J = 5.6Hz).

【0198】[α] D 20 =-6.9 ゜(c=1.03,CHCl 3 )。 [0198] [α] D 20 = -6.9 DEG (c = 1.03, CHCl 3) .

【0199】5)化合物1205の合成 化合物1204、 0.477gにメタノール3ml及びベンゼン6 [0199] 5) Compound 1204 Compound 1205, methanol 3ml and benzene in 0.477 g 6
mlを加えて溶かした。 It was dissolved by the addition of ml. ここに28%ナトリウムメトキシドメタノール溶液を6滴加えてpH=12とし、室温で 1.5 And pH = 12 by adding 6 drops of here 28% sodium methoxide methanol solution, 1.5 at room temperature
時間攪拌した。 Time and the mixture was stirred. ここに「ダウエックス50X−8」イオン交換樹脂(H型)を加えて中和し、樹脂を濾去した。 Here was neutralized by adding "Dowex 50X-8" ion exchange resin (H-type), it was filtered off the resin. 溶媒を減圧下留去し、残渣を「セファデックスLH−20」 The solvent was evaporated under reduced pressure, the residue "Sephadex LH-20"
で精製し(溶出溶媒:クロロホルム−メタノール 1: In purified (eluent: chloroform - methanol 1:
1)、目的物を0.389 g得た。 1), to give the desired compound 0.389 g.

【0200】 1 H-NMR(δ, pyridine-d 5 -D 2 O):0.89(t, [0200] 1 H-NMR (δ, pyridine -d 5 -D 2 O): 0.89 (t,
6H,J=7.0Hz),1.20-1.39(m,52H),1.44-1.62(m,6H) , 6H, J = 7.0Hz), 1.20-1.39 (m, 52H), 1.44-1.62 (m, 6H),
1.92-2.01(m,2H) ,2.55-2.60(m,1H) ,3.65-3.78(m,7 1.92-2.01 (m, 2H), 2.55-2.60 (m, 1H), 3.65-3.78 (m, 7
H) ,4.09(ddd,1H,J=3.3Hz,6.0Hz,10.8Hz) ,4.14(dd,1 H), 4.09 (ddd, 1H, J = 3.3Hz, 6.0Hz, 10.8Hz), 4.14 (dd, 1
H,J=5.3Hz,11.8Hz),4.27(dd,1H,J=3.3Hz,11.8Hz) 4.55 H, J = 5.3Hz, 11.8Hz), 4.27 (dd, 1H, J = 3.3Hz, 11.8Hz) 4.55
(d,1H,J=4.9Hz) ,4.72-4.75(m,1H) ,4.84-4.86(m,1H) (D, 1H, J = 4.9Hz), 4.72-4.75 (m, 1H), 4.84-4.86 (m, 1H)
,5.48(s,1H),8.84(bt,1H) 。 , 5.48 (s, 1H), 8.84 (bt, 1H).

【0201】 [α] D 20 =-13.3゜(c=1.00,CHCl 3 -MeOH 1:1 )。 [0202] [α] D 20 = -13.3 ° (c = 1.00, CHCl 3 -MeOH 1: 1).

【0202】FAB-MS:[M+H] + ;m/z=772 。 [0202] FAB-MS: [M + H ] +; m / z = 772.

【0203】 (m) 化合物4−3の合成(図17) (i) 化合物1−1と化合物3−1のグリコシル化反応 化合物1−1(6.00g)とアルコール体(化合物3− [0203] (m) Synthesis of Compound 4-3 (FIG. 17) (i) and the alcohol form compound 1-1 and compound 3-1 glycosylation reaction compound 1-1 (6.00 g) (Compound 3
1)(8.04g)を塩化メチレン(180ml )に溶解し、B 1) (8.04 g) was dissolved in methylene chloride (180 ml), B
3・Et 2 O(9.05g)を加え、室温で5日間攪拌した。 F 3 · Et 2 O a (9.05 g) was added, followed by stirring at room temperature for 5 days.

【0204】反応液をクロロホルムで希釈し、水、5% [0204] The reaction solution was diluted with chloroform, water, 5%
NaHCO 3水、水で順次洗浄、乾燥後溶媒を減圧下留去した。 Aqueous NaHCO 3, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル( 200g)を用いるカラムクロマトグラフィー(クロロホルム)で2回精製し、α− The residue was purified twice on silica gel (200 g) column chromatography (chloroform) using, alpha-
グリコシド(化合物3−2)(3.66g)とβ−グリコシド(化合物3−3)(1.60g)を得た。 It was obtained glycoside (compound 3-2) and (3.66 g) beta-glycoside (Compound 3-3) (1.60 g).

【0205】(α−グリコシド) [α] D +92.1°(c 0.91,CHCl 3 ). [0205] (alpha-glycosides) [α] D + 92.1 ° (c 0.91, CHCl 3). 1 H−NMR(CDCl 3 )δ:2.02(3H,s),2.0 1 H-NMR (CDCl 3) δ: 2.02 (3H, s), 2.0
3(3H,s),2.06(3H,s),3.63−3.73(9 3 (3H, s), 2.06 (3H, s), 3.63-3.73 (9
H,m),3.75(3H,s),3.77(2H,m),3.82 H, m), 3.75 (3H, s), 3.77 (2H, m), 3.82
−3.87(1H,m),4.45(1H,d,J=10.02 H -3.87 (1H, m), 4.45 (1H, d, J = 10.02 H
z),4.88(1H,dd,J=3.67Hz,10.26 H z), 4.88 (1H, dd, J = 3.67Hz, 10.26 H
z),5.17(1H,dd,J=9.77Hz,10.02H z), 5.17 (1H, dd, J = 9.77Hz, 10.02H
z),5.21(1H,d,J=3.67Hz),5.54(1H, z), 5.21 (1H, d, J = 3.67Hz), 5.54 (1H,
dd,J=9.77Hz,10.26 Hz). dd, J = 9.77Hz, 10.26 Hz). (ii)化合物3−4の合成 化合物3−2(3.70g)をDMF(40ml)に溶解し、アジ化ナトリウム(0.74g)を加え、浴温60℃で20時間攪拌した。 (Ii) Synthesis of Compound 3-4 3-2 (3.70 g) was dissolved in DMF (40 ml), was added sodium azide (0.74 g), and stirred for 20 hours at a bath temperature of 60 ° C..

【0206】反応液混合物を酢酸エチルで希釈し、水洗、乾燥後溶媒を減圧下留去した。 [0206] The reaction mixture was diluted with ethyl acetate, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル( 200g)を用いるカラムクロマトグラフィー(クロロホルム)で精製し、目的化合物3−4(2.10g)を無色油状物質として得た。 The residue was purified on silica gel (200 g) column chromatography using (chloroform), to give the desired compound 3-4 (2.10 g) as a colorless oil.

【0207】 1 H−NMR(CDCl 3 )δ:2.02(3 [0207] 1 H-NMR (CDCl 3) δ: 2.02 (3
H,s),2.03(3H,s),2.06(3H,s),3.40 H, s), 2.03 (3H, s), 2.06 (3H, s), 3.40
(2H,t,J=5.13Hz),3.63−3.73(9H, (2H, t, J = 5.13Hz), 3.63-3.73 (9H,
m),3.75(3H,s),3.82−3.87(1H,m),4. m), 3.75 (3H, s), 3.82-3.87 (1H, m), 4.
45(1H,d,J=10.26 Hz),4.88(1H,dd, 45 (1H, d, J = 10.26 Hz), 4.88 (1H, dd,
J=3.66Hz, 10.26Hz),5.17(1H,dd,J= J = 3.66Hz, 10.26Hz), 5.17 (1H, dd, J =
9.77Hz,10.26 Hz),5.21(1H,d,J=3.66H 9.77Hz, 10.26 Hz), 5.21 (1H, d, J = 3.66H
z),5.54(1H,dd,J=9.77Hz,10.26 H z), 5.54 (1H, dd, J = 9.77Hz, 10.26 H
z). z). (iii) 化合物3−5の合成 化合物3−4(1.70g)とp−トルエンスルホン酸1水和物(0.66g)をエタノール( 100ml)に溶解し、リンドラー触媒(3.00g)を加え、室温40psi で5時間接触還元を行った。 (Iii) Synthesis of Compound 3-5 3-4 and (1.70 g) p-toluenesulfonic acid monohydrate (0.66 g) was dissolved in ethanol (100 ml), Lindlar catalyst of (3.00 g) was added, at room temperature 5 hours catalytic reduction was carried out at 40psi.

【0208】触媒を濾過後、濾液を減圧下濃縮し、目的物化合物3−5(2.05g)を無色泡状物質として得た。 [0208] After the catalyst is filtered, the filtrate was concentrated under reduced pressure to obtain the desired product compound 3-5 (2.05 g) as a colorless foam.

【0209】(iv)化合物4−2の合成 カルボン酸(化合物4−1)( 204mg)、N−ヒドロキシスクシンイミド(HOSu)(46mg)およびN,N′ [0209] (iv) Synthesis carboxylic acid compound 4-2 (Compound 4-1) (204mg), N- hydroxysuccinimide (HOSu) (46 mg) and N, N '
−ジシクロヘキシルカルボジイミド(DCC)(83mg) - dicyclohexylcarbodiimide (DCC) (83mg)
の塩化メチレン(20ml)溶液を室温で20時間攪拌した。 The methylene chloride (20ml) and the solution was stirred at room temperature for 20 hours.
反応液に塩化メチレン(5ml)に溶かしたアミン体(化合物3−5)( 364mg)を加え、ついでトリエチルアミン( 115mg)を加え室温で3時間攪拌した。 Reaction to the amine was dissolved in methylene chloride (5ml) body (Compound 3-5) (364 mg) was added, followed by stirring for 3 hours at room temperature was added triethylamine (115 mg).

【0210】反応液をクロロホルムで希釈し、水、5% [0210] The reaction solution was diluted with chloroform, water, 5%
NaHCO 3水、水、クエン酸水、水で順次洗浄、乾燥後溶媒を減圧下留去した。 Aqueous NaHCO 3, water, aqueous citric acid, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(30g)を用いるカラムクロマトグラフィー(ヘキサン−酢酸エチル 1:1)で精製し、目的化合物4−2(65mg)を無色粉末として得た。 The residue on silica gel (30 g) column chromatography (hexane - ethyl acetate 1: 1) to give the target compound 4-2 (65 mg) as a colorless powder.

【0211】 [α] D +50.0°(c 0.83,CHCl 3 ). [0211] [α] D + 50.0 ° ( c 0.83, CHCl 3). 1 H−NMR(CDCl 3 )δ:0.88(6H,t,J= 1 H-NMR (CDCl 3) δ: 0.88 (6H, t, J =
6.59Hz),1.20−1.33(56H,m),1.34−1.43(2 6.59Hz), 1.20-1.33 (56H, m), 1.34-1.43 (2
H,m),1.53−1.63(2H,m),1.98−2.05(1 H, m), 1.53-1.63 (2H, m), 1.98-2.05 (1
H,m),2.03(6H,s),2.06(3H,s),3.45 H, m), 2.03 (6H, s), 2.06 (3H, s), 3.45
−3.50(2H,m 2 ),3.25−3.57(2H,m),3.58 -3.50 (2H, m 2), 3.25-3.57 (2H, m), 3.58
−3.64(4H,m),3.64−3.69(2H,m),3.70− -3.64 (4H, m), 3.64-3.69 (2H, m), 3.70-
3.76(1H,m),3.75(3H,s),3.81−3.87(1 3.76 (1H, m), 3.75 (3H, s), 3.81-3.87 (1
H,m),4.45(1H,d,J=10.26 Hz),4.88 H, m), 4.45 (1H, d, J = 10.26 Hz), 4.88
(1H,dd,J=3.66Hz,10.26Hz),5.17(1 (1H, dd, J = 3.66Hz, 10.26Hz), 5.17 (1
H,dd,J=9.28Hz,10.26 Hz),5.24(1H, H, dd, J = 9.28Hz, 10.26 Hz), 5.24 (1H,
d,J=3.66Hz),5.55(1H,dd,J=9.28H d, J = 3.66Hz), 5.55 (1H, dd, J = 9.28H
z,10.26 Hz),6.04(1H,m). z, 10.26 Hz), 6.04 (1H, m). (v) 化合物4−3の合成 化合物4−2( 540mg)をメタノール(3ml)に加え、 (V) Synthesis of Compound 4-3 4-2 (540 mg) in methanol (3 ml),
28%NaOMe inMeOH(20μl)を加え、室温で24時間攪拌した。 28% NaOMe inMeOH a (20 [mu] l) was added and stirred for 24 hours at room temperature. 反応液を減圧下濃縮し、残渣にメタノール(3ml)と0.1 N NaOH水(2ml)を加え、 The reaction solution was concentrated under reduced pressure, methanol (3 ml) and 0.1 N NaOH water (2 ml) was added to the residue,
室温で6時間攪拌した。 And the mixture was stirred for 6 hours at room temperature.

【0212】反応液を氷冷し、母液をデカンテーションで除き、析出した目的化合物4−3(35mg)を無色粉末として得た。 [0212] The reaction solution was ice-cooled, remove the mother liquor by decantation, precipitated desired compound 4-3 (35 mg) as a colorless powder.

