JPH07109288A - Novel 16-membered macrolide derivative and novel production process thereof - Google Patents
Novel 16-membered macrolide derivative and novel production process thereofInfo
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- JPH07109288A JPH07109288A JP19438494A JP19438494A JPH07109288A JP H07109288 A JPH07109288 A JP H07109288A JP 19438494 A JP19438494 A JP 19438494A JP 19438494 A JP19438494 A JP 19438494A JP H07109288 A JPH07109288 A JP H07109288A
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Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明はグラム陽性菌に有効な新
規な16員環マクロリド誘導体とそれらの新規製造法に
関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel 16-membered ring macrolide derivatives which are effective against Gram-positive bacteria and a novel method for producing them.
【0002】[0002]
【従来の技術】医薬品における抗菌剤の占める役割は重
要であり、臨床における、特に小児科領域等での安全性
並びに主に経口での投与形態等を考慮すると、グラム陽
性菌、マイコプラズマ、及びクラミジア等に有効なマク
ロリド系抗生物質は必要不可欠な抗菌剤として分類され
る。最近では、着目した感染症の起因菌が次第に特定化
されるに至り、マクロリド系抗生物質の臨床での重要性
が増加している。本発明者らは患者のクオリティー・オ
ブ・ライフを第一に考え、腸管に与える影響が少なく、
他の薬剤との相互作用の少ない16員環マクロリド系抗
生物質を研究対象に選択し、各種グラム陽性菌に有効で
あり、in vivoにおいて抗菌力の持続する誘導体の合成
化学的及び生化学的探索研究を重ねてきた。2. Description of the Related Art The role of antibacterial agents in pharmaceuticals is important, and in consideration of clinical safety, especially in the pediatric field and mainly oral administration forms, Gram-positive bacteria, mycoplasma, chlamydia, etc. Effective macrolide antibiotics are classified as indispensable antibacterial agents. Recently, the causative bacteria of infectious diseases of interest have been gradually specified, and the clinical importance of macrolide antibiotics is increasing. The present inventors consider the quality of life of patients first, and have little influence on the intestinal tract,
A 16-membered macrolide antibiotic with low interaction with other drugs was selected as a research object, and it was effective against various Gram-positive bacteria and was searched for synthetic chemical and biochemical activity of a derivative with long-lasting antibacterial activity in vivo . I have been carrying out research.
【0003】始めに本発明者らは、「優れた臨床効果を
有するミオカマイシン(MOM)(ジャーナル・オブ・
アンチビオチックス, 29(5), 536(1976)、ジャパニーズ
・ジャーナル・オブ・アンチビオチックス, 35(6), 146
2(1982))でさえ、生体内での代謝によりマイカロース
部分のアシル基が切断されてin vitroの抗菌活性が低下
する」という事実(薬学雑誌, 102(8), 781(1982))を
ドラッグデザインにフィードバックし、新しい思想の下
に誘導体のデザインを行なった。即ち生体内でより安定
であり、たとえ代謝されても抗菌活性が低下しにくい1
6員環マクロリド誘導体を指向し合成化学的研究を重ね
た結果、16員環マクロリド誘導体のマイカロース部分
の2つの水酸基が共にアルキル基によりエーテル結合し
た誘導体を新しく合成する事に成功し、in vitroにおい
て抗菌活性が顕著に持続する事を証明し特許出願した
(特願平4-39013)。[0003] First, the inventors of the present invention said, "Myokamycin (MOM) (Journal of
Antibiotics, 29 (5), 536 (1976), Japanese Journal of Antibiotics, 35 (6), 146
2 (1982)), the in vitro metabolism cleaves the acyl group of the mycarose moiety, reducing the in vitro antibacterial activity ”(Pharmaceutical Journal, 102 (8), 781 (1982)). We fed back to the drug design and designed the derivative based on a new idea. That is, it is more stable in vivo, and its antibacterial activity is less likely to decrease even if it is metabolized.
6-membered macrolide derivatives directed to a result of repeated synthetic chemical studies and succeeded in two hydroxyl groups of mycarose portion of 16-membered macrolide derivative together newly synthesized ether linked derivatives with alkyl groups, in vitro Has proved that the antibacterial activity lasts remarkably, and applied for a patent (Japanese Patent Application No. 4-39013).
【0004】次いで、それら誘導体の9位のカルボニル
基を天然型の立体配置を有する水酸基へと微生物変換す
る事により、優れた体内動態を示す新規16員環マクロ
リド誘導体を造出し、特許出願した(特願平4-29143
8)。さらに本発明者らは、これら誘導体のラクトン環
の3位水酸基に結合するアシル基を微生物変換を用いて
切断する事により、ロイコマイシン類誘導体中最も優れ
た部類のin vitroの抗菌活性を有し、マイカロース部分
がいたって代謝されにくい新規16員環マクロリド誘導
体を創製する事に成功し、特許出願した(特願平5-1162
31)。Then, by microbial conversion of the carbonyl group at the 9-position of these derivatives into hydroxyl groups having a natural configuration, a novel 16-membered ring macrolide derivative exhibiting excellent pharmacokinetics was created and applied for a patent. (Japanese Patent Application No. 4-29143
8). Furthermore, the present inventors have the most excellent class of in vitro antibacterial activity among leucomycin derivatives by cleaving the acyl group bonded to the 3-position hydroxyl group of the lactone ring of these derivatives using microbial conversion. , Succeeded in creating a novel 16-membered ring macrolide derivative in which the mycalose moiety is not easily metabolized, and filed a patent application (Japanese Patent Application No. 5-1162).
31).
【0005】[0005]
【発明が解決しようとする課題】最近本発明者らにより
調製されたマイカロース部分に2つのエーテル結合を有
し、かつ9位が天然型立体配置を有する水酸基である新
規16員環マクロリド誘導体、例えば4"-O-デプロピオ
ニル-4"-O-イソアミル-3"-O-メチルミデカマイシンA
1(特願平4-291438)は、そのマイカロース部分がエス
テラーゼによる攻撃を受けにくく、かつ9位が水酸基で
あることにより、近年上市された16員環マクロリド抗
生物質と比較して、マウス動物実験における血清中濃度
及びその持続性、並びに尿中回収率は顕著に改善され
た。またそれらのラクトン環の3位水酸基に結合したア
シル基を切断した誘導体、例えば4"-O-イソアミル-3"-O
-メチルロイコマイシンV(特願平5-116231)は、極めて
優れたin vitroの抗菌活性を有していた。A novel 16-membered ring macrolide derivative having two ether bonds in the mycalose moiety and a hydroxyl group having a natural configuration at the 9-position, which was recently prepared by the present inventors, For example 4 "-O-depropionyl-4" -O-isoamyl-3 "-O-methylmidecamycin A
1 (Japanese Patent Application No. 4-291438) is a mouse animal compared with the recently marketed 16-membered macrolide antibiotic because its mycalose part is not easily attacked by esterase and the 9-position is a hydroxyl group. Serum concentration and its persistence in the experiment, and urinary recovery were significantly improved. Derivatives obtained by cleaving the acyl group bonded to the 3-hydroxyl group of those lactone rings, such as 4 "-O-isoamyl-3" -O
-Methylleucomycin V (Japanese Patent Application No. 5-116231) had extremely excellent in vitro antibacterial activity.
【0006】しかしながらこれらの誘導体を実際に調製
するにあたっては、中性糖を導入するための、位置及び
立体選択的グリコシル化反応を含む多工程の化学反応
(特願平4-39013)と、一段階の、或いは連続する二段
階の微生物変換を実施する事が必要であり、これらの誘
導体を製造するために要するコスト並びに時間は、必ず
しも完全に満足し得るものではない。同時に当該グリコ
シル化反応においては、危険であり取扱いに注意を要す
る活性化剤を化学量論的に用いる必要があり、そのスケ
ール・アップには問題が無かった訳ではない。また、当
該グリコシル化反応にて実際に用いたグリコシル・ドナ
ーの3位の3級水酸基はいずれもメチル化されており、
メチル基以外のアルキル基が導入された中性糖のグリコ
シル・ドナーを用いて、当該グリコシル化反応を実施し
た例は報告されていない。However, in order to actually prepare these derivatives, a multi-step chemical reaction including a regio- and stereoselective glycosylation reaction for introducing a neutral sugar (Japanese Patent Application No. 4-39013) and It is necessary to carry out a two-step or continuous two-step microbial conversion, and the costs and the time required to produce these derivatives are not always completely satisfactory. At the same time, in the glycosylation reaction, an activator that is dangerous and requires careful handling needs to be used stoichiometrically, and there is no problem in its scale-up. Further, the tertiary hydroxyl group at the 3-position of the glycosyl donor actually used in the glycosylation reaction is methylated,
No example has been reported of carrying out the glycosylation reaction using a glycosyl donor of a neutral sugar having an alkyl group other than a methyl group introduced.
【0007】そこで、グリコシル化反応を用いる事無
く、本発明者らが特許出願したマイカロース部分の2つ
の水酸基が共にアルキル基によりエーテル結合した16
員環マクロリド誘導体を化学合成により製造する方法に
関する発明が期待されている。さらにその方法を用いる
事により、ラクトン環の3位が遊離の水酸基であり、9
位が遊離の水酸基であり、マイカロース部分の2つの水
酸基が共に同一の、或いは異なるアルキル基によりエー
テル結合した種々の16員環マクロリド誘導体、特に3"
位の3級水酸基にメチル基以外のアルキル基が導入され
た誘導体の出現が期待されている。事実、マイカロース
部分の3"位の3級水酸基にメチル基以外のアルキル基が
導入された16員環マクロリド誘導体は、天然物も含め
現在までのところ全く知られていない。Therefore, without using the glycosylation reaction, the two hydroxyl groups of the mycarose moiety for which the present inventors applied for a patent were both ether-bonded with an alkyl group.
An invention relating to a method for producing a membered ring macrolide derivative by chemical synthesis is expected. Furthermore, by using this method, the 3-position of the lactone ring is a free hydroxyl group,
Various 16-membered macrolide derivatives in which the position is a free hydroxyl group and the two hydroxyl groups of the mycarose moiety are both ether-bonded with the same or different alkyl groups, especially 3 "
It is expected that a derivative in which an alkyl group other than a methyl group is introduced into the tertiary hydroxyl group at the position will appear. In fact, a 16-membered macrolide derivative in which an alkyl group other than a methyl group has been introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose moiety, including natural products, has not been known so far.