【0213】 [α] D +23.1°(c 0.46,MeOH). [0213] [α] D + 23.1 ° ( c 0.46, MeOH). 1 H−NMR(CD 3 OD)δ:0.90(6H,t,J= 1 H-NMR (CD 3 OD ) δ: 0.90 (6H, t, J =
6.84Hz),1.12−1.34(56H,m),1.34−1.45(2 6.84Hz), 1.12-1.34 (56H, m), 1.34-1.45 (2
H,m),1.50−1.58(2H,m),2.19(1H, H, m), 1.50-1.58 (2H, m), 2.19 (1H,
m),3.34−3.46(4H,m),3.52−3.56(2H, m), 3.34-3.46 (4H, m), 3.52-3.56 (2H,
m),3.60−3.64(2H,m),3.64−3.74(6H, m), 3.60-3.64 (2H, m), 3.64-3.74 (6H,
m),3.88−3.92(1H,m),3.93(1H,d,J= m), 3.88-3.92 (1H, m), 3.93 (1H, d, J =
10.26 Hz),4.86(1H,d,J=3.91Hz). 10.26 Hz), 4.86 (1H, d, J = 3.91Hz). (n) 化合物8−2の合成(図18) (i) 化合物6−1と化合物3−1のグリコシル化反応 化合物6−1( 876mg)とアルコール(化合物3−1) Synthesis of (n) Compound 8-2 (FIG. 18) (i) Compound 6-1 and Compound 3-1 glycosylation reaction compound 6-1 (876 mg) and alcohol (Compound 3-1)
( 830mg)を塩化メチレン(50ml)に溶解し、BF 3 The (830 mg) was dissolved in methylene chloride (50ml), BF 3 ·
Et 2 O( 932mg)を加え、室温で21時間攪拌した。 Et 2 O a (932 mg) was added, followed by stirring at room temperature for 21 hours.

【0214】反応液をクロロホルムで希釈し、水、5% [0214] The reaction solution was diluted with chloroform, water, 5%
NaHCO 3水、水で順次洗浄、乾燥後溶媒を減圧下留去した。 Aqueous NaHCO 3, washed with water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル( 150g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 200:1 The residue on silica gel (150 g) column chromatography (chloroform - methanol 200: 1
→クロロホルム−メタノール100:1)で精製し、β− → chloroform - methanol 100: Purification by 1), beta-
グリコシド(化合物7−2)( 566mg)、ついでβ−グリコシド(化合物7−2)とα−グリコシド(化合物7 Glycoside (Compound 7-2) (566 mg), followed β- glycoside (compound 7-2) and α- glycoside (compound 7
−1)の3:1の混合物( 208mg)を得た。 -1) of 3: to afford a mixture of 1 (208 mg).

【0215】(β−グリコシド) [α] D +4.6 °(c 1.75,CHCl 3 ). [0215] (beta-glycosides) [α] D +4.6 ° ( c 1.75, CHCl 3). 1 H−NMR(CDCl 3 )δ:1.89(1H,dd,J 1 H-NMR (CDCl 3) δ: 1.89 (1H, dd, J
=11.70 Hz,12.95Hz),1.89(3H,s),2.01 = 11.70 Hz, 12.95Hz), 1.89 (3H, s), 2.01
(3H,s),2.03(3H,s),2.06(3H,s), (3H, s), 2.03 (3H, s), 2.06 (3H, s),
2.15(3H,s),2.43(1H,dd,J=4.88Hz, 2.15 (3H, s), 2.43 (1H, dd, J = 4.88Hz,
12.95 Hz),3.51−3.56(1H,m),3.62−3.85 12.95 Hz), 3.51-3.56 (1H, m), 3.62-3.85
(9H,m),3.80(3H,s),3.88−3.97(2H, (9H, m), 3.80 (3H, s), 3.88-3.97 (2H,
m),4.12(1H,dd,J=8.30Hz,12.46 H m), 4.12 (1H, dd, J = 8.30Hz, 12.46 H
z),4.13(1H,ddd,J=10.26 Hz,10.51 H z), 4.13 (1H, ddd, J = 10.26 Hz, 10.51 H
z,10.99 Hz),4.56(1H,dd,J=2.20Hz, z, 10.99 Hz), 4.56 (1H, dd, J = 2.20Hz,
10.51 Hz),4.89(1H,dd,J=2.44Hz,12.4 10.51 Hz), 4.89 (1H, dd, J = 2.44Hz, 12.4
6 Hz),5.25(1H,ddd,J=4.88Hz,10.99 6 Hz), 5.25 (1H, ddd, J = 4.88Hz, 10.99
Hz,11.70 Hz),5.28(1H,ddd,J=2.44H Hz, 11.70 Hz), 5.28 (1H, ddd, J = 2.44H
z,3.42Hz,8.30Hz),5.40(1H,dd,J=2. z, 3.42Hz, 8.30Hz), 5.40 (1H, dd, J = 2.
20Hz,3.42Hz),5.93(1H,d,J=10.26 H 20Hz, 3.42Hz), 5.93 (1H, d, J = 10.26 H
z). z). (ii)化合物7−3の合成 化合物7−2( 675mg)をDMF(15ml)に溶解し、アジ化ナリトウム( 137mg)を加え、浴温60℃で40時間攪拌した。 (Ii) Synthesis of Compound 7-3 7-2 (675 mg) was dissolved in DMF (15 ml), azide Naritoumu a (137 mg) was added and the mixture was stirred for 40 hours at a bath temperature of 60 ° C..

【0216】反応混合物を酢酸エチルで希釈し、水洗、 [0216] The reaction mixture was diluted with ethyl acetate, washed with water,
乾燥後溶媒を減圧下留去した。 After drying the solvent was distilled off under reduced pressure. 残渣をシリカゲル(50 The residue on silica gel (50
g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール 150:1)で精製し、目的化合物7−3 Column chromatography using g) (chloroform - methanol 150: 1) to give the desired compound 7-3
( 510mg)を無色油状物質として得た。 The (510 mg) as a colorless oily substance.

【0217】 [α] D +2.6 °(c 1.02,CHCl 3 ). [0217] [α] D +2.6 ° (c 1.02, CHCl 3). 1 H−NMR(CDCl 3 )δ:1.89(1H,dd,J 1 H-NMR (CDCl 3) δ: 1.89 (1H, dd, J
=11.70 Hz,12.94Hz),1.89(3H,s),2.01 = 11.70 Hz, 12.94Hz), 1.89 (3H, s), 2.01
(3H,s),2.03(3H,s),2.06(3H,s), (3H, s), 2.03 (3H, s), 2.06 (3H, s),
2.15(3H,s),2.44(1H,dd,J=4.89Hz, 2.15 (3H, s), 2.44 (1H, dd, J = 4.89Hz,
12.94 Hz),3.43−3.50(2H,m),3.50−3.54 12.94 Hz), 3.43-3.50 (2H, m), 3.50-3.54
(1H,m),3.61−3.73(7H,m),3.75−3.90 (1H, m), 3.61-3.73 (7H, m), 3.75-3.90
(2H,m),3.80(3H,s),4.12(1H,dd, (2H, m), 3.80 (3H, s), 4.12 (1H, dd,
J=8.55Hz,12.46 Hz),4.14(1H,ddd,J J = 8.55Hz, 12.46 Hz), 4.14 (1H, ddd, J
=10.02 Hz,10.50 Hz,10.75 Hz),4.46(1 = 10.02 Hz, 10.50 Hz, 10.75 Hz), 4.46 (1
H,dd,J=2.20Hz,10.50 Hz),4.90(1H, H, dd, J = 2.20Hz, 10.50 Hz), 4.90 (1H,
dd,J=2.44Hz,12.46 Hz),5.25(1H,dd dd, J = 2.44Hz, 12.46 Hz), 5.25 (1H, dd
d,J=4.89Hz,10.75 Hz,11.70 Hz),5.27 d, J = 4.89Hz, 10.75 Hz, 11.70 Hz), 5.27
(1H,ddd,J=2.44Hz,3.42Hz,8.55H (1H, ddd, J = 2.44Hz, 3.42Hz, 8.55H
z),5.40(1H,dd,J=2.20Hz,3.42Hz), z), 5.40 (1H, dd, J = 2.20Hz, 3.42Hz),
5.94(1H,d,J=10.02 Hz). 5.94 (1H, d, J = 10.02 Hz). (iii) 化合物7−4の合成 化合物7−3(510mg )とp−トルエンスルホン酸1水和物(150mg )をメタノール(50ml)に溶解し、リンドラー触媒(1.50g)を加え、室温50psi で7時間接触還元を行った。 (Iii) Synthesis of Compound 7-4 7-3 and (510 mg) p-toluenesulfonic acid monohydrate (150 mg) was dissolved in methanol (50 ml), was added Lindlar catalyst (1.50 g), at room temperature 50psi 7 hours catalytic reduction was carried out. 触媒を濾去後、濾液を減圧下で濃縮し、目的化合物(590mg )を得た。 After filtering off the catalyst, the filtrate was concentrated under reduced pressure, to give the desired compound (590 mg).

【0218】(iv)化合物8−1の合成 カルボン酸(化合物4−1)(153mg )、N−ヒドロキシスクシイミド(35mg)およびN,N′−ジシクロヘキシルカルボジイミド(62mg)の塩化メチレン(40ml)とヘキサン(20ml)との混合溶液を室温15時間撹拌した。 [0218] (iv) Synthesis carboxylic acid compound 8-1 (Compound 4-1) (153mg), N- hydroxysuccinimide (35 mg) and N, N'-dicyclohexylcarbodiimide (62 mg) in methylene chloride (40 ml) a mixed solution of hexane (20ml) was stirred at room temperature for 15 hours.
反応液にアセトニトリル(20ml)に溶かしたアミン体化合物7−4(200mg )を加え、ついでトリエチルアミン(53mg)を加え室温で24時間撹拌した。 Acetonitrile (20ml) to dissolve the amine Compounds 7-4 (200 mg) was added to the reaction solution, then stirred at room temperature for 24 hours was added triethylamine (53 mg). 反応液を減圧下濃縮し、クロロホルムで希釈し、水、5%NaHCO 3 The reaction solution was concentrated under reduced pressure, diluted with chloroform, water, 5% NaHCO 3
水、水、クエン酸水及び水で順次洗浄し、乾燥後溶媒を減圧下留去した。 Water, washed successively with water, aqueous citric acid and water, dried and then the solvent was distilled off under reduced pressure. 残渣をシリカゲル(50g)を用いるカラムクロマトグラフィー(クロロホルム−メタノール The residue on silica gel (50 g) column chromatography (chloroform - methanol
150 :1)で精製し、目的化合物8−1(162mg )を無色ワックスとして得た。 150: 1) to obtain the target compound 8-1 (162 mg) as a colorless wax.

【0219】 [α] D +5.9 °(c 1.03,CHCl 3 ). [0219] [α] D +5.9 ° (c 1.03, CHCl 3). 1 H−NMR(CDCl 3 )δ:0.88(6H,t,J= 1 H-NMR (CDCl 3) δ: 0.88 (6H, t, J =
6.84Hz),1.20−1.33(56H,m),1.33−1.44(2 6.84Hz), 1.20-1.33 (56H, m), 1.33-1.44 (2
H,m),1.53−1.64(2H,m),1.86(3H, H, m), 1.53-1.64 (2H, m), 1.86 (3H,
s),1.90(1H,dd,J=11.48 Hz,12.94 H s), 1.90 (1H, dd, J = 11.48 Hz, 12.94 H
z),1.99−2.05(1H,m),2.01(3H,s),2. z), 1.99-2.05 (1H, m), 2.01 (3H, s), 2.
03(3H,s),2.05(3H,s),2.15(3H, 03 (3H, s), 2.05 (3H, s), 2.15 (3H,
s),2.43(1H,dd,J=4.89Hz,12.94 H s), 2.43 (1H, dd, J = 4.89Hz, 12.94 H
z),3.30−3.38(1H,m),3.40−3.70(9H, z), 3.30-3.38 (1H, m), 3.40-3.70 (9H,
m),3.80(3H,s),3.79−3.89(1H,m),4. m), 3.80 (3H, s), 3.79-3.89 (1H, m), 4.
12(1H,dd,J=8.55Hz,12.46 Hz),4.12 12 (1H, dd, J = 8.55Hz, 12.46 Hz), 4.12
(1H,ddd,J=10.02 Hz,10.75 Hz,10.75 (1H, ddd, J = 10.02 Hz, 10.75 Hz, 10.75
Hz),4.51(1H,dd,J=2.44Hz,10.75 H Hz), 4.51 (1H, dd, J = 2.44Hz, 10.75 H
z),4.91(1H,dd,J=2.44Hz,12.46 H z), 4.91 (1H, dd, J = 2.44Hz, 12.46 H
z),5.25(1H,ddd,J=2.44Hz,3.42Hz, z), 5.25 (1H, ddd, J = 2.44Hz, 3.42Hz,
8.55Hz),5.28(1H,ddd,J=4.89Hz,10.7 8.55Hz), 5.28 (1H, ddd, J = 4.89Hz, 10.7
5 Hz,11.48 Hz),5.41(1H,dd,J=2.44H 5 Hz, 11.48 Hz), 5.41 (1H, dd, J = 2.44H
z,3.42Hz),6.28(1H,m),6.36(1H,d, z, 3.42Hz), 6.28 (1H, m), 6.36 (1H, d,
J=10.02 Hz). J = 10.02 Hz). (v) 化合物8−2の合成 化合物8−1(155mg )をメタノール(4ml)に溶解し、28%NaOMe in MeOH(20μl)を加え、室温で3時間撹拌した。 (V) Synthesis of Compound 8-2 8-1 (155 mg) was dissolved in methanol (4ml), 28% NaOMe in MeOH and (20 [mu] l) was added and stirred for 3 hours at room temperature. 反応液を減圧下濃縮し、残渣をメタノール(12ml)に溶解し、0.1 N NaOH水(3ml)を加え、室温で16時間撹拌した。 The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methanol (12ml), 0.1 N NaOH water (3 ml) was added and stirred for 16 hours at room temperature. 反応液を加熱後「アンバーライトIRC−50」を加え、不溶物を濾去後濾液を減圧下濃縮乾固し、残渣をエーテルで洗浄し、 The reaction solution "Amberlite IRC-50" after heating added, insoluble material the filtrate after filtration concentrated to dryness under reduced pressure, the residue was washed with ether,
目的化合物8−2(99mg)を無色粉末として得た。 To give the desired compound 8-2 (99 mg) as a colorless powder.

【0220】 1 H−NMR(CD 3 OD)δ:0.90(6 [0220] 1 H-NMR (CD 3 OD ) δ: 0.90 (6
H,t,J=6.59Hz),1.20−1.44(58H,m),1. H, t, J = 6.59Hz), 1.20-1.44 (58H, m), 1.
50−1.58(2H,m),1.63(1H,dd,J=11.72 50-1.58 (2H, m), 1.63 (1H, dd, J = 11.72
Hz,12.95 Hz),1.99(3H,s),2.18(1H, Hz, 12.95 Hz), 1.99 (3H, s), 2.18 (1H,
m),2.42(1H,dd,J=4.89Hz,12.95 H m), 2.42 (1H, dd, J = 4.89Hz, 12.95 H
z),3.36−3.40(2H,m),3.43−3.47(1H, z), 3.36-3.40 (2H, m), 3.43-3.47 (1H,
m),3.51−3.59(3H,m),3.60−3.74(8H, m), 3.51-3.59 (3H, m), 3.60-3.74 (8H,
m),3.76−3.83(2H,m),3.84−3.94(2H, m), 3.76-3.83 (2H, m), 3.84-3.94 (2H,
m),3.96−4.02(1H,m). m), 3.96-4.02 (1H, m). (o) 化合物12−8の合成(図19) (i) 化合物12−3の合成 1,6−アンヒドロラクトースパーアセテート(化合物 (o) Synthesis of Compound 12-8 (FIG. 19) (i) Synthesis of 1,6-anhydroerythromycin lactose peracetate (Compound of Compound 12-3
12−1)(50g,86.7mmol)、28%ナトリウムメチラート2mlおよびメタノール 600mlの混合物を室温で4時間攪拌し、常法で処理して1,6−アンヒドロラクトース(化合物12−2)(28.5g)を得た。 12-1) (50 g, 86.7 mmol), a mixture of 28% sodium methylate 2ml and methanol 600ml stirred for 4 hours at room temperature, and treated in a conventional manner 1,6-anhydroerythromycin lactose (compound 12-2) ( 28.5g) was obtained.

【0221】[α] D −46.5°(c 1.0 ,H 2 O). [0221] [α] D -46.5 ° (c 1.0, H 2 O). 化合物12−2(16.2g)をピリジン 150mlに溶解し、塩化トリチル(20.9g)を加えて50℃で2時間反応させた。 Compound 12-2 (16.2 g) was dissolved in pyridine 150 ml, was allowed to react for 2 hours at 50 ° C. was added trityl chloride (20.9 g). 次いで、室温で塩化ベンゾイルのピリジン溶液(5 Then, at room temperature pyridine benzoyl chloride solution (5
0.6g)を加えて1晩攪拌した。 0.6g) was stirred overnight added.

【0222】反応液を氷水中に注ぎ、クロロホルムで抽出して、シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン、1:1)で精製して、化合物12−3 [0222] The reaction mixture was poured into ice water, extracted with chloroform, silica gel column chromatography (ethyl acetate - hexane, 1: 1) to give compound 12-3
(35g)を得た。 The (35g) was obtained.

【0223】C 665415としての元素分析値は、計算値:C, 72.93;H,5.01に対し実測値C, 72.63; [0223] Elementary analysis as C 66 H 54 O 15 is Calculated: C, 72.93; H, Found to 5.01 C, 72.63;
H,5.30であった。 H, was 5.30.

【0224】 [α] D +54.2°(c 1.0 ,CHCl 3 ). [0224] [α] D + 54.2 ° ( c 1.0, CHCl 3). 1 H−NMR(CDCl 3 ):3.16(1H,dd,J= 1 H-NMR (CDCl 3) : 3.16 (1H, dd, J =
9.5 Hz,8.8 Hz),3.35(1H,dd,J=9.5 H 9.5 Hz, 8.8 Hz), 3.35 (1H, dd, J = 9.5 H
z,5.6 Hz),3.74(1H,s),3.76(1H,d z, 5.6 Hz), 3.74 (1H, s), 3.76 (1H, d
d,J=7.6 Hz,6.0 Hz),4.01(1H,d,J= d, J = 7.6 Hz, 6.0 Hz), 4.01 (1H, d, J =
7.6 Hz),4.08(1H,dd,J=8.8 Hz,5.6 H 7.6 Hz), 4.08 (1H, dd, J = 8.8 Hz, 5.6 H
z),4.53(1H,d,J=5.4 Hz),4.94(1H, z), 4.53 (1H, d, J = 5.4 Hz), 4.94 (1H,
s),5.24(1H,d,J=8.1 Hz),5.63(1H, s), 5.24 (1H, d, J = 8.1 Hz), 5.63 (1H,
dd,J=10.3Hz,3.4 Hz),5.64−5.65(2H, dd, J = 10.3Hz, 3.4 Hz), 5.64-5.65 (2H,
m),5.78(1H,dd,J=10.3Hz,8.1 Hz), m), 5.78 (1H, dd, J = 10.3Hz, 8.1 Hz),
7.0 −8.1 (40H,m). 7.0 -8.1 (40H, m). (ii)化合物12−4の合成 化合物12−3(34.5g)をクロロホルム−メタノール− (Ii) Compound 12-3 Compound 12-4 (34.5 g) in chloroform - methanol -
水( 100: 100:1)の混合溶媒 400mlに溶解し、パラトルエンスルホン酸( 1.2g)を添加し、50℃で6時間反応させた。 Water (100: 100: 1) mixed solvent 400ml of was added p-toluenesulfonic acid (1.2 g), and allowed to react for 6 hours at 50 ° C..

【0225】反応液を飽和重曹水で中和し、溶媒を留去し、クロロホルムで抽出し、シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン、1:1)で精製して化合物12−4(18.6g)を得た。 [0225] The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, the solvent was evaporated, extracted with chloroform, silica gel column chromatography (ethyl acetate - hexane, 1: 1) give to compound 12-4 (18.6 g ) was obtained.

【0226】C 474015としての元素分析値は、計算値:C,66.86 ;H,4.77に対し実測値:C,66.43 ; [0226] Elementary analysis as C 47 H 40 O 15 is Calculated: C, 66.86; H, Found to 4.77: C, 66.43;
H,4.95であった。 H, was 4.95.

【0227】 [α] D + 104.3°(c 1.02,CHCl 3 ). [0227] [α] D + 104.3 ° ( c 1.02, CHCl 3). (iii) 化合物12−5の合成 化合物12−4(18.5g)をビリジン90mlに溶解して氷冷し、ジフェニルホスホロクロリデート(8.27g)を加え、室温に戻して1時間攪拌した。 It was dissolved (iii) Synthesis of Compound 12-5 12-4 a (18.5 g) in Pyridine 90ml ice-cold, diphenyl phosphorochloridate a (8.27 g) was added and stirred for 1 hour to warm to room temperature.

【0228】反応液を氷水中に注加し、クロロホルムで抽出し、シリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン、1:1)により精製して、化合物12− [0228] was poured into ice water and the reaction mixture was extracted with chloroform, silica gel column chromatography (ethyl acetate - hexane, 1: 1) to give Compound 12
5(18.6g)を得た。 5 (18.6g) was obtained.

【0229】C 594918 Pとしての元素分析値は、計算値:C,65.79 ;H,4.59;P,2.88に対し実測値C,65.66 ;H,4.83;P,3.24であった。 [0229] Elementary analysis as C 59 H 49 O 18 P is Calculated: C, 65.79; H, 4.59 ; P, Found to 2.88 C, 65.66; H, 4.83 ; P, was 3.24.

【0230】 [α] D + 53.8 °(c 0.976 ,CHCl 3 ). [0230] [α] D + 53.8 ° ( c 0.976, CHCl 3). 1 H−NMR(CDCl 3 ):3.78(2H,m),4.02 1 H-NMR (CDCl 3) : 3.78 (2H, m), 4.02
(1H,d,J=7.6Hz),4.04(1H,ddd,J (1H, d, J = 7.6Hz), 4.04 (1H, ddd, J
=10.5Hz,7.5 Hz,7.0 Hz),4.22(1H,dd = 10.5Hz, 7.5 Hz, 7.0 Hz), 4.22 (1H, dd
d,J=10.5Hz,8.0 Hz,7.0 Hz),4.34(1 d, J = 10.5Hz, 8.0 Hz, 7.0 Hz), 4.34 (1
H,t,J=6.0Hz),4.56(1H,d,J=5.4 H H, t, J = 6.0Hz), 4.56 (1H, d, J = 5.4 H
z),4.96(1H,s),5.31(1H,d,J=8.1 H z), 4.96 (1H, s), 5.31 (1H, d, J = 8.1 H
z),5.58(1H,dd,J=10.4Hz,3.4 Hz), z), 5.58 (1H, dd, J = 10.4Hz, 3.4 Hz),
5.67(2H,m),5.86(1H,dd,J=10.4Hz, 5.67 (2H, m), 5.86 (1H, dd, J = 10.4Hz,
8.1 Hz),7.0 −8.1 (35H,m). 8.1 Hz), 7.0 -8.1 (35H, m). (iv)化合物12−6の合成 化合物12−5(18.2g)、トリフロロ酢酸29mlおよび無水酢酸 356mlの混合物を室温で20時間攪拌した。 (Iv) Synthesis of Compound 12-6 12-5 (18.2g), a mixture of trifluoroacetic acid 29ml and acetic anhydride 356ml was stirred at room temperature for 20 hours.

【0231】反応液を減圧濃縮し、残固体をシリカゲルカラムクロマトグラフィー(酢酸エチル−ヘキサン、 [0231] The reaction was concentrated under reduced pressure, residue solid was purified by silica gel column chromatography (ethyl acetate - hexane,
1:1)により精製して化合物12−6(α/β=71/2 1: 1 compound to give) 12-6 (α / β = 71/2
9、17g)を得た。 9,17g) was obtained.

【0232】C 635521 Pとしての元素分析値は、計算値:C,64.18 ;H,4.70;P,2.63に対し実測値: [0232] Elementary analysis as C 63 H 55 O 21 P is Calculated: C, 64.18; H, 4.70 ; P, Found to 2.63:
C,64.10 ;H,4.79;P,2.88であった。 C, 64.10; H, 4.79; P, was 2.88.

【0233】 [α] D +50.5°(c 1.02,CHCl 3 ). [0233] [α] D + 50.5 ° ( c 1.02, CHCl 3). 1 H−NMR(CDCl 3 ):(α−アノマー);2.0 1 H-NMR (CDCl 3) :( α- anomer); 2.0
3,2.14(each s),3.43(dt,J=10.5Hz,7.0 3,2.14 (each s), 3.43 (dt, J = 10.5Hz, 7.0
Hz,7.0 Hz),3.63(dt,J=10.5Hz,10.5H Hz, 7.0 Hz), 3.63 (dt, J = 10.5Hz, 10.5H
z,7.0 Hz),3.90(t,J=7.0 Hz),4.03 z, 7.0 Hz), 3.90 (t, J = 7.0 Hz), 4.03
(m),4.06(t,J=10.3Hz),4.22(dd,J= (M), 4.06 (t, J = 10.3Hz), 4.22 (dd, J =
11.4Hz,3.4 Hz),4.27(dd,J=11.4Hz,1. 11.4Hz, 3.4 Hz), 4.27 (dd, J = 11.4Hz, 1.
7 Hz),4.77(d,J=8Hz),5.37(dd,J= 7 Hz), 4.77 (d, J = 8Hz), 5.37 (dd, J =
8.5 Hz,3.5Hz),5.67(dd,J=10.2Hz,7.8 8.5 Hz, 3.5Hz), 5.67 (dd, J = 10.2Hz, 7.8
Hz),5.69(s),5.97(dd,J=10.3Hz,8.5 Hz), 5.69 (s), 5.97 (dd, J = 10.3Hz, 8.5
Hz),6.47(d,J=3.5 Hz),7.1 −8.0 Hz), 6.47 (d, J = 3.5 Hz), 7.1 -8.0
(m). (M). (β−アノマー);2.02,2.10(each s,2×OA (Beta-anomer); 2.02,2.10 (each s, 2 × OA
c),3.40(dt,J=10.5Hz,7.0 Hz),3.56 c), 3.40 (dt, J = 10.5Hz, 7.0 Hz), 3.56
(dt,J=10.5Hz,10.5Hz,7.0 Hz),3.77 (Dt, J = 10.5Hz, 10.5Hz, 7.0 Hz), 3.77
(m),4.71(d,J=7.8 Hz),5.50(dd,J= (M), 4.71 (d, J = 7.8 Hz), 5.50 (dd, J =
10.0Hz,8.3 Hz),5.64(dd,J=10.5Hz,7. 10.0Hz, 8.3 Hz), 5.64 (dd, J = 10.5Hz, 7.
8 Hz),5.74(t,J=9.5 Hz),5.86(d,J= 8 Hz), 5.74 (t, J = 9.5 Hz), 5.86 (d, J =
8.3 Hz),7.1 −8.0 (m). 8.3 Hz), 7.1 -8.0 (m). (v) 化合物12−7の合成 化合物12−6(10g)、トリエチレングリコールn−オクタデシルエーテル(3.4 g)、塩化メチレン 150mlおよび「モレキュラーシーブ4A」(MS4A)の混合物を氷冷し、トリメチルシリルトリフレート(2.82g)を滴下し、室温で3時間反応させた。 (V) Synthesis of Compound 12-7 12-6 (10g), triethylene glycol n- octadecyl ether (3.4 g), ice-cooled mixture of methylene chloride 150ml and "molecular sieves 4A" (MS4A), trimethylsilyl triflate It was added dropwise rate (2.82 g), and reacted at room temperature for 3 hours.