【0008】ところで16員環マクロリド抗生物質の化
学修飾において、グリコシル化反応を経由すること無く
マイカロース部分の4"位の2級水酸基にアルキル基を導
入した例が知られている。大村・佐野らは、スピラマイ
シンIの3,18位で形成するヘミアセタール性の水酸基を
シリル基で保護するなどして、マイカロース部分の4"位
の2級水酸基にアルキル基を導入している(特開昭60-5
8998、特開昭60-239494)。一方吉岡らは、16員環マ
クロリド誘導体のマイカロース部分の2つの水酸基をジ
・アルキル錫で修飾するなどして、それらの内の1つで
ある4"位の2級水酸基にベンジル基等を導入している
(特開昭62-234093)。しかしながら現在までのとこ
ろ、グリコシル化反応を経由せずに16員環マクロリド
誘導体のマイカロース部分の3"位の3級水酸基に、アル
キル基を導入した反応に関しては報告がない。By the way, in the chemical modification of a 16-membered macrolide antibiotic, an example is known in which an alkyl group is introduced into the secondary hydroxyl group at the 4 "-position of the mycarose moiety without going through a glycosylation reaction. Have introduced an alkyl group into the secondary hydroxyl group at the 4 "-position of the mycarose moiety by protecting the hemiacetal hydroxyl group formed at the 3,18-position of spiramycin I with a silyl group. Kaisho 60-5
8998, JP-A-60-239494). On the other hand, Yoshioka et al. Modified the two hydroxyl groups of the 16-membered macrolide derivative of the mycarose moiety with dialkyl tin, and added a benzyl group to the secondary hydroxyl group at the 4 "position, which is one of them. However, up to now, an alkyl group has been introduced to the tertiary hydroxyl group at the 3 "-position of the mycalose portion of the 16-membered ring macrolide derivative without going through the glycosylation reaction. There is no report on the reaction.
【0009】[0009]
【課題を解決するための手段】本発明者らは上記の期待
に応えるべく合成化学的研究を重ね、相間移動触媒を用
いる特定の脱アシル化反応を実用化し、さらに塩酸又は
シリカゲル等を用いるシリル基の選択的脱保護法を新た
に開発した。それらの新技術を有機的に組み立てる事に
より、天然に存在する公知の16員環マクロリド抗生物
質であるロイコマイシンFrグループ、例えばロイコマイ
シンA7(ジャーナル・オブ・アンチビオチックス, Ser.
A, 20(4), 234(1967))を出発物質として5工程ないし
は6工程の化学反応を経て、ラクトン環の3位が遊離の
水酸基であり、9位が遊離の水酸基であり、マイカロー
ス部分の2つの水酸基が共に同一の、或いは異なるアル
キル基によりエーテル結合している16員環マクロリド
誘導体を効率良く合成する事に成功した。しかも本発明
製造法を用いて、マイカロース部分の3"位の3級水酸基
にメチル基以外のアルキル基を導入した誘導体を含む新
規の誘導体を多数合成し、それらが臨床上重要なグラム
陽性菌の発育を強く阻止する事を見い出し、本発明を完
成した。Means for Solving the Problems The present inventors have repeatedly conducted synthetic chemical research in order to meet the above expectations, put a specific deacylation reaction using a phase transfer catalyst into practical use, and further used silyl using hydrochloric acid or silica gel. A new method for selective deprotection of groups was newly developed. By organically assembling these new technologies, the known naturally occurring 16-membered macrolide antibiotics, the leucomycin Fr group, such as leucomycin A 7 (Journal of Antibiotics, Ser.
A, 20 (4), 234 (1967)) as a starting material and undergoing a chemical reaction in 5 or 6 steps, the 3-position of the lactone ring is a free hydroxyl group, the 9-position is a free hydroxyl group, and mycarose We succeeded in efficiently synthesizing a 16-membered ring macrolide derivative in which the two hydroxyl groups of both moieties are ether-bonded by the same or different alkyl groups. Moreover, by using the production method of the present invention, a large number of novel derivatives including a derivative in which an alkyl group other than a methyl group has been introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose portion are synthesized, and these are clinically important Gram-positive bacteria. The present invention has been completed by finding that the growth of peaches is strongly inhibited.
【0010】第一の本発明の要旨とするところは、新規
化合物としての次の式(I)The gist of the first aspect of the present invention resides in the following formula (I) as a novel compound.
【化4】 [Chemical 4]
【0011】[式中、R1は水素原子又は式CORの基(但
しRは炭素数1〜3の直鎖のアルキル基)であり、R2は
水素原子又は式CORの基(但しRは前記と同じ意味を持
つ)であり、R3は炭素数1〜4の直鎖のアルキル基、置
換された又は置換されていないアリル基であり、R4は置
換された又は置換されていない炭素数1〜10の直鎖又
は分枝鎖のアルキル基、アルケニル基又はアラルキル
基]で表される化合物、又はその薬学的に許容し得る塩
に関するものである。本発明による一般式(I)で表さ
れる化合物は、R1及びR2がいずれも水素原子である場合
を除き、次の式(III)[Wherein R 1 is a hydrogen atom or a group of formula COR (where R is a linear alkyl group having 1 to 3 carbon atoms), R 2 is a hydrogen atom or a group of formula COR (where R is R 3 is a linear alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R 4 is a substituted or unsubstituted carbon group. A linear or branched alkyl group, alkenyl group or aralkyl group of the formulas 1 to 10], or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) according to the present invention has the following formula (III) except that R 1 and R 2 are both hydrogen atoms.
【化5】 [Chemical 5]
【0012】[式中、R3は炭素数1〜4の直鎖のアルキ
ル基、置換された又は置換されていないアリル基であ
り、R4は置換された又は置換されていない炭素数1〜1
0の直鎖又は分枝鎖のアルキル基、アルケニル基又はア
ラルキル基]で表される化合物、又はその塩を用いて、
9位及び/又はマイカミノース部分の2'位の水酸基に対
し公知の選択的或いは非選択的合成化学反応(発酵と工
業, 37(12), 1171(1979))を実施する事によって容易に
製造される。[Wherein R 3 is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R 4 is a substituted or unsubstituted C 1 to C 1 1
0 straight chain or branched chain alkyl group, alkenyl group or aralkyl group] or a salt thereof,
It is easily produced by carrying out a known selective or non-selective synthetic chemical reaction (fermentation and industry, 37 (12), 1171 (1979)) for the hydroxyl group at the 9-position and / or the 2'-position of the mycaminose moiety. It
【0013】第二の本発明の要旨とするところは、次の
式(II)The gist of the second invention is that the following formula (II)
【化6】 [Chemical 6]
【0014】[式中、R5は炭素数2〜5の直鎖又は分枝
鎖の脂肪族アシル基]で表される化合物、又はその塩を
出発原料として用いて、次の式(III)[Wherein R 5 is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms] or a salt thereof as a starting material, and the following formula (III)
【化7】 [Chemical 7]
【0015】[式中、R3は炭素数1〜4の直鎖のアルキ
ル基、置換された又は置換されていないアリル基であ
り、R4は置換された又は置換されていない炭素数1〜1
0の直鎖又は分枝鎖のアルキル基、アルケニル基又はア
ラルキル基]で表される化合物、又はその塩を効率よく
化学合成する事のできる新規製造法に関するものであ
る。本発明による一般式(III)で表される化合物は、
工程図1に示す方法により以下の様に製造される。[In the formula, R 3 is a linear alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R 4 is a substituted or unsubstituted C 1 to C 1 1
0 straight-chain or branched alkyl group, alkenyl group or aralkyl group], or a salt thereof, can be chemically synthesized efficiently. The compound represented by the general formula (III) according to the present invention is
It is manufactured as follows by the method shown in the process drawing 1.
【0016】[0016]
【化8】 [Chemical 8]
【0017】[0017]
【化9】 [Chemical 9]
【0018】始めにマクロリド系化合物における水酸基
のアルキル化に関して簡単に触れる。遊離の水酸基にア
ルキル側鎖を導入しエーテル結合を形成する方法はいく
つか知られている。しかしながら根本的には、古典的で
ありよく知られた強塩基を用いるウイリアムソン反応を
修飾した方法に過ぎず、メチル化、アリル化及びベンジ
ル化等比較的反応性の良いアルキル化を除き、穏和な反
応条件でのエーテル結合の生成反応はあまり知られてい
ない。ところで14員環マクロリド系化合物では、ラク
トン環のエステル結合の両近接部位が主にC-メチル基
(2位)及びC-エチル基(13位)であるが、これに対し
て16員環、例えばロイコマイシン類では同両近接部位
が主に水素原子(2位)及びC-メチル基(15位)であ
る。それ故、それらの立体障害及び2位の電子的要因等
を主な理由として、塩基性条件下における14員環ラク
トンのエステル結合は、ロイコマイシン類の16員環ラ
クトンのエステル結合に比較して有意に安定である。そ
の一例として、14員環マクロリド系化合物における中
性糖部分の2級水酸基のメチル化は、他の水酸基の保護
を行なう事により容易に進行する(ジャーナル・オブ・
アンチビオチックス, 43(5), 566(1990))。First, a brief description will be given of alkylation of hydroxyl groups in macrolide compounds. Several methods are known for introducing an alkyl side chain into a free hydroxyl group to form an ether bond. However, basically, it is only a modified method of the Williamson reaction using a classical and well-known strong base. The formation reaction of ether bond under various reaction conditions is not well known. By the way, in the 14-membered ring macrolide compound, the sites near both sides of the ester bond of the lactone ring are mainly C-methyl group (2-position) and C-ethyl group (13-position). For example, in leucomycins, both adjacent sites are mainly hydrogen atom (2nd position) and C-methyl group (15th position). Therefore, the ester bond of the 14-membered ring lactone under basic conditions is more likely to be compared with the ester bond of the 16-membered ring lactone of the leucomycins, mainly due to their steric hindrance and electronic factors at the 2-position. It is significantly stable. As an example, the methylation of the secondary hydroxyl group of the neutral sugar moiety in the 14-membered ring macrolide compound can be facilitated by protecting the other hydroxyl group (Journal of
Antibiotics, 43 (5), 566 (1990)).
【0019】即ち16員環マクロリド系化合物、特にロ
イコマイシン類においては、上述したラクトン環のエ
ステル結合の他に、ラクトン環の3位の近傍及び、
アルデヒド基等、強塩基条件下において不安定な官能基
が多く存在する。然るに、マイカロース部分の2級(4"
位)及び3級(3"位)の水酸基に対して効率よく順次ア
ルキル基を導入していくためには、大村・佐野らが4"位
のアルキル化に際してその有用性を実証したスピラマイ
シンIに関するシリル基による保護法(特開昭60-5899
8、特開昭60-239494)を発展的に修飾し、さらにロイコ
マイシン類に応用する事が理想的であると考えられた。That is, in a 16-membered ring macrolide compound, especially leucomycin, in addition to the ester bond of the lactone ring described above, the vicinity of the 3-position of the lactone ring, and
There are many functional groups that are unstable under strong basic conditions such as aldehyde groups. By the way, the second grade of the micarose part (4 "
Position) and tertiary (3 "position) hydroxyl groups can be efficiently and sequentially introduced by Omura and Sano et al. Protection method using silyl group (JP-A-60-5899)
It was thought that it would be ideal to modify 8 and JP-A-60-239494) progressively and further apply it to leucomycins.
【0020】第一に、天然に存在する16員環マクロリ
ド抗生物質であるロイコマイシンFrグループ(ジャーナ
ル・オブ・アンチビオチックス, 28(6), 401(1975))
の、シリル基による水酸基及びアルデヒド基の保護につ
いて述べる。式(II)(式中、R5はアシル基である)で
表される化合物、即ちロイコマイシンFrグループの単一
化合物又は複数成分の混合物、或いはそれらの塩に対
し、塩基存在下に必要量の、或いは過剰量のシリル化試
薬と反応させる事により、3,18位で形成したヘミアセタ
ール性の水酸基、9位及び2'位の水酸基がそれぞれシリ
ル化された式(IV)(式中、R5はアシル基であり、R6は
シリル保護基である)で表される化合物又はその塩を得
る。例えば、ロイコマイシンA7(式(II)において、R5
がプロピオニル基で表される化合物)をジメチルホルム
アミド(DMF)中、イミダゾールの存在下にt-ブチルジ
メチルシリルクロリド(TBDMSCl)と反応させて、3,18
位で形成したヘミアセタール性の水酸基、9位及び2'位
の水酸基の合計3つの水酸基がそれぞれt-ブチルジメチ
ルシリル(TBDMS)化された化合物(1)(式(IV)に
おいて、R5がプロピオニル基で表され、R6がTBDMS基で
表される化合物)を高収率で得た(なお工程図1に示し
た式(IV)、(V)、(VI)、(VII)で表される化合物
の構造式において、3位の水酸基と18位の炭素を結ぶ結
合と、5位の水酸基と1'位の炭素を結ぶ結合の空間的な
相対位置関係(前後関係)に関しては、現在までのとこ
ろ明瞭ではない)。First, the naturally occurring 16-membered macrolide antibiotic Leucomycin Fr group (Journal of Antibiotics, 28 (6), 401 (1975))
The protection of the hydroxyl group and the aldehyde group by the silyl group will be described. For a compound represented by the formula (II) (wherein R 5 is an acyl group), that is, a single compound of the leucomycin Fr group or a mixture of a plurality of components, or a salt thereof, a necessary amount in the presence of a base. Of the hemiacetal hydroxyl group formed at the 3,18-position, and the hydroxyl groups at the 9-position and the 2'-position are respectively silylated by reacting with an excess amount of the silylating reagent or the formula (IV) (wherein R 5 is an acyl group and R 6 is a silyl protecting group) or a salt thereof is obtained. For example, leucomycin A 7 (in formula (II), R 5
Is represented by a propionyl group) in dimethylformamide (DMF) in the presence of imidazole with t-butyldimethylsilyl chloride (TBDMSCl) to give 3,18
A compound (1) (in the formula (IV) in which R 5 is R 5 is a hemiacetal-type hydroxyl group formed at the position and a total of three hydroxyl groups at the 9-position and the 2′-position are converted to t-butyldimethylsilyl (TBDMS). A compound represented by a propionyl group and R 6 represented by a TBDMS group was obtained in high yield (note that the compounds represented by the formulas (IV), (V), (VI) and (VII) shown in the process chart 1). In the structural formula of the compound described below, regarding the spatial relative positional relationship (front-back relationship) between the bond connecting the 3-position hydroxyl group and the 18-position carbon and the bond connecting the 5-position hydroxyl group and the 1'position carbon, Not clear so far).
【0021】この時の18位の立体化学については、一方
のジアステレオ異性体の生成が甚だ優先しており、スピ
ラマイシンIでの保護において観察された様な18位の他
方のジアステレオ異性体(ジャーナル・オブ・アンチビ
オチックス, 37(7), 750(1984))は目立って生成してい
ない。一方で、用いるシリル保護基の種類並びにシリル
化条件、さらに反応基質の違い等によっては、18位のジ
アステレオ異性体が副生する可能性は否定できない。し
かしながら、本発明における製造法を実施するにあたっ
ては、当該異性体を分離しても分離しなくともよい。Regarding the stereochemistry at the 18-position at this time, the production of one diastereoisomer is very preferential, and the other diastereoisomer at the 18-position as observed in the protection with spiramycin I was observed. (Journal of Antibiotics, 37 (7), 750 (1984)) is not prominently produced. On the other hand, it is undeniable that the 18-position diastereoisomer may be by-produced, depending on the type of silyl protecting group used, the silylation conditions, and the difference in the reaction substrate. However, in carrying out the production method of the present invention, the isomers may or may not be separated.
【0022】当該保護工程に用いるシリル基としては、
TBDMS基の他、イソプロピルジメチルシリル基、エチル
ジメチルシリル基等、他のシリル基も可能であり、特に
イソプロピルジメチルシリル基等は本発明製造法に適用
可能である。ところでTBDMS基を導入する際のシリル化
試薬としては、TBDMSClの他、TBDMSOClO3、TBDMSOSO2CF
3、TBDMSCN等、水酸基への通常のTBDMS化の際用いる事
のできる試薬を使用する事が可能であるが、好ましくは
TBDMSClを3当量ないしは過剰量用いるとよい。シリル
化の際用いる塩基としては、イミダゾールの他、ピリジ
ン、ジメチルアミノピリジン、ルチジン、トリエチルア
ミン等が可能であるが、好ましくはイミダゾールを6当
量ないしは過剰量用いるとよい。反応溶媒はDMFの他、
アセトニトリル、塩化メチレン、テトラヒドロフラン
(THF)等を用いる事が可能であるが、DMFを用いる反応
が好結果を与える事が多い。本保護工程は0℃〜80℃の
範囲で収率良く進行し、反応時間は1時間〜数日間であ
る。The silyl group used in the protection step is
In addition to the TBDMS group, other silyl groups such as isopropyldimethylsilyl group and ethyldimethylsilyl group are also possible, and particularly isopropyldimethylsilyl group is applicable to the production method of the present invention. By the way, as the silylation reagent when introducing the TBDMS group, in addition to TBDMSCl, TBDMSOClO 3 , TBDMSOSO 2 CF
3 , it is possible to use a reagent such as TBDMSCN, which can be used in the usual TBDMS conversion to a hydroxyl group, but preferably
It is advisable to use 3 equivalents or excess of TBDMSCl. As the base used in the silylation, pyridine, dimethylaminopyridine, lutidine, triethylamine and the like can be used in addition to imidazole, but it is preferable to use 6 equivalents or an excess amount of imidazole. The reaction solvent is DMF,
Although it is possible to use acetonitrile, methylene chloride, tetrahydrofuran (THF), etc., the reaction using DMF often gives good results. This protection step proceeds with good yield in the range of 0 ° C to 80 ° C, and the reaction time is 1 hour to several days.
【0023】第二に、式(IV)で表される化合物のマイ
カロース部分の4"位のアシル側鎖を合成化学的に切断す
る。式(IV)で表される化合物は、3,18位で形成したヘ
ミアセタール性の水酸基にシリル基が導入されており、
アルデヒド基が保護された上に、それらを含む7員環部
分が16員環ラクトンに縮環している。そのため、3位
が遊離の水酸基であり、同時に遊離のアルデヒド基を有
し縮環していない16員環マクロリド誘導体と比較し
て、式(IV)で表される化合物それ自体の強塩基条件下
におけるラクトン環の安定性は飛躍的に向上している。
それゆえ通常のアルカリ処理によりラクトン環を開裂す
ることなく、4"位の水酸基に結合しているアシル基を選
択的に切断する事が可能である。しかしながらその収率
は必ずしも満足できるものではない。そこで本発明者
は、式(IV)で表される化合物が特に脂溶性である事か
ら、相間移動触媒を用いる不均一反応による4"位脱アシ
ル化の可能性を探り、その結果、マイカロース部分の4"
位のアシル基を定量的に切断する事に成功した。Secondly, the 4 "-position acyl side chain of the mycarose moiety of the compound represented by the formula (IV) is chemically cleaved. The compound represented by the formula (IV) is 3,18 A silyl group is introduced into the hemiacetal hydroxyl group formed at the position,
In addition to protecting the aldehyde groups, the 7-membered ring portion containing them is condensed to a 16-membered lactone. Therefore, compared with a 16-membered ring macrolide derivative having a free hydroxyl group at the 3-position and a free aldehyde group at the same time, a strong basic condition of the compound itself represented by the formula (IV) is obtained. The stability of the lactone ring in is dramatically improved.
Therefore, it is possible to selectively cleave the acyl group bonded to the 4 "-position hydroxyl group without cleaving the lactone ring by usual alkali treatment. However, the yield is not always satisfactory. Therefore, the present inventor investigated the possibility of 4 "-deacylation by a heterogeneous reaction using a phase transfer catalyst because the compound represented by the formula (IV) is particularly fat-soluble, and as a result, mica 4 "of loin
We succeeded in quantitatively cleaving the acyl group at position.
【0024】即ちその一例として、化合物(1)(式
(IV)において、R5がプロピオニル基で表され、R6がTB
DMS基で表される化合物)をベンゼンに溶解し、硫酸水
素テトラ-n-ブチルアンモニウムの存在下に25%水酸化ナ
トリウム水溶液と室温で激しく撹拌し、化合物(2)
(式(V)において、R6がTBDMS基で表される化合物)を
効率良く得た。当該不均一反応は、一般に強塩基性の水
層と、式(IV)で表される化合物を溶解した(水と均一
に混ざらない)有機溶媒との混合物を、相間移動触媒の
存在下に激しく撹拌して行なわれる。水層に溶解する強
塩基は、水酸化ナトリウム或いは水酸化カリウムの何れ
であってもよく、その濃度は通常濃厚である事が好まし
い。水と均一に混ざらない有機溶媒には、ベンゼン、ト
ルエン、キシレン、n-ペンタン、n-ヘキサン、シクロヘ
キサン、塩化メチレン、1,2-ジクロロエタン等でよく、
好ましくはベンゼン等である。相間移動触媒としては、
テトラ-n-ブチルアンモニウムブロミド、テトラ-n-ブチ
ルアンモニウムクロリド、ベンジルトリエチルアンモニ
ウムブロミド、ベンジルトリエチルアンモニウムクロリ
ド、硫酸水素テトラ-n-ブチルアンモニウム等を用いる
事ができ、その量は式(IV)で表される化合物に対し触
媒量〜数当量であり、通常は1当量用いる。反応は5℃
〜40℃の間で容易に進行し、反応系中の撹拌効率が反応
時間の短縮と収率の向上につながるが、通常10分〜数時
間で反応は完結する。That is, as an example thereof, in the compound (1) (formula (IV), R 5 is represented by a propionyl group and R 6 is TB.