【0234】反応液を10%重曹水中に注加し、有機層をシリカゲルカラムクロマトグラフィー(ベンゼン−酢酸エチル−ヘキサン、1:1:1)により精製し化合物12 [0234] The reaction solution was poured into 10% sodium bicarbonate in water, and the organic layer silica gel column chromatography (benzene - ethyl acetate - hexane, 1: 1: 1) give to the compound 12
−7( 2.7g)を得た。 It was obtained -7 (2.7g).

【0235】mp:39〜40℃. [0235] mp: 39~40 ℃. 8510123 Pとしての元素分析値は、計算値:C, Elementary analysis as C 85 H 101 O 23 P is Calculated: C,
67.08 ;H,6.69に対し実測値:C,66.65 ;H,6.72 67.08; H, Found to 6.69: C, 66.65; H, 6.72
であった。 Met.

【0236】 [α] D +18.4°(c 0.964 ,CHCl 3 ). [0236] [α] D + 18.4 ° ( c 0.964, CHCl 3). 1 H−NMR(CDCl 3 ):0.89(3H,t,J=7.0 1 H-NMR (CDCl 3) : 0.89 (3H, t, J = 7.0
Hz),1.27(30H,s),1.57(2H,m),2.00 Hz), 1.27 (30H, s), 1.57 (2H, m), 2.00
(3H,s),3.3 −3.7 (14H,m),3.65(1H, (3H, s), 3.3 -3.7 (14H, m), 3.65 (1H,
ddd,J=9.4 Hz,5.0 Hz,1.7 Hz),3.98 ddd, J = 9.4 Hz, 5.0 Hz, 1.7 Hz), 3.98
(1H,t,J=9.4 Hz),4.15(1H,dd,J= (1H, t, J = 9.4 Hz), 4.15 (1H, dd, J =
12.0Hz,5.0 Hz),4.32(1H,dd,J=12.0H 12.0Hz, 5.0 Hz), 4.32 (1H, dd, J = 12.0H
z,1.7 Hz),4.72(1H,d,J=7.9 Hz),4. z, 1.7 Hz), 4.72 (1H, d, J = 7.9 Hz), 4.
74(1H,d,J=7.9 Hz),5.34(1H,dd,J 74 (1H, d, J = 7.9 Hz), 5.34 (1H, dd, J
=10.0Hz,3.0 Hz),5.37(1H,dd,J=10.0 = 10.0Hz, 3.0 Hz), 5.37 (1H, dd, J = 10.0
Hz,7.9 Hz),5.64(1H,dd,J=10.0Hz, Hz, 7.9 Hz), 5.64 (1H, dd, J = 10.0Hz,
7.9Hz),5.67(1H,m),5.69(1H,t,J=1 7.9Hz), 5.67 (1H, m), 5.69 (1H, t, J = 1
0.0Hz),7.1 −8.0 (35H). 0.0Hz), 7.1 -8.0 (35H). (vi)化合物12−8の合成 化合物12−7( 0.9g)を酢酸エチル18mlに溶解し、酸化白金を触媒に用いて常温常圧で20時間接触還元した。 (Vi) Synthesis of Compound 12-8 12-7 (0.9 g) was dissolved in ethyl acetate 18 ml, and the platinum oxide for 20 hours catalytic reduction at room temperature and atmospheric pressure with a catalyst.
触媒を濾去し、28%ナトリウムメチラートで中和後(p The catalyst was removed by filtration, neutralized with 28% sodium methylate (p
H6)溶媒を留去した。 H6) and the solvent was evaporated. 残固体をベンゼン−メタノール(1:1、24ml)に溶解し、28%ナトリウムメチラート Benzene residue solid - methanol were dissolved in (1 1,24ml), 28% sodium methylate
0.6mlを添加して室温で20時間攪拌した。 It was stirred at room temperature for 20 hours with the addition of 0.6 ml.

【0237】反応液に1N HCl 3.1mlを加えてから溶媒を留去し、カラムクロマトグラフィー(「CHP− [0237] The reaction solution was evaporated after addition of 1N HCl 3.1 ml, column chromatography ( "CHP-
20」、22mm×40cm、0〜50%アセトニトリル)により精製して化合物12−8の粉末を得た( 0.402g,80%)。 20 ", 22 mm × 40 cm, to obtain a powder of the compound 12-8 to give 0-50% acetonitrile) (0.402g, 80%).
この一部を 0.5N NaOH−エタノールで再結晶して化合物12−8の二ナトリウム塩として分析用試料とした。 A portion of this was analyzed sample as recrystallized disodium salt of compound 12-8 0.5 N NaOH-ethanol.

【0238】mp:195 〜199 ℃(dec). [0238] mp: 195 ~199 ℃ (dec). 366917 PNa 2・4H 2 Oとしての元素分析値は、計算値:C,46.85;H,8.40;P,3.36;Na, C 36 H 69 O 17 PNa Elementary analysis as 2 · 4H 2 O is Calculated: C, 46.85; H, 8.40 ; P, 3.36; Na,
4.98に対し実測値C,47.06 ;H,8.32;P,3.31;N Found to 4.98 value C, 47.06; H, 8.32; P, 3.31; N
a,4.83であった。 a, it was 4.83.

【0239】[α] D − 4.5°(c 0.8,H 2 O). [0239] [α] D - 4.5 ° ( c 0.8, H 2 O). 1 H−NMR(D 2 O):0.91(3H,bs),1.33(3 1 H-NMR (D 2 O ): 0.91 (3H, bs), 1.33 (3
0H,bs),1.60(2H,bs),3.3 −4.5 (28 0H, bs), 1.60 (2H, bs), 3.3 -4.5 (28
H,bm). H, bm). (p) 化合物15−2の合成(図20) (i) 化合物14−1の合成 マンノースパーアセテート(20.0g,51.24mmol )および2−[2−(2−クロロエトキシ)エトキシ]エタノール(11.232g)の塩化メチレン(300ml )溶液にボロントリフルオライドエーテル錯体(25.21ml )の塩化メチレン(25ml)溶液を氷冷下加え、一晩室温にて撹拌した。 (p) Synthesis of Compound 15-2 (FIG. 20) (i) Synthesis mannose peracetate compound 14-1 (20.0g, 51.24mmol) and 2- [2- (2-chloroethoxy) ethoxy] ethanol (11.232G ) in methylene chloride (300 ml) methylene chloride solution of boron trifluoride ether complex (25.21ml) (25ml) solution under ice-cooling, and the mixture was stirred overnight at room temperature.

【0240】得られた溶液を氷水に加え、クロロフォルム200ml を加えて抽出した。 [0240] The resulting solution was added to ice water and extracted by adding chloroform 200 ml. 有機層を4回水洗し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed with water 4 times and dried over anhydrous sodium sulfate. 溶媒を減圧下濃縮し、残渣を1700mlのシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1:1)、目的物を得た。 The solvent was concentrated under reduced pressure, the residue was separated by silica gel column chromatography 1700 ml (hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired compound. 6.861 g。 6.861 g.

【0241】 [α] D 23 =+33.3°(c 1.35、CHCl 3 ). [0241] [α] D 23 = + 33.3 ° (c 1.35, CHCl 3). 1 H−NMR(CDCl 3 ,δ):1.987, 2.039, 2,10 1 H-NMR (CDCl 3, δ): 1.987, 2.039, 2,10
0. 2.153(4s,3H),3.397 (t,2H,J=5.1 0. 2.153 (4s, 3H), 3.397 (t, 2H, J = 5.1
Hz),3.61−3.85(m,10H),4.064 (m,1 Hz), 3.61-3.85 (m, 10H), 4.064 (m, 1
H),4.107 (dd,1H,J=2.4 Hz,12.2H H), 4.107 (dd, 1H, J = 2.4 Hz, 12.2H
z),4.286 (dd,1H,J=5.1 Hz),4.873 z), 4.286 (dd, 1H, J = 5.1 Hz), 4.873
(d,1H,J=1.7 Hz),5.270 (dd,1H,J (D, 1H, J = 1.7 Hz), 5.270 (dd, 1H, J
=3.4 Hz),5.288 (t,1H,J=10.0Hz),5. = 3.4 Hz), 5.288 (t, 1H, J = 10.0Hz), 5.
364 (dd,1H). 364 (dd, 1H). (ii)化合物14−2の合成 化合物14−1(5.861 g)およびナトリウムアジド(1. (Ii) Synthesis of Compound 14-2 14-1 (5.861 g) and sodium azide (1.
146 g)にDMF(50ml)を加え、60℃にて17時間加熱撹拌した。 146 g) in DMF (50ml) was added, and 17 hours heated with stirring at 60 ° C..

【0242】得られた溶液に水100ml 加え、酢酸エチルで抽出した。 [0242] The resulting solution of water 100ml added and the mixture was extracted with ethyl acetate. 有機層を3回水洗し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed with water three times, and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を350ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=1:1)、目的物を得た。 The solvent was evaporated under reduced pressure, the residue was separated by silica gel column chromatography 350 ml (hexane: ethyl acetate = 1: 1) to obtain the desired compound. 4.468 g。 4.468 g.

【0243】 [α] D 21 =+35.6°(c 1.04、CHCl 31 H−NMR(CDCl 3 ,δ):1.988, 2.040,2.100 [0243] [α] D 21 = + 35.6 ° (c 1.04, CHCl 3) 1 H-NMR (CDCl 3, δ): 1.988, 2.040,2.100
,2.153 (4s,3H),3.640 (t,2H,J=5.9 , 2.153 (4s, 3H), 3.640 (t, 2H, J = 5.9
Hz),3.64−3.84(m,10H),4.068 (m,1 Hz), 3.64-3.84 (m, 10H), 4.068 (m, 1
H),4.117 (dd,1H,J=2.4 Hz,12.2H H), 4.117 (dd, 1H, J = 2.4 Hz, 12.2H
z),4.287 (dd,1H,J=5.1 Hz),4.874 z), 4.287 (dd, 1H, J = 5.1 Hz), 4.874
(d,1H,J=1.5 Hz),5.267 (dd,1H,J (D, 1H, J = 1.5 Hz), 5.267 (dd, 1H, J
=3.7 Hz),5.289 (t,1H,J=10.0Hz),5. = 3.7 Hz), 5.289 (t, 1H, J = 10.0Hz), 5.
362 (dd,1H). 362 (dd, 1H). (iii) 化合物14−3の合成 化合物14−2(4.4676g)のメタノール(100ml )溶液にナトリウムメチラートメタノール溶液(5モル/l) (Iii) methanol Compound 14-2 Compound 14-3 (4.4676g) (100ml) was added sodium methylate methanol solution (5 mol / l)
を10滴加え、室温にて3時間撹拌した。 10 drops of the mixture was stirred for 3 hours at room temperature. 得られた溶液に酸性イオン交換樹脂「ダウエックス50W×8」を加え中和した後、樹脂を濾別し、溶媒を減圧下留去した。 The resulting solution was neutralized by adding acidic ion exchange resin "Dowex 50 W × 8", the the resin is filtered off and the solvent was evaporated under reduced pressure. 残渣を100ml のピリジンに溶解し、トリチルクロリド(3.20 The residue was dissolved in pyridine 100 ml, trityl chloride (3.20
3 g)を加え、50℃で3時間加熱撹拌した。 3 g) and the mixture was stirred for 3 hours at 50 ° C.. さらにトリチルクロリド(1.231 g)を加え、70℃で14時間加熱した。 Further trityl chloride and (1.231 g) was added and heated at 70 ° C. 14 hours. 得られた溶液を室温まで冷却し、ベンゾイルクロリド(3.692ml )を加え、一晩室温で撹拌した。 The resulting solution was cooled to room temperature, benzoyl chloride (3.692ml) was added and stirred at room temperature overnight. 溶液を氷水に加え、クロロフォルム200ml にて抽出した。 Solution was added to ice water, and extracted with chloroform 200 ml. 有機層を2N塩酸で2回、水で3回洗浄し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed twice with 2N hydrochloric acid, washed three times with water, and dried over anhydrous sodium sulfate. 溶媒を減圧下濃縮し、残渣にパラトルエンスルホン酸200mg を加え、クロロフォルム:メタノール:水=65:15:1の混合溶媒を50ml加えて溶解し、 The solvent was concentrated under reduced pressure, the residue paratoluenesulfonic acid 200mg addition, chloroform: methanol: water = 65: 15: 1 mixed solvent of was dissolved by adding 50 ml,
50℃にて5時間加熱撹拌した。 Was 5 hours stirring at 50 ° C..

【0244】得られた溶液をトリエチルアミンにて中和し、溶媒を減圧下留去した。 [0244] The resulting solution was neutralized with triethylamine, and the solvent was removed under reduced pressure. 残渣に水50mlを加え、クロロフォルムにて抽出した。 The residue 50ml of water was added, followed by extraction with chloroform. 溶媒を減圧下留去し、残渣を The solvent was evaporated under reduced pressure, the residue
500ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1:1)、目的物を得た。 Was separated by silica gel column chromatography 500 ml (hexane: ethyl acetate = 2: 1-1: 1) to obtain the desired compound. 2.4106g,42.0%。 2.4106g, 42.0%.