Compound represented by DMS group) is dissolved in benzene and vigorously stirred with 25% aqueous sodium hydroxide solution at room temperature in the presence of tetra-n-butylammonium hydrogen sulfate to give compound (2)
(Compound in which R 6 is a TBDMS group in formula (V)) was efficiently obtained. In the heterogeneous reaction, generally, a strongly basic aqueous layer and a mixture of an organic solvent in which the compound represented by the formula (IV) is dissolved (not uniformly mixed with water) are vigorously mixed in the presence of a phase transfer catalyst. It is performed with stirring. The strong base that dissolves in the aqueous layer may be either sodium hydroxide or potassium hydroxide, and the concentration is usually preferably concentrated. The organic solvent that is not uniformly mixed with water may be benzene, toluene, xylene, n-pentane, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, etc.,
Preferred is benzene and the like. As a phase transfer catalyst,
Tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride, tetra-n-butylammonium hydrogensulfate and the like can be used, and the amount thereof is represented by the formula (IV). The amount is a catalytic amount to several equivalents, usually 1 equivalent. Reaction is 5 ℃
The reaction proceeds easily between -40 ° C and the stirring efficiency in the reaction system shortens the reaction time and improves the yield, but the reaction is usually completed in 10 minutes to several hours.
【0025】本発明製造法に用いる出発原料はロイコマ
イシンFrグループの何れの化合物であっても適するが、
それらのマイカロース部分の4"位のアシル側鎖は、当該
不均一反応においてイソバレリル基(ロイコマイシン
A1)よりもプロピオニル基(ロイコマイシンA7)の方が
反応時間は短縮され、僅かながら収率は向上する。しか
しながら4"位の水酸基に結合する側鎖が何れの天然型ア
シル基であっても、本不均一反応によって所望とする脱
アシル化反応を達成する事が可能である。The starting material used in the production method of the present invention may be any compound of the leucomycin Fr group,
The acyl side chain at the 4 "-position of the mycarose moiety is an isovaleryl group (leucomycin) in the heterogeneous reaction.
The reaction time of the propionyl group (leucomycin A 7 ) is shorter than that of A 1 ) and the yield is slightly improved. However, the desired deacylation reaction can be achieved by this heterogeneous reaction regardless of which natural acyl group the side chain bonded to the 4 "-position hydroxyl group is.
【0026】第三に、式(V)(式中、R6はシリル保護
基である)で表される化合物のマイカロース部分の4"位
の水酸基への、選択的或いは非選択的アルキル化につい
て述べる。式(V)で表される化合物には2つの遊離の
水酸基が存在するが、3"位の水酸基は第3級アルコール
であり4"位の水酸基は第2級アルコールであるために、
アルキル基の導入によるエーテル結合生成反応(ウイリ
アムソン反応)においても、2つの水酸基の間の反応性
の差を使い分ける事が可能である。即ち式(V)で表さ
れる化合物にウイリアムソン反応を行ない、そのマイカ
ロース部分の4"位水酸基へ選択的にアルキル基を導入
し、式(VI)(式中、R4はアルキル基であり、R6はシリ
ル保護基である)で表される化合物を収率良く得る。Thirdly, selective or non-selective alkylation of the compound represented by the formula (V) (wherein R 6 is a silyl protecting group) to the 4 "-position hydroxyl group of the mycarose moiety. The compound represented by the formula (V) has two free hydroxyl groups, but the hydroxyl group at the 3 "position is a tertiary alcohol and the hydroxyl group at the 4" position is a secondary alcohol. ,
Also in the ether bond formation reaction (Williamson reaction) due to the introduction of the alkyl group, it is possible to properly use the difference in reactivity between the two hydroxyl groups. That is, the compound represented by the formula (V) is subjected to a Williamson reaction to selectively introduce an alkyl group into the 4 "-position hydroxyl group of the mycarose portion, and the formula (VI) (wherein R 4 is an alkyl group) And R 6 is a silyl protecting group) can be obtained in good yield.
【0027】例えば化合物(2)(式(V)において、R
6がTBDMS基で表される化合物)をDMF中水素化ナトリウ
ムの存在下に過剰量のヨウ化イソアミルと加熱条件下反
応させ、化合物(15)(式(VI)において、R4がイソ
アミル基で表され、R6がTBDMS基で表される化合物)を
収率良く合成した。この様に、イソアミル基の如く導入
すべきアルキル側鎖がある程度嵩高い場合、反応の位置
選択性は良いが、アルキル側鎖が小さくなる事に伴い当
該選択性は次第に低下する。事実、化合物(2)或いは
その類縁物質に対し、水素化ナトリウムの存在下にヨウ
化メチルを反応させると、4"位のみならず3"位の3級水
酸基もメチル化された化合物が生成する(実施例23参
照)。For example, compound (2) (in formula (V), R
6 is a compound represented by TBDMS group) in DMF in the presence of sodium hydride in the presence of an excess amount of isoamyl iodide under heating conditions, and compound (15) (in formula (VI), R 4 is an isoamyl group) Compound in which R 6 is represented by TBDMS group) was synthesized in good yield. Thus, when the alkyl side chain to be introduced, such as an isoamyl group, is bulky to some extent, the regioselectivity of the reaction is good, but the selectivity gradually decreases as the alkyl side chain becomes smaller. In fact, when compound (2) or its analogue is reacted with methyl iodide in the presence of sodium hydride, a compound in which not only the 4 "-position but also the tertiary hydroxyl group at the 3" -position is methylated is formed. (See Example 23).
【0028】本アルキル化反応の際、遊離の水酸基より
プロトンを引き抜きアルコキシドを生成するには、水素
化ナトリウムの他、水素化カリウムの如く金属水素化物
でよく、アルキル基を導入するための試薬は、ヨウ化ア
ルキルの他、臭化アルキル等のハロゲン化アルキルでよ
い。その際のアルキル鎖は第1級アルキル基又は第2級
アルキル基が適当であるが、好ましくは第1級アルキル
基である。反応溶媒としては、DMF等の他、THF、ジオキ
サン等を用いてもよい。アルキル化反応は0℃〜100℃
の間の温度で容易に進行するが、好ましくは40℃〜50℃
である。ところで、本反応を収率良く完結させる為に
は、反応温度の制御が特に重要である。In the present alkylation reaction, a metal hydride such as potassium hydride may be used in addition to sodium hydride for extracting a proton from a free hydroxyl group to generate an alkoxide. A reagent for introducing an alkyl group is used. In addition to alkyl iodide, alkyl halide such as alkyl bromide may be used. The alkyl chain in that case is preferably a primary alkyl group or a secondary alkyl group, but is preferably a primary alkyl group. As the reaction solvent, THF, dioxane or the like may be used in addition to DMF or the like. Alkylation reaction is 0 ℃ -100 ℃
Easily progresses at temperatures between, but preferably 40 ℃ ~ 50 ℃
Is. By the way, in order to complete this reaction with a high yield, control of the reaction temperature is particularly important.
【0029】第四に、式(VI)で表される化合物のマイ
カロース部分の3"位の3級水酸基へのアルキル基の導入
と、マイカミノース部分の2'位水酸基に結合していたシ
リル基の選択的脱保護について述べる。始めに式(VI)
で表される化合物を、ウイリアムソン反応に付し、マ
イカロース部分の3"位の3級水酸基にアルキル基を導入
した。次いで、有機過酸化物を用いて酸素1原子を賦
与した。最後に、酸素1原子の除去を伴う2'位の選択
的脱シリル化反応により、式(VII)(式中、R 3及びR4
はアルキル基であり、R6はシリル保護基である)で表さ
れる化合物を得る。Fourthly, the compound of the formula (VI)
Introducing an alkyl group into the tertiary hydroxyl group at the 3 "position of the callose part
And the chain bonded to the 2'-hydroxyl group of the mycaminose moiety.
The selective deprotection of the ryl group will be described. First Expression (VI)
The compound represented by
Introducing an alkyl group into the tertiary hydroxyl group at the 3 "position of the squid
did. Then, one atom of oxygen is added using an organic peroxide.
I gave it. Finally, selection of 2'position with removal of one oxygen atom
(VII) (wherein R 3And RFour
Is an alkyl group, R6Is a silyl protecting group)
To obtain the compound.
【0030】例えば化合物(15)(式(VI)におい
て、R4がイソアミル基で表され、R6がTBDMS基で表され
る化合物)を、DMF中水素化ナトリウムの存在下に、
過剰量のヨウ化エチルと反応させて3"位の3級水酸基を
エチル化し、次いで、m-クロロ過安息香酸を用いて酸
素1原子を賦与した。続いて、《A》有機溶媒の共存
下或いは非共存下でのシリカゲルとの反応によって、或
いは、《B》酸加水分解反応によって、酸素1原子の
除去を伴う2'位の選択的脱TBDMS化を行ない、化合物
(18)(式(VII)において、R3がエチル基で表さ
れ、R4がイソアミル基で表され、R6がTBDMS基で表され
る化合物)を得た。For example, the compound (15) (in the formula (VI), R 4 is an isoamyl group and R 6 is a TBDMS group) is added to DMF in the presence of sodium hydride,
By reacting with an excess amount of ethyl iodide, the tertiary hydroxyl group at the 3 "position was ethylated, and then one atom of oxygen was donated using m-chloroperbenzoic acid. Subsequently, in the coexistence of << A >> organic solvent Alternatively, by selective reaction with silica gel in the absence of coexistence, or by << B >> acid hydrolysis reaction, selective removal of TBDMS at the 2'-position accompanied by removal of one oxygen atom is carried out, and compound (18) (formula (VII ), R 3 represents an ethyl group, R 4 represents an isoamyl group, and R 6 represents a TBDMS group).
【0031】一般の3級水酸基へのアルキル基の導入の
際のウイリアムソン反応に関しては、銅(I)第3級ア
ルコキシドを経由する方法(ジャーナル・オブ・アメリ
カン・ケミカル・ソシエチー, 96(9), 2829(1974))等
が確立されているが、本発明におけるマイカロース部分
の3"位の3級水酸基へのアルキル化()は、反応基質
が3つのシリル基により保護・安定化されているため
に、通常のウイリアムソン反応を特別に修飾すること無
く応用する事が可能であった。したがって、反応条件そ
れ自体は、式(V)で表される化合物のマイカロース部
分の4"位水酸基をアルキル化した場合と概ね類似してい
るが、反応の際の温度制御はさらに重要となる。また、
導入するアルキル側鎖に関しては、嵩高いアルキル基で
は幾分収率の低下を招く事がある。Regarding the Williamson reaction at the time of introducing an alkyl group into a general tertiary hydroxyl group, a method via a copper (I) tertiary alkoxide (Journal of American Chemical Society, 96 (9) , 2829 (1974)) and the like have been established. However, in the alkylation () of the mycarose moiety to the tertiary hydroxyl group at the 3 "position in the present invention, the reaction substrate is protected and stabilized by three silyl groups. Therefore, it was possible to apply the ordinary Williamson reaction without special modification. Therefore, the reaction conditions themselves are the 4 "position of the mycarose moiety of the compound represented by formula (V). It is almost similar to the case where the hydroxyl group is alkylated, but the temperature control during the reaction becomes more important. Also,
Regarding the alkyl side chain to be introduced, a bulky alkyl group may cause a slight decrease in yield.
【0032】ところで式(VI)で表される化合物から式
(VII)で表される化合物を合成するための3段階の化
学反応(3"-O-アルキル化、酸素1原子の賦与、
酸素1原子の除去を伴う2'位の選択的脱シリル化)を含
む本工程は、アルキル化試薬の種類及びシリル保護基の
種類等により、必ずしも上記の反応順序が最良であると
は限らず、の酸素1原子の賦与の後に、の3"-O-ア
ルキル化を行ない、次いでを行なう反応経路も又当該
工程を完了する為に有用である。事実、実施例7、10
等においては、の酸素1原子の賦与を行なった後に、
の3"-O-メチル化を実行している。即ち、有機過酸化
物によるこの酸素1原子の賦与は、3"位の3級水酸基の
アルキル化に際して必ずしも必要不可欠ではないが、以
下に述べる様にシリル基の選択的脱保護に関してその効
果を発揮する。By the way, a three-step chemical reaction (3 "-O-alkylation, donation of one oxygen atom, for synthesizing the compound represented by the formula (VII) from the compound represented by the formula (VI),
In this step including selective desilylation of 2'position accompanied by removal of one oxygen atom, the above reaction sequence is not always the best depending on the type of alkylating reagent and the type of silyl protecting group. The reaction pathway of donating one oxygen atom of ,, followed by 3 "-O-alkylation of, and then is also useful to complete the process. In fact, Examples 7, 10
Etc., after giving one oxygen atom of
3 "-O-methylation is performed. That is, the donation of one oxygen atom by an organic peroxide is not essential for alkylation of the tertiary hydroxyl group at the 3" position, but is described below. Thus, it exerts its effect on the selective deprotection of the silyl group.
【0033】即ちマイカロース部分の2つの水酸基が共
にアルキル基によりエーテル結合した16員環マクロリ
ド誘導体においては、3,18位で形成したヘミアセタール
性の水酸基並びに9位及び2'位のそれぞれの水酸基に導
入された3つのシリル基、例えば3つのTBDMS基を、基
質の他の部分に影響を与える事なく公知の脱保護法(Th
eodora W. Greene; Peter G. M. Wuts. Protective Gro
ups in Organic Synthesis, 2nd ed., Wiley: New Yor
k, 1991)によって、完全に脱保護する事は、極めて困
難であった。しかしながら、当該トリシリル保護体に酸
素1原子を賦与()した誘導体においては、酸素1原
子の除去を伴う2'位の選択的脱シリル化()、例えば
2'位の選択的脱TBDMS化が効率よく進行し、更なる工程
により他の2つのシリル基も完全に脱保護される事を発
見した。That is, in the 16-membered macrolide derivative in which the two hydroxyl groups of the mycarose moiety are both ether-bonded by an alkyl group, the hemiacetal hydroxyl group formed at the 3,18-position and the hydroxyl groups at the 9-position and the 2'-position, respectively. The three silyl groups introduced into the substrate, eg, three TBDMS groups, can be deprotected by known deprotection methods (Th
eodora W. Greene; Peter GM Wuts. Protective Gro
ups in Organic Synthesis , 2nd ed., Wiley: New Yor
K, 1991), it was extremely difficult to completely deprotect. However, in the derivative in which one oxygen atom is added () to the trisilyl protected body, selective desilylation () of the 2'position accompanied by removal of one oxygen atom, for example,
It was discovered that the selective deprotection of TBDMS at the 2'position proceeded efficiently and that the other two silyl groups were completely deprotected by a further step.
【0034】ところで有機過酸化物による酸素1原子の
賦与()は、マイカミノース部分の近傍に為されてい
ると推定しているが、酸素1原子が賦与された化合物は
幾分不安定であるために、特に酸性側の条件において極
めて不安定であるために、それらの化合物の化学構造は
現在までのところ確定していない。一方、当該酸素原子
賦与反応を実行する過酸化物としては、m-クロロ過安息
香酸、過安息香酸、過酢酸等の有機過酸化物の他、過酸
化水素等でもよく、好ましくはm-クロロ過安息香酸であ
る。反応溶媒としては、クロロホルム、塩化メチレン、
エーテル、t-ブタノール等でよく、反応は-10℃〜室温
ないしはそれ以上の温度で短時間に完結する。By the way, it is presumed that the donation of one oxygen atom by the organic peroxide () is performed in the vicinity of the mycaminose portion, but the compound to which one oxygen atom is donated is somewhat unstable. In addition, the chemical structures of these compounds have not yet been determined because they are extremely unstable, especially under acidic conditions. On the other hand, as the peroxide for carrying out the oxygen atom donating reaction, other organic peroxides such as m-chloroperbenzoic acid, perbenzoic acid and peracetic acid, hydrogen peroxide may be used, and preferably m-chloro. It is perbenzoic acid. As the reaction solvent, chloroform, methylene chloride,
Ether, t-butanol, etc. may be used, and the reaction is completed in a short time at a temperature of -10 ° C to room temperature or higher.
【0035】そこで、3つのシリル基で保護されてお
り、マイカロース部分の2つの水酸基が共にアルキル基
によりエーテル結合されており、さらに酸素1原子が賦
与された16員環マクロリド化合物の、酸素1原子の除
去を伴う2'位のシリル基の選択的脱保護、即ちについ
て詳しく述べる。本反応は、《A》シリカゲルの存在
下に室温で放置する事によって定量的に進行する事が確
認されている。シリカゲルとの反応は、反応系中に有機
溶媒が共存していても、或いは共存していなくともよ
く、その反応形態は、バッチ法であってもカラム法であ
ってもよく、さらに少量の化合物の製造にあたってはTL
C法も又有用である。Therefore, the 16-membered ring macrolide compound, which is protected by three silyl groups, has two hydroxyl groups in the mycarose moiety both ether-bonded by an alkyl group, and has one oxygen atom, is further added. The selective deprotection of the silyl group at the 2'position accompanied by removal of the atom, that is, will be described in detail. It has been confirmed that this reaction proceeds quantitatively by leaving it at room temperature in the presence of << A >> silica gel. The reaction with silica gel may or may not coexist with an organic solvent in the reaction system, and the reaction form may be a batch method or a column method, and a small amount of compound TL for manufacturing
Method C is also useful.
【0036】始めにバッチ法について述べる。当該反応
基質に有機溶媒を加え溶解し、シリカゲルを均一となる
ように添加する。室温にて有機溶媒の共存下に放置して
も、又は有機溶媒を減圧濃縮等によって除去した後、有
機溶媒の非共存下に放置しても、何れの場合においても
所望とする酸素1原子の除去を伴う2'位のシリル基の選
択的脱保護が効率良く進行する。次にカラム法について
述べる。湿式にて充填されたシリカゲルカラムの上底
に、当該反応基質の濃厚溶液を付した後室温に放置する
事によってもまた、所望とする本反応が効率良く進行し
た。放置後、シリカゲルカラムを順次展開する事によ
り、効率良く式(VII)で表される化合物を得る事が可
能であった。本反応の際用いる有機溶媒は特に限定され
る事はなく、クロロホルム、塩化メチレン、アセトニト
リル、メタノール等を、単一で、或いは混合して使用す
る事が可能である。さらに、この際用いるシリカゲルに
ついても、通常の実験操作において使用されている一般
のシリカゲル、例えばワコーゲルC-200、同C-300、メル
ク・キーゼルゲルArt.15101、同Art.9385等を自由に適
用する事が可能である。First, the batch method will be described. An organic solvent is added to the reaction substrate to dissolve it, and silica gel is added so as to be uniform. In either case, even if it is left in the coexistence of an organic solvent at room temperature, or after the organic solvent is removed by concentration under reduced pressure or the like, it is left in the absence of an organic solvent, the desired oxygen 1 atom The selective deprotection of the silyl group at the 2'position accompanied by removal proceeds efficiently. Next, the column method will be described. The desired main reaction also proceeded efficiently by attaching a concentrated solution of the reaction substrate to the upper bottom of a silica gel column packed by a wet method and then leaving it at room temperature. After standing, it was possible to efficiently obtain the compound represented by the formula (VII) by successively developing the silica gel column. The organic solvent used in this reaction is not particularly limited, and chloroform, methylene chloride, acetonitrile, methanol and the like can be used alone or as a mixture. Furthermore, regarding the silica gel used at this time, general silica gel used in ordinary experimental operations such as Wakogel C-200, C-300, Merck Kieselgel Art.15101, and Art.9385 can be freely applied. Things are possible.
【0037】最後に少量の化合物の製造に適しているTL
C法について述べる。当該反応基質を少量の有機溶媒に
溶解した後TLC板上にチャージし、室温で放置したのち
通常に展開する事により、効率良く式(VII)で表され
る化合物を得る事が可能であった。これらバッチ法、カ
ラム法、TLC法のいずれの方法を選択し放置時間をどの
程度に設定するのかは、当該反応基質の構造と反応のス
ケールにより決定されるが、室温で放置した場合、反応
の完結に要する時間は通常数時間〜数日間である。Finally, a TL suitable for the production of small amounts of compounds
The C method will be described. It was possible to efficiently obtain the compound represented by the formula (VII) by dissolving the reaction substrate in a small amount of an organic solvent, charging it on a TLC plate, allowing it to stand at room temperature, and then developing it normally. . Which of the batch method, the column method, and the TLC method is selected and how long the standing time is set is determined by the structure of the reaction substrate and the scale of the reaction. The time required for completion is usually several hours to several days.