【0245】 [α] D 23 =−107.2 °(c 1.75、CHCl 3 ). [0245] [α] D 23 = -107.2 ° (c 1.75, CHCl 3). 1 H−NMR(CDCl 3 ,δ):3.376 (t,2H, 1 H-NMR (CDCl 3, δ): 3.376 (t, 2H,
J=5.1 Hz),3.68−3.86(m,12H),3.92−3.96 J = 5.1 Hz), 3.68-3.86 (m, 12H), 3.92-3.96
(m,1H),4.166 (brd,dd),4.196 (br (M, 1H), 4.166 (brd, dd), 4.196 (br
d,1H),5.168 (d,1H,J=1.5 Hz),5.70 d, 1H), 5.168 (d, 1H, J = 1.5 Hz), 5.70
2 (dd,1H,J=3.4 Hz),5.823 (t,1H, 2 (dd, 1H, J = 3.4 Hz), 5.823 (t, 1H,
J=10.0Hz),5.993 (dd,1H),7.23−7.63 J = 10.0Hz), 5.993 (dd, 1H), 7.23-7.63
(m,9H),7.80−8.12(m,6H). (M, 9H), 7.80-8.12 (m, 6H). (iv)化合物14−4の合成 化合物14−3(2.4066g)のピリジン(20ml)溶液に氷冷下ジフェニル燐酸クロリド(1.493 g)のピリジン(3ml)溶液を滴下し、室温で一晩撹拌した。 (Iv) was added dropwise pyridine (3 ml) solution of the synthesis of Compound 14-4 14-3 pyridine (2.4066g) (20ml) under ice-cooling diphenyl phosphate chloride solution (1.493 g), stirred overnight at room temperature . 得られた溶液を氷水に加え、クロロフォルム(100ml )にて抽出した。 The resulting solution was added to ice water, and extracted with chloroform (100ml). 有機層を2N塩酸で2回、飽和食塩水で3回洗浄し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed twice with 2N hydrochloric acid, washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を500ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1)、目的物を得た。 The solvent was evaporated under reduced pressure, the residue was separated by silica gel column chromatography 500 ml (hexane: ethyl acetate = 2: 1) to obtain the desired compound. 2.848 g,87.2%。 2.848 g, 87.2%.

【0246】 [α] D 27 =−58.6°(c 1.04、CHCl 3 ). [0246] [α] D 27 = -58.6 ° (c 1.04, CHCl 3). 1 H−NMR(CDCl 3 ,δ):3.384 (t,2H, 1 H-NMR (CDCl 3, δ): 3.384 (t, 2H,
J=5.0 Hz),3.68−3.75(m,9H),3.83−3.89 J = 5.0 Hz), 3.68-3.75 (m, 9H), 3.83-3.89
(m,1H),4.39−4.43(m,1H),4.45−4.48 (M, 1H), 4.39-4.43 (m, 1H), 4.45-4.48
(m,2H),5.092 (d,1H,J=1.7 Hz),5. (M, 2H), 5.092 (d, 1H, J = 1.7 Hz), 5.
683 (dd,1H,J=2.5 Hz),5.86−5.92(m, 683 (dd, 1H, J = 2.5 Hz), 5.86-5.92 (m,
2H),7.10−7.59(m,19H),7.80−8.08(m,6 2H), 7.10-7.59 (m, 19H), 7.80-8.08 (m, 6
H). H). (v) 化合物の14−5の合成 化合物14−4(2.8443g)およびパラトルエンスルホン酸1水和物(613.5mg)をメタノール20mlおよび酢酸エチル20mlの混合溶媒に溶解し、リンドラー触媒(1.0 (V) A solution of compound 14-5 Compound 14-4 (2.8443g) and p-toluenesulfonic acid monohydrate (613.5Mg) was dissolved in a mixed solvent of methanol 20ml, and ethyl acetate 20ml, Lindlar catalyst (1.0
g)を加え、50psi の水素雰囲気下6時間撹拌した。 g), and the mixture was stirred under a hydrogen atmosphere of 50 psi 6 hours. さらにリンドラー触媒(1.0 g)を加え、50psi の水素雰囲気下3時間撹拌した。 Further Lindlar catalyst a (1.0 g) was added, and stirred for 3 hours under a hydrogen atmosphere of 50 psi.

【0247】触媒を濾過し、溶媒を減圧下留去して目的物を得た。 [0247] The catalyst was filtered to give the desired product the solvent was evaporated under reduced pressure. 3.075 g。 3.075 g. この化合物は特に精製をする事なく次の段階の合成に用いた。 This compound was used in the synthesis of the next stage without particular purification.

【0248】(vi)化合物15−1の合成 化合物14−5(2.1047)、2−パルミチルステアリン酸(1.354 g)、N−ヒドロキシスクシイミド(306mg ) [0248] (vi) Synthesis of Compound 15-1 14-5 (2.1047), 2-palmityl stearic acid (1.354 g), N-hydroxysuccinimide (306 mg)
およびトリエチルアミン(0.683ml )の混合物を塩化メチレン40mlおよびヘキサン20mlに溶解し、この溶液にD And mixtures triethylamine (0.683ml) was dissolved in methylene chloride 40ml and hexane 20 ml, D to this solution
CC(549mg )を加え、室温下一晩撹拌した。 CC The (549 mg) was added, and the mixture was stirred at room temperature overnight. 溶液を氷水に加えクロロフォルムにて抽出した。 The solution was extracted with chloroform was added to ice water. 有機層を水洗し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed with water and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を200ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1: The solvent was distilled off under reduced pressure, the residue was separated by silica gel column chromatography 200 ml (hexane: ethyl acetate = 2: 1-1:
1)、目的物を得た。 1), the desired product was obtained. 796mg 。 796mg.

【0249】 [α] D 27 =−52.4(c 1.11、CHCl 3 ). [0249] [α] D 27 = -52.4 ( c 1.11, CHCl 3). 1 H−NMR(CDCl 3 ,δ):0.876 (t,6H, 1 H-NMR (CDCl 3, δ): 0.876 (t, 6H,
J=6.9 Hz),1.18−1.39(m,56H),1.52−1.60 J = 6.9 Hz), 1.18-1.39 (m, 56H), 1.52-1.60
(m,4H),1.95−2.01(m,1H),3.43−3.47 (M, 4H), 1.95-2.01 (m, 1H), 3.43-3.47
(m,2H),3.538(m,2H),3.62−3.77(m,11 (M, 2H), 3.538 (m, 2H), 3.62-3.77 (m, 11
H),3.85−3.89(m,1H),4.39−4.48(m,3 H), 3.85-3.89 (m, 1H), 4.39-4.48 (m, 3
H),5.103 (d,1H,J=1.8 Hz),5.679(d H), 5.103 (d, 1H, J = 1.8 Hz), 5.679 (d
d,1H,J=2.7 Hz),5.86−5.93(m,2H), d, 1H, J = 2.7 Hz), 5.86-5.93 (m, 2H),
6.062(br t,1H),7.09−7.59(m,19H),7. 6.062 (br t, 1H), 7.09-7.59 (m, 19H), 7.
80−8.08(m,6H). 80-8.08 (m, 6H). (vii) 化合物15−2の合成 化合物15−1(780mg )および酸化白金50mgに酢酸エチル20mlおよびメタノール10mlを加え、一晩常圧の水素雰囲気下で撹拌した。 (Vii) Synthesis of Compound 15-2 15-1 (780 mg) and platinum oxide 50mg of ethyl acetate 20ml and methanol 10ml, and the mixture was stirred under a hydrogen atmosphere overnight normal pressure. 触媒を濾過し、溶媒を減圧下留去した。 The catalyst was filtered, and the solvent was evaporated under reduced pressure. 残渣にベンゼン2mlおよびメタノール6mlを加え溶解し、ナトリウムメチラートメタノール溶液(5モル/ The residue was dissolved was added benzene 2ml and methanol 6 ml, sodium methylate methanol solution (5 mol /
l)を30滴加えてpHを11とし、室温にて一晩撹拌した。 pH was 11 added to l) 30 drops, and stirred at room temperature overnight.

【0250】溶液を1N塩酸にて中和した後、溶媒を減圧下留去した。 [0250] The solution was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. 残渣をクロロフォルム:メタノール:水=65:15:1の混合溶媒2mlに溶解し、150ml のシリカゲルカラムクロマトグラフィー(クロロフォルム:メタノール:水=65:25:3から60:35:7までのグラジエント溶離、総量2000ml、100 フラクション)にて分離した。 The residue chloroform: methanol: water = 65: 15 were dissolved in 1 mixed solvent of 2 ml, 150 ml of silica gel column chromatography (chloroform: methanol: water = 65: 25: 3 to 60: 35: gradient elution up to 7, They were separated by the total amount 2000ml, 100 fraction). フラクション38−47を濃縮した。 It was concentrated fractions 38-47. 残渣をクロロフォルム:メタノール:水=65:15:1の混合溶媒に溶解し、強酸性イオン交換樹脂「ダウエックス50W×8」にて処理した後、樹脂を濾去した。 The residue chloroform: methanol: water = 65: 15: was dissolved in a mixed solvent of 1, after processing by a strongly acidic ion exchange resin "Dowex 50 W × 8" and the resin was filtered off. 溶媒を減圧下濃縮し、 The solvent was concentrated under reduced pressure,
クロロフォルム:メタノール=9:1の混合溶媒に溶解し、「Sephadex LH−20」(22mmφ×400mm Chloroform: methanol = 9: was dissolved in a mixed solvent of 1, "Sephadex LH-20" (22mmφ × 400mm
、クロロフォルム:メタノール=9:1溶離)にて分離した。 , Chloroform: methanol = 9: were separated by 1 elution). フラクション5−10を濃縮して目的物を得た。 The desired product was obtained by concentration of the fractions 5-10.
230mg ,65.8%。 230mg, 65.8%.

【0251】[α] D 23 =+15.3°(c 1.12、クロロフォルム:メタノール=9:1). [0251] [α] D 23 = + 15.3 ° (c 1.12, chloroform: methanol = 9: 1). (q) 化合物28−2の合成(図21) (i) 化合物11−4の合成 化合物11−3、0.745 gに塩化チオニル4mlを加え、5 (q) Synthesis of Compound 28-2 (FIG. 21) (i) of thionyl chloride 4ml addition to synthetic compounds 11-3,0.745 g of compound 11-4, 5
時間加熱下還流させた。 It was allowed to reflux time under heating. 塩化チオニルを減圧下留去し、 Thionyl chloride was evaporated under reduced pressure,
残渣にベンゼンを加え、減圧下留去した(2回)。 The residue of benzene was added to and distilled off under reduced pressure (twice). それ以上の精製はせずに以下の反応に用いた。 It was used in the following reaction without any further purification.

【0252】(ii)化合物28−1の合成 化合物27−4、1.175 gに塩化メチレン10mlを加えて溶かし、氷冷下撹拌した。 [0252] (ii) Synthesis of Compound 28-1 27-4,1.175 g and dissolve in methylene chloride 10 ml, and stirred under ice-cooling. ここにトリエチルアミン350 μ Here in triethylamine 350 μ
lを加え、さらに(a) で得られた化合物11−4全量を塩化メチレン5mlに溶かして加え、室温に昇温させつつ14 l was added, added dissolved further compound 11-4 the total amount obtained in (a) in methylene chloride 5 ml, while allowed to warm to room temperature 14
時間撹拌した。 And the mixture was stirred time.

【0253】溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィーで精製し(溶出溶媒;n−ヘキサン− [0253] The solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (elution solvent; n-hexane -
酢酸エチル 1:1)、目的物を無色非晶質として1.23 Ethyl acetate 1: 1), 1.23 of the desired product as a colorless amorphous
2 g得た。 2 was obtained g.

【0254】 1 H−NMR(δ,CDCl 3 ):0.88 [0254] 1 H-NMR (δ, CDCl 3): 0.88
(t,6H,J=7.0 Hz),1.18−1.31(m,56 (T, 6H, J = 7.0 Hz), 1.18-1.31 (m, 56
H),1.33−1.41(m,2H),1.52−1.60(m,2 H), 1.33-1.41 (m, 2H), 1.52-1.60 (m, 2
H),1.93−1.99(m,1H),3.33−3.34(m,2 H), 1.93-1.99 (m, 1H), 3.33-3.34 (m, 2
H),3.37−3.42(m,4H),3.45−3.48(m,2 H), 3.37-3.42 (m, 4H), 3.45-3.48 (m, 2
H),3.56−3.64(m,2H),3.73(ddd,1H, H), 3.56-3.64 (m, 2H), 3.73 (ddd, 1H,
J=3.6 Hz,7.2 Hz,10.9Hz),3.94(ddd, J = 3.6 Hz, 7.2 Hz, 10.9Hz), 3.94 (ddd,
1H,J=3.5 Hz,4.7 Hz,11.2Hz),4.06−4. 1H, J = 3.5 Hz, 4.7 Hz, 11.2Hz), 4.06-4.
10(m,1H),4.41(ddd,1H,J=6.3 Hz, 10 (m, 1H), 4.41 (ddd, 1H, J = 6.3 Hz,
11.5Hz,8.7 Hz),4.47(ddd,1H,J=2.5 11.5Hz, 8.7 Hz), 4.47 (ddd, 1H, J = 2.5
Hz,7.3 Hz,11.5Hz),4.89(d,1H,J=8. Hz, 7.3 Hz, 11.5Hz), 4.89 (d, 1H, J = 8.
0 Hz),5.45(dd,1H,J=8.0 Hz,9.8 H 0 Hz), 5.45 (dd, 1H, J = 8.0 Hz, 9.8 H
z),5.45(t,J=9.8 Hz),5.85(t,1H,J z), 5.45 (t, J = 9.8 Hz), 5.85 (t, 1H, J
=9.8 Hz),5.96(brs,1H),7.13−7.54 = 9.8 Hz), 5.96 (brs, 1H), 7.13-7.54
(m,19H),7.81(dd,2H,J=1.2 Hz,8.3 (M, 19H), 7.81 (dd, 2H, J = 1.2 Hz, 8.3
Hz),7.90(dd,2H,J=1.2 Hz,8.3 H Hz), 7.90 (dd, 2H, J = 1.2 Hz, 8.3 H
z),7.95(dd,2H,J=1.2 Hz,8.3 Hz). z), 7.95 (dd, 2H, J = 1.2 Hz, 8.3 Hz). [α] D 25 =+1.3 °(c=1.02,CHCl 3 −MeO [Α] D 25 = + 1.3 ° (c = 1.02, CHCl 3 -MeO
H 1:1) R f :0.27(n−hexane−AcOEt 2:3). H 1: 1) R f: 0.27 (n-hexane-AcOEt 2: 3). (iii) 化合物28−2の合成 化合物28−1、1.216 gにテトラヒドロフラン30ml及びメタノール10mlを加えて溶かした。 (Iii) it was dissolved by adding tetrahydrofuran 30ml and methanol 10ml to Compound 28-1,1.216 g of compound 28-2. ここに酸化白金0.01 Here in platinum oxide 0.01
5 gを加え、常圧で6日間接触還元した。 5 g was added and catalytic reduction for 6 days at atmospheric pressure. 触媒を濾去し、溶媒を減圧下留去した。 The catalyst was filtered off, the solvent was evaporated under reduced pressure. 残渣にベンゼン8ml及びメタノール8mlを加えて溶かし、28%ナトリウムメトキシドメタノール溶液を22滴加え(pH=11)、室温で11.5時間撹拌した。 Residue dissolved by adding benzene 8ml and methanol 8ml, 28% sodium methoxide methanol solution 22 drops of (pH = 11), was stirred at room temperature for 11.5 hours.