【0038】一方本反応を、《B》酸加水分解により
達成するには、希薄な有機酸又は無機酸の水溶液と、水
と均一に混ざる有機溶媒との混液を用いればよい。本法
は、《A》法と比較してシリカゲルを用いないと言う長
所がある。本法に用いる酸の水溶液としては、例えば塩
酸の濃度は0.001規定〜0.5規定が可能であり、好ましく
は0.01規定〜0.05規定である。酸の種類としては、塩酸
の他、硫酸、燐酸、メタンスルホン酸、トリフルオロ酢
酸等を用いる事が可能である。有機溶媒としては、メタ
ノール、エタノール、アセトニトリル、THF、ジオキサ
ン等が可能であり、好ましくはメタノール又はアセトニ
トリルである。希薄な酸の水溶液と有機溶媒の混合比
は、当該反応基質が溶解しさえすれば任意でよく、通常
は1:1程度の混合比のものが用いられる。反応温度及
び同時間は、用いる酸の種類及び濃度によっても大きく
左右されるが、反応は通常0℃〜60℃の間で行なわれ、
数分間〜数時間で完結する(実施例17を参照)。On the other hand, in order to achieve this reaction by << B >> acid hydrolysis, a mixed solution of a dilute aqueous solution of an organic acid or an inorganic acid and an organic solvent which is uniformly mixed with water may be used. This method has an advantage that silica gel is not used as compared with the << A >> method. The aqueous acid solution used in this method may have a hydrochloric acid concentration of 0.001 to 0.5 normal, preferably 0.01 to 0.05 normal. As the type of acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoroacetic acid or the like can be used in addition to hydrochloric acid. As the organic solvent, methanol, ethanol, acetonitrile, THF, dioxane and the like can be used, and preferably methanol or acetonitrile. The dilute aqueous solution of the acid and the organic solvent may be mixed at any ratio as long as the reaction substrate is dissolved, and a mixture ratio of about 1: 1 is usually used. The reaction temperature and the same time largely depend on the type and concentration of the acid used, but the reaction is usually performed at 0 ° C to 60 ° C.
It is completed within a few minutes to a few hours (see Example 17).
【0039】ところで、当該反応()を実施する際に
本加水分解法(《B》)を選択するもう一つの長所は、
反応をさらに継続する事によって、2'位以外の2つのシ
リル基、例えばTBDMS基をも順次脱保護され、式(III)
(式中、R3及びR4はアルキル基である)で表される最終
目的物が得られる事である。例えば、化合物(15)
(式(VI)において、R4がイソアミル基で表され、R6が
TBDMS基で表される化合物)の3"位の3級水酸基がメチ
ル化されており、同時に酸素1原子が賦与された化合物
を、0.025規定塩酸/アセトニトリル(1:1)の混液で45℃
4時間酸加水分解する事により、効率良く化合物(1
7)(式(III)において、R3がメチル基で表され、R4
がイソアミル基で表される化合物)を与える反応条件を
見い出した(実施例25参照)。本反応は、化合物(1
7)の他に、分離可能な化合物(17)のアリル転位体
(ケミカル・アンド・ファーマシューチカル・ブレタ
ン, 18(8), 1501(1970)、明治製菓研究年報, 12, 85(19
72)、ジャーナル・オブ・アンチビオチックス, 35(11),
1521(1982))を微量に副生するものの、本発明の工程
図1に示した式(VII)で表される化合物を経由する製
造法と比較して、反応工程数の減少及び反応試薬類の削
減が実現されており、製造コストの低減に大きく貢献す
る事が可能である。最終的に3つのシリル基、例えばTB
DMS基が脱保護されるまでに要する反応時間は、2'位の
選択的脱シリル化に比較して長時間であるが、反応条件
それ自体は、前述した、《B》酸加水分解法と同様で
ある。By the way, another advantage of selecting the present hydrolysis method (<< B >>) when carrying out the reaction () is:
By further continuing the reaction, two silyl groups other than the 2'position, for example, TBDMS group are sequentially deprotected, and the formula (III)
(In the formula, R 3 and R 4 are alkyl groups) to obtain the final target product. For example, compound (15)
(In the formula (VI), R 4 is represented by an isoamyl group, and R 6 is
The compound represented by the TBDMS group) is methylated at the tertiary hydroxyl group at the 3 "position, and at the same time, a compound to which one oxygen atom is endowed is added to a mixture of 0.025N hydrochloric acid / acetonitrile (1: 1) at 45 ° C.
By acid hydrolysis for 4 hours, the compound (1
7) (in the formula (III), R 3 is represented by a methyl group, and R 4
Was found to be a compound represented by an isoamyl group) (see Example 25). In this reaction, the compound (1
In addition to 7), separable allylic rearrangement of compound (17) (Chemical and Pharmaceutical Bretan, 18 (8), 1501 (1970), Annual Report of Meiji Seika, 12 , 85 (19)
72), Journal of Antibiotics, 35 (11),
1521 (1982)) as a by-product in a trace amount, but the number of reaction steps is reduced and the reaction reagents are compared with the production method of the present invention via the compound represented by the formula (VII) shown in the process chart 1. Has been realized, and it can greatly contribute to the reduction of manufacturing cost. Finally 3 silyl groups, eg TB
The reaction time required until the DMS group is deprotected is longer than that in the selective desilylation at the 2'position, but the reaction conditions themselves are the same as those in the << B >> acid hydrolysis method described above. It is the same.
【0040】第五に、3,18位で形成したヘミアセタール
性の水酸基及び9位の水酸基に結合している2つのシリ
ル基の脱保護について述べる。これらのシリル基、例え
ばTBDMS基は、テトラ-n-ブチルアンモニウムフルオリド
(TBAF)試薬又はある種の酸による反応条件を始め、水
酸基に結合するシリルエーテルに関する公知の脱保護条
件(Theodora W. Greene; Peter G. M. Wuts. Protecti
ve Groups in OrganicSynthesis, 2nd ed., Wiley: New
York, 1991)によって、完全に、或いは不完全に脱保
護する事が可能である。式(VII)で表される化合物を
反応基質として、種々の脱シリル化の反応試薬を用いて
その有用性を観察すると、TBAFを用いて当該脱保護を実
施した場合に好結果が得られる事が判明した。事実、R6
がTBDMS基である式(VII)で表される化合物に対して、
TBAFを用いて脱保護を行なうと、式(III)で表される
最終目的物に化学変換される。例えば、化合物(18)
(式(VII)において、R3がエチル基で表され、R4がイ
ソアミル基で表され、R6がTBDMS基で表される化合物)
を、THF中過剰量のTBAFと加熱条件下反応させる事によ
り、化合物(19)(式(III)において、R3がエチル
基で表され、R4がイソアミル基で表される化合物)が主
生成物として得られた。Fifth, the deprotection of the two silyl groups bonded to the hemiacetal hydroxyl group formed at the 3,18-position and the hydroxyl group at the 9-position will be described. These silyl groups, such as the TBDMS group, are well known for their deprotection conditions (Theodora W. Greene ; Peter GM Wuts. Protecti
ve Groups in Organic Synthesis , 2nd ed., Wiley: New
York, 1991) allows complete or incomplete deprotection. Using the compound of formula (VII) as a reaction substrate and observing its usefulness using various desilylation reaction reagents, good results are obtained when the deprotection is carried out using TBAF. There was found. In fact, R 6
For a compound of formula (VII) in which is a TBDMS group,
Deprotection using TBAF results in chemical conversion to the final end product of formula (III). For example, compound (18)
(A compound represented by the formula (VII) in which R 3 is an ethyl group, R 4 is an isoamyl group, and R 6 is a TBDMS group)
Is reacted with an excess amount of TBAF in THF under heating conditions to give a compound (19) (a compound represented by the formula (III) in which R 3 is an ethyl group and R 4 is an isoamyl group). Obtained as the product.
【0041】TBAFを用いて2つのシリル基、例えばTBDM
S基を脱保護する際は、反応系中に水分を混入させぬ様
工夫する事で、反応の完結は早まり副反応を完全に抑制
する事が可能である。なおTBAFは強い塩基として遊離の
アルデヒド基に作用するために、本脱保護工程を収率良
く遂行する為には、反応終了後の後処理に細心の注意を
払う必要があるが、詳細は実施例において記載した。TB
AFを用いる本脱保護での反応溶媒としては、エーテル系
の溶媒の他、ハロゲン系の溶媒、ニトリル系の溶媒等を
用いる事が可能であるが、THFを用いた際に好結果を与
える事が多い。さらに本反応を完結させる為には、反応
溶媒に対するTBAFそれ自身の濃度が重要な要因になり得
る。すなわち反応基質に対するTBAFの当量数を一定にし
た場合、TBAFの反応溶媒に対する濃度は希薄過ぎても
(反応溶媒が多過ぎても)或いは同濃度が濃厚過ぎても
(反応溶媒が少な過ぎても)当該反応は完結しにくく、
通常0.5M〜4Mの濃度で、好ましくは1M〜2Mの濃度で反応
は効率良く進行する。TBAFは2当量〜過剰量用いるが、
通常10当量以上のTBAFとの反応により、完全な脱保護が
速やかに進行する。Using TBAF, two silyl groups, eg TBDM
When deprotecting the S group, by devising such that water is not mixed in the reaction system, the completion of the reaction is accelerated and side reactions can be completely suppressed. Since TBAF acts as a strong base on the free aldehyde group, in order to carry out this deprotection step in high yield, it is necessary to pay close attention to the post-treatment after the reaction, but details are not provided. Described in the examples. TB
As the reaction solvent in the main deprotection using AF, it is possible to use an ether-based solvent, a halogen-based solvent, a nitrile-based solvent, etc., but a good result is obtained when THF is used. There are many. Furthermore, in order to complete the reaction, the concentration of TBAF itself in the reaction solvent can be an important factor. That is, when the number of TBAF equivalents to the reaction substrate is constant, the concentration of TBAF with respect to the reaction solvent is too dilute (too much reaction solvent) or too high (if there is too little reaction solvent). ) The reaction is difficult to complete,
Usually, the reaction proceeds efficiently at a concentration of 0.5M to 4M, preferably at a concentration of 1M to 2M. TBAF is used in 2 equivalent to excess amount,
Complete deprotection proceeds rapidly by reaction with 10 or more equivalents of TBAF.