【0255】氷冷して1N塩酸で中和し、溶媒を減圧下留去した。 [0255] ice-cooled and neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. 残渣を「Sepphadex LH−20」カラムで精製した(樹脂:約150ml 、溶出溶媒:クロロホルム−メタノール−水 10:10:3)。 The residue was purified by "Sepphadex LH-20" column (resin: about 150 ml, elution solvent: chloroform - methanol - water 10: 10: 3). 目的化合物を無色粉末として0.640 g得た。 The desired compound was obtained 0.640 g as a colorless powder.

【0256】 1 H−NMR(δ,CDCl 3 −D 2 [0256] 1 H-NMR (δ, CDCl 3 -D 2 O
5:1):0.88(t,6H,J=7.0 Hz),1.16−1. 5: 1): 0.88 (t, 6H, J = 7.0 Hz), 1.16-1.
34(m,56H),1.34−1.44(m,2H),1.46−1.59 34 (m, 56H), 1.34-1.44 (m, 2H), 1.46-1.59
(m,2H),2.04−2.11(m,1H),3.26−6.36 (M, 2H), 2.04-2.11 (m, 1H), 3.26-6.36
(m,19H). (M, 19H). 13 C−NMR(δ,CDCl 3 −CD 3 OD−D 2 13 C-NMR (δ, CDCl 3 -CD 3 OD-D 2 O
10:10:3):14.25,23.04 ,27.83 ,29.71 ,29.84 10: 10: 3): 14.25,23.04, 27.83, 29.71, 29.84
,30.02 ,32.30 ,33.07 ,39.23 ,47.78,63.09 , 30.02, 32.30, 33.07, 39.23, 47.78,63.09
(J=2.4 Hz),69.00 −70.50 ,69.28 ,74.12 , (J = 2.4 Hz), 69.00 -70.50, 69.28, 74.12,
75.70 ,76.42(J=5.5 Hz),103.55,178.38. 75.70, 76.42 (J = 5.5 Hz), 103.55,178.38. [α] D 26 =−14.2°(c=1.05,CHCl 3 −MeO [Α] D 26 = -14.2 ° (c = 1.05, CHCl 3 -MeO
H 1:1). H 1: 1). f :0.44(CHCl 3 −MeOH−H 2 O 60:35: R f: 0.44 (CHCl 3 -MeOH -H 2 O 60:35:
7). 7). FAB−MS:[M+H] + ;M/Z=882 ,[M+N FAB-MS: [M + H ] +; M / Z = 882, [M + N
a] + ;M/Z=904. a] +; M / Z = 904. (r) 化合物18−2の合成(図22) (i) 化合物17−1の合成 ガラクトースパーアセテート(10.0g)および2−[2 (r) Synthesis of Compound 18-2 (FIG. 22) (i) Synthesis galactose peracetate compound 17-1 (10.0 g) and 2- [2
−(クロロエトキシ)エトキシ]−エタノール(5.616 - (chloro) ethoxy] - ethanol (5.616
g)の塩化メチレン(150ml )溶液にボロントリフルオライドエーテル錯体(12.6ml)の塩化メチレン(30ml) g) in dichloromethane (150ml) was added boron trifluoride etherate (12.6 ml) in methylene chloride (30ml)
溶液を氷冷下加え、一晩室温にて撹拌した。 Solution under ice cooling, and the mixture was stirred overnight at room temperature.

【0257】得られた溶液を氷水に加え、クロロフォルム(150ml )を加えて抽出した。 [0257] The resulting solution was added to ice water and extracted by adding chloroform (150 ml). 有機層を2回水洗し、 The organic layer was washed with water twice,
無水硫酸ナトリウムにて乾燥した。 And then dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を1000mlのシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1: The solvent was distilled off under reduced pressure, the residue was separated by silica gel column chromatography 1000 ml (hexane: ethyl acetate = 2: 1-1:
1)、目的物を得た。 1), the desired product was obtained. 6.51g。 6.51g.

【0258】[α] D 20 =−0.4 °(c 1.098 、クロロフォルム). [0258] [α] D 20 = -0.4 ° (c 1.098, chloroform). 1 H−NMR(CDCl 3 ,δ):1.986 ,2.051 ,2.0 1 H-NMR (CDCl 3, δ): 1.986, 2.051, 2.0
63 ,2.152 (4s,3H),3.63−3.78(m,11 63, 2.152 (4s, 3H), 3.63-3.78 (m, 11
H),3.95−3.98(m,1H),3.917 (brt,1 H), 3.95-3.98 (m, 1H), 3.917 (brt, 1
H),4.131 (dd,1H,J=6.8 Hz,11.2H H), 4.131 (dd, 1H, J = 6.8 Hz, 11.2H
z),4.178 (dd,1H,J=6.6 Hz),4.576 z), 4.178 (dd, 1H, J = 6.6 Hz), 4.576
(d,1H,J=8.1 Hz),5.023 (dd,1H,J (D, 1H, J = 8.1 Hz), 5.023 (dd, 1H, J
=3.4 Hz),5.212 (dd,1H,J=10.5Hz), = 3.4 Hz), 5.212 (dd, 1H, J = 10.5Hz),
5.390 (brd,1H). 5.390 (brd, 1H). (ii)化合物17−2の合成 化合物17−1(6.445 g)およびナトリウムアジド(1. (Ii) Compound 17-1 Compound 17-2 (6.445 g) and sodium azide (1.
26g)にDMF(50ml)を加え、60℃にて17時間加熱撹拌した。 DMF (50ml) was added to 26 g), 17 hours heated with stirring at 60 ° C..

【0259】得られた溶液に水(100ml )を加え、酢酸エチルで抽出した。 [0259] The resulting solution was washed with water (100ml) was added, and the mixture was extracted with ethyl acetate. 有機層を水洗し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed with water and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を500ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1.5−1:1)、目的物を得た。 The solvent was evaporated under reduced pressure, the residue was separated by silica gel column chromatography 500 ml (hexane: ethyl acetate = 2: 1.5-1: 1), to give the desired product. 5.30g。 5.30g.

【0260】 [α] D 17 =−3.2 °(c 1.04、CHCl 3 ). [0260] [α] D 17 = -3.2 ° (c 1.04, CHCl 3). 1 H−NMR(CDCl 3 ,δ):1.984 ,2.048 ,2.0 1 H-NMR (CDCl 3, δ): 1.984, 2.048, 2.0
60 ,2.148 (4s,3H),3.398 (t,2H,J= 60, 2.148 (4s, 3H), 3.398 (t, 2H, J =
5.0 Hz),3.63−3.69(m,8H),3.73−3.78 5.0 Hz), 3.63-3.69 (m, 8H), 3.73-3.78
(m,1H),3.95−3.98(m,1H),3.910 (br (M, 1H), 3.95-3.98 (m, 1H), 3.910 (br
t,1H),4.131 (dd,1H,J=6.8 Hz,1 t, 1H), 4.131 (dd, 1H, J = 6.8 Hz, 1
1.2Hz),4.176 (dd,1H,J=6.3 Hz),4,5 1.2Hz), 4.176 (dd, 1H, J = 6.3 Hz), 4,5
71 (d,1H,J=7.8 Hz),5.023 (dd,1 71 (d, 1H, J = 7.8 Hz), 5.023 (dd, 1
H,J=3.4 Hz),5.210 (dd,1H,J=10.5H H, J = 3.4 Hz), 5.210 (dd, 1H, J = 10.5H
z),5.387 (dd,1H,J=1.0 Hz). z), 5.387 (dd, 1H, J = 1.0 Hz). (iii) 化合物17−3の合成 化合物17−2(4.957 g)のメタノール(70ml)溶液にナトリウムメチラートメタノール溶液(5モル/l)を (Iii) methanol Synthesis of Compound 17-3 17-2 (4.957 g) (70ml) was added sodium methylate solution in methanol (5 mol / l)
10滴加え、室温にて3時間撹拌した。 10 drops of the mixture was stirred for 3 hours at room temperature. 溶液に酸性イオン交換樹脂「ダウエックス50W×8」を加えて中和した後、溶媒を減圧下留去した。 After neutralizing by adding an acidic ion exchange resin "Dowex 50 W × 8" to the solution, and the solvent was evaporated under reduced pressure. 残渣をピリジン(30ml)に溶解し、この溶液に氷冷下ジフェニル燐酸クロリド(3. The residue was dissolved in pyridine (30 ml), under ice-cooling diphenyl phosphate chloride to the solution (3.
688 g)のピリジン溶液を滴下し、室温で8時間撹拌した。 Of pyridine was dropwise added a solution of 688 g), and stirred at room temperature for 8 hours. 得られた溶液にベンゾイルクロリド(4.55ml)を加え、一晩撹拌した。 The resulting solution benzoyl chloride (4.55 ml) was added and stirred overnight.

【0261】溶液を氷水に加え、クロロフォルム(200m [0261] solution was added to ice water, chloroform (200m
l )にて抽出した。 It was extracted with l). 有機層を2N塩酸で2回、飽和食塩水で3回洗浄し、無水硫酸ナトリウムにて乾燥した。 The organic layer was washed twice with 2N hydrochloric acid, washed 3 times with saturated brine, and dried over anhydrous sodium sulfate. 溶媒を減圧下留去し、残渣を500ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル= The solvent was distilled off under reduced pressure, the residue was separated by silica gel column chromatography 500 ml (hexane: ethyl acetate =
2:1−1:1)、目的物を得た。 2: 1-1: 1) to obtain the desired compound. 3.468 g。 3.468 g.

【0262】 [α] D 21 =+91.8°(c 1.02、CHCl 3 ). [0262] [α] D 21 = + 91.8 ° (c 1.02, CHCl 3). 1 H−NMR(CDCl 3 ,δ):3.305 (t,2H, 1 H-NMR (CDCl 3, δ): 3.305 (t, 2H,
J=5.0 Hz),3.35−3.63(m,8H),3.753 J = 5.0 Hz), 3.35-3.63 (m, 8H), 3.753
(m,1H),3.978 (m,1H),4.196 (brt, (M, 1H), 3.978 (m, 1H), 4.196 (brt,
1H),4.364 (ddd,1H,J=5.6 Hz,10.7H 1H), 4.364 (ddd, 1H, J = 5.6 Hz, 10.7H
z,8.3 Hz),4.467 (ddd,1H,J=7.1 H z, 8.3 Hz), 4.467 (ddd, 1H, J = 7.1 H
z,9.0 Hz),4.859 (d,1H,J=8.1 Hz), z, 9.0 Hz), 4.859 (d, 1H, J = 8.1 Hz),
5.524 (dd,1H,J=3.4 Hz),5.746 (dd, 5.524 (dd, 1H, J = 3.4 Hz), 5.746 (dd,
1H,J=10.5Hz),5.881 (brd,1H),7.14 1H, J = 10.5Hz), 5.881 (brd, 1H), 7.14
−7.62(m,19H),7.78−8.05(m,6H). -7.62 (m, 19H), 7.78-8.05 (m, 6H). (iv)化合物17−4の合成 化合物17−3(3.424 g)およびパラトルエンスルホン酸1水和物(739mg )をメタノール(20ml)および酢酸エチル(120ml )の混合溶媒に溶解し、リンドラー触媒(1.2 g)を加え、50psi の水素雰囲気下7時間撹拌した。 (Iv) Synthesis of Compound 17-4 17-3 (3.424 g) and p-toluenesulfonic acid monohydrate (739 mg) was dissolved in a mixed solvent of methanol (20ml) and ethyl acetate (120 ml), Lindlar catalyst ( 1.2 g) and the mixture was stirred under a hydrogen atmosphere for 7 hours of 50 psi.

【0263】触媒を濾過し、溶媒を減圧下留去して目的物(4.00g)を得た。 [0263] The catalyst was filtered to obtain the desired product (4.00 g) and the solvent was distilled off under reduced pressure. この化合物は特に精製をする事なく次の段階の合成に用いた。 This compound was used in the synthesis of the next stage without particular purification.

【0264】(v) 化合物18−1の合成 化合物17−4(2.00g)、2−パルミチルステアリン酸(1.188 g)、N−ヒドロキシスクシイミド(269mg ) [0264] (v) Synthesis of Compound 18-1 17-4 (2.00g), 2- palmityl stearate (1.188 g), N- hydroxysuccinimide (269 mg)
および4−ジメチルアミノピリジン(523mg )のDMF And 4-dimethylaminopyridine (523 mg) DMF
(100ml)溶液にN,N′ージシクロヘキシルカルボジイミド(482mg )を加え、室温下一晩撹拌した。 N, N 'over-dicyclohexylcarbodiimide (482 mg) was added to (100ml) solution and stirred at room temperature overnight. N,N′ N, N '
−ジシクロエキシルカルボジイミド(200mg )をさらに加え、さらに一晩撹拌した。 - further adding dicyanamide Chloe cyclohexyl carbodiimide (200 mg), and stirred further overnight.

【0265】折出したN,N′−ジシクロヘキシル尿素を濾去し、40℃にて溶媒を留去した。 [0265] folding out the N, it was filtered off N'- dicyclohexylurea, the solvent was distilled off at 40 ° C.. 残渣に酢酸エチル(40ml)を加え、不溶物を濾別した。 The residue ethyl acetate (40 ml) was added to, and insoluble matters were filtered off. 濾液を減圧下濃縮し、残渣を200ml のシリカゲルカラムクロマトグラフィーにて分離し(ヘキサン:酢酸エチル=2:1−1: The filtrate was concentrated under reduced pressure, the residue was separated by silica gel column chromatography 200 ml (hexane: ethyl acetate = 2: 1-1:
1)、目的物を得た。 1), the desired product was obtained. 773mg 。 773mg.

【0266】 [α] D 21 =+58.9°(c 1.13、CHCl 3 ). [0266] [α] D 21 = + 58.9 ° (c 1.13, CHCl 3). 1 H−NMR(CDCl 3 ,δ):0.877 (t,6H, 1 H-NMR (CDCl 3, δ): 0.877 (t, 6H,
J=6.9 Hz),1.16−1.34(m,56H),1.52−1.61 J = 6.9 Hz), 1.16-1.34 (m, 56H), 1.52-1.61
(m,4H),1.91−1.99(m,1H),3.30−3.33 (M, 4H), 1.91-1.99 (m, 1H), 3.30-3.33
(m,2H),3.35−3.63(m,8H),3.73−3.77 (M, 2H), 3.35-3.63 (m, 8H), 3.73-3.77
(m,1H),3.97−4.01(m,1H),4.196 (br (M, 1H), 3.97-4.01 (m, 1H), 4.196 (br
t,1H),4.357 (ddd,1H,J=5.6 Hz, t, 1H), 4.357 (ddd, 1H, J = 5.6 Hz,
10.7Hz,8.5 Hz),4.468 (ddd,1H,J=7. 10.7Hz, 8.5 Hz), 4.468 (ddd, 1H, J = 7.
1 Hz,9.0Hz),4.848 (d,1H,J=8.1 H 1 Hz, 9.0Hz), 4.848 (d, 1H, J = 8.1 H
z),5.523 (dd,1H,J=3.5 Hz),5.747 z), 5.523 (dd, 1H, J = 3.5 Hz), 5.747
(dd,1H,J=10.4Hz),5.878 (brd,1 (Dd, 1H, J = 10.4Hz), 5.878 (brd, 1
H),7.13−7.62(m,19H),7.77−8.05(m,6 H), 7.13-7.62 (m, 19H), 7.77-8.05 (m, 6
H). H). (vi)化合物18−2の合成 化合物18−1(506mg )および酸化白金(50mg)にテトラヒドロフラン(20ml)およびメタノール(10ml)を加え、一晩常圧の水素雰囲気下撹拌した。 (Vi) Compound 18-1 Compound 18-2 (506 mg) and platinum oxide (50 mg) in tetrahydrofuran (20ml) and methanol (10ml) was added, and stirred under a hydrogen atmosphere overnight normal pressure. 触媒を濾過し、 The catalyst was filtered,
溶媒を減圧下留去した。 The solvent was distilled off under reduced pressure. 残渣にメタノール(15ml)を加え溶解し、ナトリウムメチラートメタノール溶液(5モル/l)を20滴加えてpHを11とし、室温にて5時間撹拌した。 Residue was dissolved by adding methanol (15 ml), pH was between 11 sodium methylate methanol solution (5 mol / l) was added 20 drops, and stirred for 5 hours at room temperature.

【0267】溶液を1N塩酸にて中和した後、溶媒を減圧下留去した。 [0267] The solution was neutralized with 1N hydrochloric acid, and the solvent was evaporated under reduced pressure. 残渣をクロロフォルム:メタノール= The residue chloroform: methanol =
1:1の混合溶媒に溶解し、2.5 gのシリカゲルを加え、溶媒を減圧下留去した。 1 were dissolved in a mixed solvent of 1, added silica gel 2.5 g, and the solvent was evaporated under reduced pressure. 得られた乾燥シリカゲルを The resulting dried silica gel
150ml のクロロフォルム:メタノール:水=65:25:4 150ml of chloroform: methanol: water = 65: 25: 4
の溶媒混合物で充填したシリカゲルカラムに詰め、目的物を含むフラクションを採取した(22mmφ×400mm 、クロロフォルム:メタノール:水=65:25:4から2: Packed in a silica gel column packed in a solvent mixture, it was collected and fractions containing the desired product (22mmφ × 400mm, chloroform: methanol: water = 65: 25: 4 to 2:
2:0.5 までのグラジエント溶離、総量1000ml、100フラクション)。 2: gradient elution, the total amount 1000ml, 100 fractions of up to 0.5). フラクション13−41を濃縮した。 It was concentrated fractions 13-41. 残渣をクロロフォルム:メタノール=9:1の混合溶媒に溶解し、同溶剤で詰めた「Sephadex LH−20」 The residue chloroform: methanol = 9: was dissolved in a mixed solvent of 1, "Sephadex LH-20" packed in the same solvent
(22mmφ×400mm 、クロロフォルム:メタノール=9: (22mmφ × 400mm, chloroform: methanol = 9:
1溶離)にて分離した。 Were separated by 1 elution). フラクション5−8を濃縮して目的物を得た。 The desired product was obtained by concentration of the fractions 5-8. 201mg 。 201mg.

【0268】[α] D 28 =−3.8 °(c 1.09、クロロフォルム:メタノール=9:1). [0268] [α] D 28 = -3.8 ° (c 1.09, chloroform: methanol = 9: 1). Mass M/Z:882 (M+H). Mass M / Z: 882 (M + H). 1 H−NMR(CDCl 3 −CD 3 OD=5/1, 1 H-NMR (CDCl 3 -CD 3 OD = 5/1,
δ):0.884 (t,6H),1.20−1.33(m,56H), δ): 0.884 (t, 6H), 1.20-1.33 (m, 56H),
1.36−1.44(m,2H),1.51−1.59(m,2H),2. 1.36-1.44 (m, 2H), 1.51-1.59 (m, 2H), 2.
05−2.11(m,1H),3.416 (br t,2H,J= 05-2.11 (m, 1H), 3.416 (br t, 2H, J =
5.0 Hz),3.51−3.77(m,12H),3.931 (br 5.0 Hz), 3.51-3.77 (m, 12H), 3.931 (br
d,1H,J=1.0 Hz),4.01−4.20(m,3H), d, 1H, J = 1.0 Hz), 4.01-4.20 (m, 3H),
4.267 (d,1H,J=7.6 Hz). 4.267 (d, 1H, J = 7.6 Hz). 13 C−NMR(CDCl 3 −CD 3 OD=5/1, 13 C-NMR (CDCl 3 -CD 3 OD = 5/1,
δ):14.16 ,22.87 ,27.83 ,32.13 ,33.18 ,39.1 δ): 14.16, 22.87, 27.83, 32.13, 33.18, 39.1
8 ,47.88 ,64.55 (J=4.9 Hz),67.97 ,68.53 8, 47.88, 64.55 (J = 4.9 Hz), 67.97, 68.53
,70.17 ,70.31 ,70.51 ,70.60 ,71.51 ,73.33 , 70.17, 70.31, 70.51, 70.60, 71.51, 73.33
,73.54 (J=8.1 Hz),103.77,177.71. , 73.54 (J = 8.1 Hz), 103.77,177.71. 実施例3(リポソームの調製) 実施例1及び2で合成した本発明の化合物のうち化合物 Compound of Example 3 (Preparation of liposomes) compounds of the present invention synthesized in Examples 1 and 2
1205及び28−2を除く計16種の化合物のそれぞれを使用し、次のようにしてリポソームを調製した。 1205 and using the respective total of 16 kinds of compounds with the exception of 28-2, liposomes were prepared as follows.

【0269】L−α−ジパルミトイルホスファテジルコリン80μmol 、コレステロール80μmol 、ジセチルリン酸8μmol 及び本発明の化合物16μmol をクロロホルムおよびメタノールの濾液(容積比1:1)に溶かした。 [0269] L-alpha-dipalmitoyl phosphorylase Fateh choline 80Myumol, cholesterol 80Myumol, dicetylphosphate 8μmol and compounds 16μmol of chloroform and methanol filtrates of the present invention (volume ratio 1: 1) was dissolved in.
次に、窒素ガス気流中で有機溶媒を除去して遠沈管のガラス壁にリピッドフィルムを生成させた。 Next, to produce a lipid film on the glass wall of the centrifuge tube was removed and the organic solvent in a nitrogen gas stream.

【0270】ここに予め約45℃に加温した1mMイヌリンのリン酸緩衝化生理食塩水(pH 7.4)8mlを加えて振蘯し、更に軽く超音波処理してリポソームの懸濁液を調製した。 [0270] and shaken by adding phosphate buffered saline (pH 7.4) 8 ml of a previously about 45 ° C. to warmed 1mM inulin herein were prepared a suspension of liposomes is further lightly sonicated . これを45〜60℃に加温し、次いで0.08μmの孔径を有するポリカーボネート製メンブランフィルターを通過させ、粒径約0.08μmのリポソームの懸濁液を調製した。 This was warmed to 45 to 60 ° C., then passed through a polycarbonate membrane filter having a pore size of 0.08 .mu.m, was prepared a suspension of liposomes having a particle size of about 0.08 .mu.m.

【0271】なお、化合物1205及び28−2も、同様にしてリポソーム化できる。 [0271] The compound 1205 and 28-2 can also be liposomal similarly.

【0272】同様にして、本発明の化合物に替えて実施例1で合成した4種のコントロール化合物をそれぞれ使用してリポソームの懸濁液を調製した。 [0272] In the same manner, to prepare a suspension of liposomes using four control compounds instead of compound synthesized in Example 1 of the present invention, respectively.

【0273】実施例4(評価試験) イ. [0273] Example 4 (evaluation test) b. 試料 実施例1で合成した4種の本発明の化合物及び4種のコントロール化合物を使用して1mMイヌリンの代わりに3 3 instead of 1mM inulin using the compounds and four control compounds of the synthesized 4 kinds of the invention in the sample Example 1
H−イヌリン 140μCiを含有する1mMイヌリンを使用した以外は、実施例3におけると同様にして計8種のリポソームを得、これらを試料とした。 Except for using 1mM inulin containing H- inulin 140μCi may give to eight kinds of liposomes in the same manner as in Example 3, was them as samples.

【0274】ロ. [0274] b. 試験方法 用意した8種の試料をそれぞれSD系雄性ラット(体重 Test method a prepared 8 kinds of samples each SD male rats (body weight
200〜250 g)の後肢静脈より体重 100g当たりL−α 200~250 g than the hind leg vein) body weight 100g per L-α
−ジパルミトイルホスファチジルコリン及びコレステロールの合計として5μmol を注入した。 - 5 [mu] mol was injected as the sum of dipalmitoyl phosphatidylcholine and cholesterol.

【0275】投与後6時間後にラットを屠殺し、各種組織を約 200mg採り、乾燥後燃焼装置にて燃焼し、液体シンチレーション法によりその放射活性を求め、各臓器1 [0275] Rats were sacrificed 6 hours after the administration, various tissue about 200mg collected, combusted in the drying after combustion device, Searching for the radioactivity by a liquid scintillation method, each organ 1
gあたりのイヌリン濃度を求めた。 It was determined inulin concentration per g.

【0276】ハ. [0276] c. 結果 結果を、図23〜26に示す。 Results The results, shown in Figure 23-26.

【0277】この結果より、少なくとも2個のアルキル基を有する脂質誘導体を含有するリポソーム(本発明) [0277] From this result, liposomes containing lipid derivative having at least two alkyl groups (the present invention)
は、1個のアルキル基を有する化合物を使用した以外は本発明の方法と同じ方法で製造したリポソーム(コントロール)に比べ、臓器認識性の向上がみられる。 , Except using the compound having one alkyl group compared to liposomes (control) was prepared in the same manner as that of the present invention, improved organ recognizability is observed.

【0278】 [0278]

【発明の効果】本発明により、安定性に優れ、臓器指向性に優れ、そして薬物保持機能等に優れたリポソームが容易に提供されるところとなった。 According to the present invention, excellent stability, excellent organ directivity and a place where excellent liposomal drug holding function such as is readily provided.

【図面の簡単な説明】 BRIEF DESCRIPTION OF THE DRAWINGS

【図1】実施例1における反応を示す。 1 shows a reaction in Example 1.

【図2】実施例1における反応を示す。 Figure 2 shows a reaction in Example 1.

【図3】実施例1における反応を示す。 Figure 3 illustrates a reaction in Example 1.

【図4】実施例1における反応を示す。 4 shows a reaction in Example 1.

【図5】実施例1における反応を示す。 Figure 5 shows the reaction in Example 1.

【図6】実施例1における反応を示す。 Figure 6 shows the reaction in Example 1.

【図7】実施例1における反応を示す。 Figure 7 shows the reactions in Example 1.

【図8】実施例1における反応を示す。 8 shows a reaction in Example 1.

【図9】実施例2における反応を示す。 Figure 9 shows a reaction in Example 2.

【図10】実施例2における反応を示す。 Figure 10 shows a reaction in Example 2.

【図11】実施例2における反応を示す。 Figure 11 shows a reaction in Example 2.

【図12】実施例2における反応を示す。 Figure 12 shows a reaction in Example 2.

【図13】実施例2における反応を示す。 Figure 13 shows a reaction in Example 2.