【0042】ところで、式(III)で表される化合物、
又はその塩に対しては、9位又は2'位の水酸基を選択的
にアシル化する公知の方法(発酵と工業, 37(12), 1171
(1979))又は希薄な酸の存在下に9位の水酸基を11位又
は13位へアリル転位させる公知の方法(ケミカル・アン
ド・ファーマシューチカル・ブレタン, 18(8), 1501(19
70)、明治製菓研究年報, 12, 85(1972)、ジャーナル・
オブ・アンチビオチックス, 35(11), 1521(1982))或い
は9位の水酸基を選択的に酸化する公知の方法(ジャー
ナル・オブ・アンチビオチックス, 24(8), 526(1971))
等を実施して、本発明を基軸とした新規有用物質を造出
することが可能である。その一例として、化合物(1
7)(式(III)において、R3がメチル基で表され、R4
がイソアミル基で表される化合物)の9位水酸基を、公
知の方法(特開昭48-13380)を用いて選択的にアセチル
化した誘導体に関して、本発明者らは既に特許出願した
(特願平5-116231)。By the way, a compound represented by the formula (III),
Alternatively, for the salt thereof, a known method of selectively acylating the hydroxyl group at the 9-position or 2'-position (Fermentation and Industry, 37 (12), 1171
(1979)) or a known method of allylic rearrangement of the 9-position hydroxyl group to the 11-position or 13-position in the presence of a dilute acid (Chemical and Pharmaceutical Bretan, 18 (8), 1501 (19).
70), Annual Report of Meiji Seika, 12 , 85 (1972), Journal ・
Of Antibiotics, 35 (11), 1521 (1982)) or a known method of selectively oxidizing the 9-position hydroxyl group (Journal of Antibiotics, 24 (8), 526 (1971))
It is possible to produce a new useful substance based on the present invention by carrying out the above. As an example, the compound (1
7) (in the formula (III), R 3 is represented by a methyl group, and R 4
The present inventors have already filed a patent application for a derivative obtained by selectively acetylating the 9-position hydroxyl group of a compound represented by an isoamyl group) using a known method (JP-A-48-13380) (Japanese Patent Application No. Flat 5-116231).
【0043】なお本発明製造法においては、マイカミノ
ース部分の2'位の水酸基に結合しているシリル基、例え
ばTBDMS基を脱保護するために、有機過酸化物等、例え
ばm-クロロ過安息香酸により酸素1原子を賦与する化学
反応が重要である事を述べた。先にも触れたが、酸素原
子を賦与する本反応は、マイカロース部分の3"位の3級
水酸基のアルキル化反応に先だって行なう事も可能であ
った。実際には、本酸素原子賦与反応は、マイカロース
部分の4"位の2級水酸基のアルキル化反応より先に行な
っても(実施例23参照)、さらに4"位の水酸基に結合
したアシル基を不均一反応により切断する以前に行なっ
ても、式(III)で表される化合物を製造する事が可能
である。しかしながら本発明者の観察する限りにおいて
は、本酸素原子賦与反応はマイカロース部分の3"位の3
級水酸基をアルキル化する直後(又は直前)に実施する
という合成経路が、全収率向上の為には最も効果的であ
る。ところで本発明法に関する工程図1においては、式
(V)で表される化合物はロイコマイシンFrグループを
出発原料として2段階を経て合成した。一方ロイコマイ
シンV(ジャーナル・オブ・アンチビオチックス, 28
(6), 401(1975))を出発原料として用い、1段階の選択
的トリシリル化により式(V)で表される化合物を合成
する事が可能である事を付記する。次に、本発明を実施
例によって詳細に記述する。In the production method of the present invention, mycamino is used.
Silyl group bonded to the 2'-position hydroxyl group of the base moiety, eg
For example, to deprotect the TBDMS group, use an organic peroxide, etc.
Chemistry to give one oxygen atom by m-chloroperbenzoic acid
He said that the reaction was important. As I mentioned earlier, the oxygen source
This reaction, which gives off pups, is a 3 "grade 3rd grade of mycarose.
It is also possible to carry out prior to the alkylation reaction of the hydroxyl groups.
It was. In fact, this oxygen atom donating reaction is
Part of the 4 "-position secondary hydroxyl group
Even (see Example 23), it is further bound to the hydroxyl group at the 4 "position.
Before cleaving the acyl group by heterogeneous reaction
However, it is possible to produce the compound represented by the formula (III).
Is. However, as far as the inventor observes
Is the oxygen atom donation reaction, which is 3 "at the 3" position of the mycalose part.
Immediately (or just before) alkylating the primary hydroxyl group
Is the most effective way to improve the overall yield.
It By the way, in the process diagram 1 relating to the method of the present invention,
The compound represented by (V) is a leucomycin Fr group
It was synthesized as a starting material through two steps. On the other hand, Leucomai
Shin V (Journal of Antibiotics,28
(6), 401 (1975)) as the starting material, one-step selection
Of compound of formula (V) by selective trisilylation
It is added that it is possible to do. Next, the present invention is carried out.
Describe in detail by an example.
【0044】[0044]
実施例1化合物(1)(式(IV)において、R5がプロピオニル基
で表され、R6がTBDMS基で表される化合物)の製造法 ロイコマイシンA7 1.00 gに無水ジメチルホルムアミド
12 mlを加え溶解し、t-ブチルジメチルシリルクロリド
1.18 g及びイミダゾール 1.08 gを加え、50℃で一昼
夜撹拌した。反応液を室温に戻した後、メタノール 50
mlを加え室温で30分間撹拌し、反応液を減圧濃縮し
た。得られた残渣をベンゼン 500 mlで抽出し、ベンゼ
ン層を飽和炭酸水素ナトリウム水溶液 500 mlで2回、
飽和食塩水500 mlで2回順次洗浄した後、有機層を無水
硫酸ナトリウムで乾燥しこれを濾過した。濾液を減圧濃
縮して乾燥後、粗化合物(1) 1.22 gを得た。このう
ち 60mgを分取用TLC(展開系:クロロホルム−メタ
ノール(50:1))で精製して、化合物(1) 35 mgを得
た。 化合物(1)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C56H105NO14Si3 (3) マススペクトル (SIMS) : m/z 1100 (M+H)
+ (4) 比旋光度 : [α]D 25 -17°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、105〜107℃で
熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.61(dd, 2-H), 4.22(m, 3-H), 3.14(br s,
4-H), 3.38(s, 4-OCH3), 3.42(br dd, 5-H), 0.41(br d
d, 7-H), 4,23(m, 9-H), 5.75(dd, 10-H), 6.12(m, 11-
H), 6.12(m, 12-H), 5.62(dt, 13-H), 4.85(ddq, 15-
H), 1.30(d, 16-H3), 1.38(dt, 17-H), 1.66(br d, 17-
H), 4.63(br dd, 18-H), 4.21(d, 1'-H), 3.52(dd, 2'-
H), 2.55(t, 3'-H), 3.35(t, 4'-H), 1.25(d, 6'-H3),
2.53(s, 3'-N(CH3)2), 5.10(d, 1"-H),1.86(dd, 2"-Ha
x), 2.00(d, 2"-Heq), 1.11(s, 3"-CH3), 4.62(d, 4"-
H), 4.37(dq, 5"-H), 1.17(t, 4"-OCOCH2CH3 )Example 1 Compound (1) (in formula (IV), R 5 is a propionyl group
And a compound in which R 6 is a TBDMS group) leucomycin A 7 1.00 g and anhydrous dimethylformamide
Add 12 ml to dissolve and t-butyldimethylsilyl chloride.
1.18 g and imidazole 1.08 g were added, and it stirred at 50 degreeC all day and night. After returning the reaction solution to room temperature, methanol 50
ml was added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was concentrated under reduced pressure. The obtained residue was extracted with 500 ml of benzene, and the benzene layer was extracted twice with 500 ml of a saturated aqueous sodium hydrogen carbonate solution,
After successively washing twice with 500 ml of saturated saline, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 1.22 g of crude compound (1). Of this, 60 mg was purified by preparative TLC (developing system: chloroform-methanol (50: 1)) to obtain 35 mg of compound (1). Physicochemical properties of compound (1) (1) Color and shape: Colorless solid (2) Molecular formula: C 56 H 105 NO 14 Si 3 (3) Mass spectrum (SIMS): m / z 1100 (M + H)
+ (4) Specific rotation: [α] D 25 -17 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 105 to 107 ° C without showing a clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.61 (dd, 2-H), 4.22 (m, 3-H), 3.14 (br s,
4-H), 3.38 (s, 4-OCH 3 ), 3.42 (br dd, 5-H), 0.41 (br d
d, 7-H), 4,23 (m, 9-H), 5.75 (dd, 10-H), 6.12 (m, 11-
H), 6.12 (m, 12-H), 5.62 (dt, 13-H), 4.85 (ddq, 15-
H), 1.30 (d, 16-H 3 ), 1.38 (dt, 17-H), 1.66 (br d, 17-
H), 4.63 (br dd, 18-H), 4.21 (d, 1'-H), 3.52 (dd, 2'-
H), 2.55 (t, 3'-H), 3.35 (t, 4'-H), 1.25 (d, 6'-H 3 ),
2.53 (s, 3'-N (CH 3 ) 2 ), 5.10 (d, 1 "-H), 1.86 (dd, 2" -Ha
x), 2.00 (d, 2 "-Heq), 1.11 (s, 3" -CH 3 ), 4.62 (d, 4 "-
H), 4.37 (dq, 5 "-H), 1.17 (t, 4" -OCOCH 2 C H 3 ).