【図14】実施例2における反応を示す。 Figure 14 shows a reaction in Example 2.

【図15】実施例2における反応を示す。 Figure 15 shows a reaction in Example 2.

【図16】実施例2における反応を示す。 Figure 16 shows a reaction in Example 2.

【図17】実施例2における反応を示す。 Figure 17 shows a reaction in Example 2.

【図18】実施例2における反応を示す。 Figure 18 shows a reaction in Example 2.

【図19】実施例2における反応を示す。 Figure 19 illustrates a reaction in Example 2.

【図20】実施例2における反応を示す。 Figure 20 illustrates a reaction in Example 2.

【図21】実施例2における反応を示す。 21 shows a reaction in Example 2.

【図22】実施例2における反応を示す。 Figure 22 shows a reaction in Example 2.

【図23】実施例4における結果を示す。 Figure 23 shows the results in Example 4.

【図24】実施例4における結果を示す。 Figure 24 shows the results of Example 4.

【図25】実施例4における結果を示す。 Figure 25 shows the results in Example 4.

【図26】実施例4における結果を示す。 Figure 26 shows the results in Example 4.

───────────────────────────────────────────────────── フロントページの続き (72)発明者 三好 詩郎 静岡県三島市安久206−1 田村ハイツ 5号 (72)発明者 青野 勝利 奈良県奈良市学園朝日元町2−529−4 エクセルハイツB−308 (72)発明者 山内 仁史 東京都葛飾区奥戸2−32−12 (72)発明者 村橋 直一 茨城県北相馬郡守谷町松前台7−2−4 (72)発明者 佐々木 淳 茨城県つくば市春日4−19−13 エーザ イ紫山寮307 (72)発明者 渡辺 宏 千葉県松戸市新松戸7−131 セブンピ ア301 (72)発明者 金子 英雄 神奈川県横浜市南区中村町1−1−25 (58)調査した分野(Int.Cl. 6 ,DB名) A61K 9/127 A61K 47/28 ────────────────────────────────────────────────── ─── of the front page continued (72) inventor Miyoshi Shiro Mishima, Shizuoka Yasuhisa 206-1 Tamura Heights No. 5 (72) inventor Katsutoshi Aono Nara, Nara Prefecture Gakuen'asahimoto-cho 2-529-4 Excel Heights B-308 (72) inventor Hitoshi Yamauchi Katsushika-ku, Tokyo Okudo 2-32-12 (72) inventor Naokazu Murahashi Ibaraki Prefecture Kitasōma District Moriya-cho, Matsumaedai 7-2-4 (72) inventor Atsushi Sasaki Tsukuba, Ibaraki Prefecture Kasuga 4-19-13 Eisai Purple Mountain dormitory 307 (72) inventor Hiroshi Watanabe Matsudo, Chiba Prefecture Matsudo 7-131 Sebunpi A 301 (72) inventor Hideo Kaneko, Yokohama, Kanagawa Prefecture, Minami-ku, Nakamura-cho 1-1-25 ( 58) investigated the field (Int.Cl. 6, DB name) A61K 9/127 A61K 47/28

Claims (4)

    (57)【特許請求の範囲】 (57) [the claims]
  1. 【請求項1】 原材料として、少なくとも、 (1)極性脂質1モル、 (2)正電荷または負電荷を与える化合物0.05 As claimed in claim 1] Raw materials, at least, (1) polar lipids 1 mol, give (2) a positive or negative charge Compound 0.05
    〜0.5 モル、 (3)コレステロール 0.3〜1.5モル、 (4) 0.5 mol, (3) cholesterol 0.3 to 1.5 mol, (4)
    分子中に臓器指向性センサー、重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物0.02〜0.5 モル並びに(5)水性溶媒50〜100 lをこの割合で使用することを特徴とするリポソームの製造法。 Organ directional sensor in the molecule, compounds 0.02 to 0.5 mole with a polyethylene glycol and at least two alkyl groups of carbon number 5-20 of polymerization degree 3-6 and (5) the aqueous solvent 50 to 100 l at this ratio preparation of liposomes, characterized in that it uses.
  2. 【請求項2】 (1)極性脂質1モル、 (2)正電荷または負電荷を与える化合物0.05〜0.5 モル、 (3)コレステロール 0.3〜1.5 モル、及び(4)分子中に臓器指向性セン Wherein (1) polar lipids 1 mol, (2) Compound 0.05 mole which gives a positive or negative charge, (3) cholesterol 0.3-1.5 mol, and (4) Organ directional sensor in the molecule
    サー重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物0. Compounds having a polyethylene glycol and at least two alkyl groups having a carbon number of 5-20 Sir polymerization degree 3-6 0.
    02〜0.5 モルをこの割合で含有する有機溶媒より溶媒を除去してリピッドフィルムを生成させ、ついでリポソームに包含させるべき薬剤の水性溶液を極性脂質1モルに対し50〜100 lを該リピッドフィルムに加えてリポソームを形成させ、更に粒径50〜1000nmのリポソームを選択採取することを特徴とする請求項1記載のリポソームの製造法。 02 to 0.5 mol to produce a lipid film by removing the solvent from the organic solvent containing at this rate, then 50 to 100 l of an aqueous solution to the polar lipid 1 mole of the drug to be included in the liposome to the lipid film in addition to forming liposomes further preparation of liposomes according to claim 1, wherein the selecting collecting liposome particle size 50-1000 nm.
  3. 【請求項3】 (1)極性脂質1モル、 (2)正電荷または負電荷を与える化合物0.05〜0.5 モル、 (3)コレステロール 0.3〜1.5 モル並びに(4)分子中に臓器指向性セン 3. (1) polar lipids 1 mol, (2) Compound 0.05 mole which gives a positive or negative charge, (3) cholesterol 0.3-1.5 mol and (4) Organ directional sensor in the molecule
    サー、重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜20のアルキル基を有する化合物 Sir, compounds having a polyethylene glycol and at least two alkyl groups of carbon number 5-20 of polymerization degree 3-6
    0.02〜0.5 モルをこの割合で含有する有機溶媒にリポソームに包含させるべき薬剤の水性溶液を極性脂質1モルに対し50〜100 lを加え、ついでこの混合溶液を超音波処理してw/o型エマルジョンとした後減圧下に有機溶媒を除去し、更にボルテキシングを行ってo/w型エマルジョンとした後に必要により再び有機溶媒を減圧下に除去することを特徴とする請求項1記載のリポソームの製造法。 0.02 mole of an aqueous solution of the agent to be included in the liposome in an organic solvent containing polar lipids relative to 1 mole of 50 to 100 l was added at this rate, then w / o type and sonicated the mixture the organic solvent was removed under reduced pressure after the emulsion, further preparation of liposomes according to claim 1, wherein the re-organic solvent as necessary after the o / w type emulsion performs vortexed and removing under reduced pressure law.
  4. 【請求項4】 原材料として、少なくとも、 (1)極性脂質1モル、 (2)正電荷荷または負電荷を与える化合物0. As wherein the raw material, at least, (1) polar lipids 1 mol, (2) compound gives a positive charge load or negative charge 0.
    05〜0.5 モル、 (3)コレステロール0.3 〜1.5 モル並び 05 to 0.5 mol, (3) cholesterol from 0.3 to 1.5 mol list
    に(4)分子中に臓器指向性センサー、重合度3〜6のポリエチレングリコール及び少なくとも2個の炭素数5〜 To (4) Organ directional sensor in the molecule, polyethylene glycol having a degree of polymerization of 3-6 and at least two carbon number 5
    20のアルキル基を有する化合物0.02〜0.5 モルをこの割合で含有し、かつ、薬剤を含有する有機溶媒並びに極性脂質1モル当り水性溶媒50〜100 lをこの割合で使用することを特徴とするリポソームの製造法。 Compounds 0.02 to 0.5 mol of an alkyl group having 20 contained in this ratio, and liposomes, characterized in that the organic solvent and polar lipid per mole aqueous solvent 50 to 100 l containing the drug used in this proportion method of production.
JP26089392A 1992-09-03 1992-09-03 Process for the preparation of liposomes Expired - Lifetime JP2854203B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP26089392A JP2854203B2 (en) 1992-09-03 1992-09-03 Process for the preparation of liposomes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP26089392A JP2854203B2 (en) 1992-09-03 1992-09-03 Process for the preparation of liposomes

Publications (2)

Publication Number Publication Date
JPH0680560A JPH0680560A (en) 1994-03-22
JP2854203B2 true JP2854203B2 (en) 1999-02-03

Family

ID=17354221

Family Applications (1)

Application Number Title Priority Date Filing Date
JP26089392A Expired - Lifetime JP2854203B2 (en) 1992-09-03 1992-09-03 Process for the preparation of liposomes

Country Status (1)

Country Link
JP (1) JP2854203B2 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6120794A (en) * 1995-09-26 2000-09-19 University Of Pittsburgh Emulsion and micellar formulations for the delivery of biologically active substances to cells
SG190613A1 (en) 2003-07-16 2013-06-28 Protiva Biotherapeutics Inc Lipid encapsulated interfering rna
NZ592917A (en) * 2003-09-15 2012-12-21 Protiva Biotherapeutics Inc Stable polyethyleneglycol (PEG) dialkyloxypropyl (DAA) lipid conjugates
JP2005170923A (en) * 2003-10-21 2005-06-30 Konica Minolta Medical & Graphic Inc Lyposome-containing x ray-imaging agent and method for producing the same
JP2005220034A (en) * 2004-02-03 2005-08-18 Konica Minolta Medical & Graphic Inc Method for producing contrast medium for roentgenologic examination
JP4654590B2 (en) * 2004-03-31 2011-03-23 コニカミノルタエムジー株式会社 Contrast composition for X-ray CT and method for producing the same
US7799565B2 (en) 2004-06-07 2010-09-21 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering RNA
US7588751B2 (en) * 2004-07-21 2009-09-15 Konica Minolta Medical & Graphic, Inc. Liposome-containing radiographic contrast medium and preparation method thereof
JP5176320B2 (en) * 2004-08-11 2013-04-03 コニカミノルタエムジー株式会社 Method for producing liposome-containing preparation
JP5087924B2 (en) * 2004-08-26 2012-12-05 日本新薬株式会社 Galactose derivatives, drug carriers and pharmaceutical compositions
JP5303269B2 (en) 2005-06-06 2013-10-02 学校法人早稲田大学 Bone marrow-directed drug delivery materials and uses thereof
KR100744825B1 (en) * 2006-02-08 2007-07-25 한국화학연구원 Liposomes modified with polyethyleneglycol-containing comb-type polymer and their formulation thereof
CA2721333A1 (en) 2008-04-15 2009-10-22 Protiva Biotherapeutics, Inc. Novel lipid formulations for nucleic acid delivery
US9018187B2 (en) 2009-07-01 2015-04-28 Protiva Biotherapeutics, Inc. Cationic lipids and methods for the delivery of therapeutic agents
US8569256B2 (en) 2009-07-01 2013-10-29 Protiva Biotherapeutics, Inc. Cationic lipids and methods for the delivery of therapeutic agents
ES2613498T3 (en) 2009-07-01 2017-05-24 Protiva Biotherapeutics Inc. New lipid formulations for the delivery of therapeutic agents to solid tumors
US9006417B2 (en) 2010-06-30 2015-04-14 Protiva Biotherapeutics, Inc. Non-liposomal systems for nucleic acid delivery
JP6238366B2 (en) * 2012-08-28 2017-11-29 国立大学法人北海道大学 Lipid membrane structure encapsulating bacterial cell component dispersible in nonpolar solvent and method for producing the same

Also Published As

Publication number Publication date
JPH0680560A (en) 1994-03-22

Similar Documents

Publication Publication Date Title
US5604207A (en) Sialyl Lex analogues as inhibitors of cellular adhesion
CA2140013C (en) Pharmaceutical compositions containing galactosylceramides
CN1143859C (en) Camptothecin derivative and its preparation
AU620901B2 (en) Lipid derivatives of antiviral nucleosides, liposomal incorporation and method of use
KR880001232B1 (en) Process for the preparation of new ganglioside derivatives
AU683026B2 (en) Novel shingoglycolipid and use thereof
EP0694558B1 (en) Novel sphingoglycolipid and use thereof
JP5090928B2 (en) Glycolipids and their analogs as antigens for NKT cells
Sammar et al. Heat-stable antigen (CD24) as ligand for mouse P-selectin
US5169636A (en) Liposomes
Danishefsky et al. Application of the glycal assembly method to the concise synthesis of neoglycoconjugates of Ley and Leb blood group determinants and of H-type I and H-type II oligosaccharides
US6113918A (en) Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
US6171614B1 (en) Synthesis of glycophospholipid and peptide-phospholipid conjugates and uses thereof
EP0823913B1 (en) Synthesis of the breast tumor-associated antigen defined by monoclonal antibody mbr1 and uses thereof
JP3865411B2 (en) Anti - endotoxin compound
EP1549322B1 (en) Lipid a and other carbohydrate ligand analogs
US5936076A (en) αgalactosylceramide derivatives
US20040102607A1 (en) Trimeric antigenic O-linked glycopeptide conjugates, methods of preparation and uses thereof
Danishefsky et al. A Highly Convergent Total Synthetic Route to Glycopeptides Carrying a High‐Mannose Core Pentasaccharide Domain N‐linked to a Natural Peptide Motif
FI105189B (en) Process for the preparation of novel glycosphingolipids
US5885968A (en) Triantennary cluster glycosides, their preparation and use
EP0688329B1 (en) Novel phospholipid-saccharide conjugates
US6645935B2 (en) Synthesis of glycoconjugates of the lewis Y epitope and uses thereof
AU750701B2 (en) Alpha-O-linked glycoconjugates, methods of preparation and uses thereof
CA1105011A (en) Synthesis of 2-amino-2-deoxyglycoses and 2-amino-2- deoxyglycosides from glycals