【0045】実施例2化合物(2)(式(V)において、R6がTBDMS基で表され
る化合物)の製造法 粗化合物(1) 1.16 gにベンゼン 130 mlを加え溶解
し、25%水酸化ナトリウム水溶液 65 ml及び硫酸水素テ
トラ-n-ブチルアンモニウム 358 mgを加え、室温で2時
間激しく撹拌した。ベンゼン層を分取した後、飽和食塩
水 150 mlで2回洗浄し、有機層を無水硫酸ナトリウム
で乾燥しこれを濾過した。濾液を減圧濃縮して得られた
残渣をシリカゲルカラムクロマトグラフィー(200 g:ク
ロロホルム−メタノール(30:1))で精製し、化合物
(2) 795 mgを得た。 化合物(2)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C53H101NO13Si3 (3) マススペクトル (SIMS) : m/z 1044 (M+H)
+ (4) 比旋光度 : [α]D 25 -12°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、98〜100℃で
熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.37(br dd, 2-H), 2.61(dd, 2-H), 4.21(m,
3-H), 3.13(br s, 4-H), 3.37(s, 4-OCH3), 3.42(br d
d, 5-H), 0.41(br dd, 7-H), 4,23(m, 9-H), 5.74(dd,
10-H), 6.11(m, 11-H), 6.11(m, 12-H), 5.62(dt, 13-
H), 4.85(ddq, 15-H), 1.30(d, 16-H3), 1.38(dt, 17-
H), 1.66(br d, 17-H), 4.63(br dd, 18-H), 4.20(d,
1'-H), 3.57(dd, 2'-H), 2.53(t, 3'-H), 3.32(t, 4'-
H), 1.25(d, 6'-H3), 2.51(s, 3'-N(CH3) 2), 5.08(d,
1"-H), 1.77(dd, 2"-Hax), 2.02(d, 2"-Heq), 1.22(s,
3"-CH3), 2.94(t, 4"-H), 3.99(dq, 5"-H), 1.30(d, 6"
-H3)Example 2Compound (2) (in formula (V), R 6 is represented by the TBDMS group
Compound) 130 ml of benzene was added to 1.16 g of crude compound (1) to dissolve it.
65% 25% aqueous sodium hydroxide solution and hydrogen sulfate.
358 mg of tra-n-butylammonium was added, and the mixture was kept at room temperature for 2 hours.
Stir vigorously. After separating the benzene layer, add saturated salt
It was washed twice with 150 ml of water, and the organic layer was dried over anhydrous sodium sulfate.
It was dried over and filtered. Obtained by concentrating the filtrate under reduced pressure
The residue was subjected to silica gel column chromatography (200 g:
The compound was purified by roloform-methanol (30: 1)).
(2) 795 mg was obtained. Physicochemical properties of compound (2) (1) Color and shape: colorless solid (2) molecular formula: C53H101NO13Si3 (3) Mass spectrum (SIMS): m / z 1044 (M + H)
+ (4) Specific rotation: [α]D twenty five -12 ° (c1.0, CH3OH) (5) Melting point: No clear melting point at 98-100 ° C
Melting (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.37 (br dd, 2-H), 2.61 (dd, 2-H), 4.21 (m,
3-H), 3.13 (br s, 4-H), 3.37 (s, 4-OCH3), 3.42 (br d
d, 5-H), 0.41 (br dd, 7-H), 4,23 (m, 9-H), 5.74 (dd,
10-H), 6.11 (m, 11-H), 6.11 (m, 12-H), 5.62 (dt, 13-
H), 4.85 (ddq, 15-H), 1.30 (d, 16-H3), 1.38 (dt, 17-
H), 1.66 (br d, 17-H), 4.63 (br dd, 18-H), 4.20 (d,
1'-H), 3.57 (dd, 2'-H), 2.53 (t, 3'-H), 3.32 (t, 4'-
H), 1.25 (d, 6'-H3), 2.51 (s, 3'-N (CH3) 2), 5.08 (d,
1 "-H), 1.77 (dd, 2" -Hax), 2.02 (d, 2 "-Heq), 1.22 (s,
3 "-CH3), 2.94 (t, 4 "-H), 3.99 (dq, 5" -H), 1.30 (d, 6 "
-H3)
【0046】実施例3化合物(3)(式(VI)において、R4がエチル基で表さ
れ、R6がTBDMS基で表される化合物)の製造法 化合物(2)200 mgに無水ジメチルホルムアミド 3.0 m
lを加え溶解し、60%油性水素化ナトリウム 38 mgを加え
室温で撹拌した。気泡の弱まった後、ヨウ化エチル 899
mgを加え45℃で30分間撹拌した。反応液を室温に
戻した後、水 100 mlを徐々に加え、クロロホルム 100
mlで抽出した。水層に再度クロロホルム100 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過し濾液を減圧濃縮した。得
られた残渣を分取用TLC(展開系:ヘキサン−酢酸エ
チル(2:1))で精製し、化合物(3) 140 mgを得た。 化合物(3)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C55H105NO13Si3 (3) マススペクトル (SIMS) : m/z 1072 (M+H)
+ (4) 比旋光度 : [α]D 26 -17°(c1.0, CH3OH) (5) 融点 : 92℃ (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.37(br dd, 2-H), 2.60(dd, 2-H), 4.21(m,
3-H), 3.37(s, 4-OCH3), 3.38(br dd, 5-H), 0.39(br
dd, 7-H), 4,21(m, 9-H), 5.73(dd, 10-H), 6.10(m, 11
-H), 6.10(m, 12-H), 5.60(dt, 13-H), 4.82(ddq, 15-
H), 1.38(dt, 17-H), 1.63(br d, 17-H), 4.61(br dd,
18-H), 4.16(d, 1'-H), 3.44(dd, 2'-H), 2.52(t, 3'-
H), 3.34(t, 4'-H), 2.50(s, 3'-N(CH3)2), 5.02(d, 1"
-H), 1.75(dd, 2"-Hax), 1.96(br d, 2"-Heq), 1.23(s,
3"-CH3), 2.70(d, 4"-H), 4.22(dq, 5"-H), 3.66(dq,
4"-OCH 2CH3), 3.68(dq, 4"-OCH 2CH3)Example 3 Compound (3) (in formula (VI), R 4 represents an ethyl group.
R 6 is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Ethyl iodide 899 after the bubbles have weakened
mg was added and the mixture was stirred at 45 ° C for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 140 mg of compound (3). Physicochemical properties of compound (3) (1) Color and shape: Colorless solid (2) Molecular formula: C 55 H 105 NO 13 Si 3 (3) Mass spectrum (SIMS): m / z 1072 (M + H)
+ (4) Specific rotation: [α] D 26 -17 ° (c1.0, CH 3 OH) (5) Melting point: 92 ° C (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.37 (br dd, 2-H), 2.60 (dd, 2-H), 4.21 (m,
3-H), 3.37 (s, 4-OCH 3 ), 3.38 (br dd, 5-H), 0.39 (br
dd, 7-H), 4,21 (m, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.60 (dt, 13-H), 4.82 (ddq, 15-
H), 1.38 (dt, 17-H), 1.63 (br d, 17-H), 4.61 (br dd,
18-H), 4.16 (d, 1'-H), 3.44 (dd, 2'-H), 2.52 (t, 3'-
H), 3.34 (t, 4'-H), 2.50 (s, 3'-N (CH 3 ) 2 ), 5.02 (d, 1 "
-H), 1.75 (dd, 2 "-Hax), 1.96 (br d, 2" -Heq), 1.23 (s,
3 "-CH 3 ), 2.70 (d, 4" -H), 4.22 (dq, 5 "-H), 3.66 (dq,
4 "-OC H 2 CH 3 ), 3.68 (dq, 4" -OC H 2 CH 3 )
【0047】実施例4化合物(4)(式(VII)において、R3がメチル基で表
され、R4がエチル基で表され、R6がTBDMS基で表される
化合物)の製造法 化合物(3) 120 mgにクロロホルム 6.0 mlを加え溶解
し、m-クロロ過安息香酸 29 mgを加え、室温で5分間撹
拌した。反応液を10%チオ硫酸ナトリウム水溶液 30 ml
に滴下し、クロロホルム 60 mlで抽出した。クロロホル
ム層を飽和炭酸水素ナトリウム水溶液 60 ml及び飽和食
塩水 60 mlで各2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた固体 127 mgに無水ジメチルホルムアミド
1.3 mlを加え溶解し、60%油性水素化ナトリウム 24 mg
を加え室温で撹拌した。気泡の弱まった後、ヨウ化メチ
ル498 mgを加え45℃で1時間撹拌した。反応液を室温
に戻した後、水 30 mlを徐々に加え、クロロホルム 60
mlで抽出した。水層に再度クロロホルム 60 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過し濾液を減圧濃縮した。得
られた残渣を分取用TLCにチャージし、2日間放置後
展開して精製し(展開系:クロロホルム−メタノール(2
0:1))、化合物(4) 68 mgを得た。 化合物(4)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C50H93NO13Si2 (3) マススペクトル (SIMS) : m/z 971 (M)+ (4) 比旋光度 : [α]D 23 -2°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、72〜74℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 4.05(br dt, 3-H), 3.43(s, 4-OCH3), 3.45
(br d, 5-H), 0.41(br dd, 7-H), 4,18(br d, 9-H), 5.
72(dd, 10-H), 6.10(m, 11-H), 6.10(m, 12-H), 5.62(d
t, 13-H), 4.80(ddq, 15-H),1.30(d, 16-H3), 1.43(dt,
17-H), 1.66(br d, 17-H), 4.56(br dd, 18-H), 4.29
(d,1'-H), 3.32(dd, 2'-H), 2.45(t, 3'-H), 3.36(t,
4'-H), 2.55(s,3'-N(CH3)2), 4.87(d, 1"-H), 1.52(dd,
2"-Hax), 2.23(d, 2"-Heq), 1.21(s,3"-CH3), 3.25(s,
3"-OCH3), 2.76(d, 4"-H), 4.45(dq, 5"-H), 3.64(dq,
4"-OCH 2CH3), 3.68(dq, 4"-OCH 2CH3)Example 4Compound (4) (in formula (VII), R 3 represents a methyl group.
And R 4 is represented by an ethyl group and R 6 is represented by a TBDMS group.
Compound) manufacturing method To compound (3) 120 mg, chloroform 6.0 ml was added and dissolved.
Then, add 29 mg of m-chloroperbenzoic acid and stir at room temperature for 5 minutes.
I stirred. 30 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 60 ml of chloroform. Chloroform
60 ml of saturated aqueous sodium hydrogen carbonate solution and saturated
After washing twice with 60 ml of brine each time, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
Anhydrous dimethylformamide was added to 127 mg of the obtained solid.
Add 1.3 ml and dissolve, 60% oily sodium hydride 24 mg
Was added and stirred at room temperature. After the bubbles are weakened
(498 mg) was added, and the mixture was stirred at 45 ° C. for 1 hour. Room temperature
Then, add 30 ml of water slowly, and add chloroform 60
extracted with ml. Add 60 ml of chloroform again to the aqueous layer and extract.
I put it out. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. Chloroform layer is anhydrous sodium sulfate
After drying with triumnium, this was filtered and the filtrate was concentrated under reduced pressure. Profit
Charge the resulting residue to a preparative TLC and allow it to stand for 2 days
Development and purification (Development system: chloroform-methanol (2
0: 1)), 68 mg of compound (4) was obtained. Physicochemical properties of compound (4) (1) Color and shape: Colorless solid (2) Molecular formula: C50H93NO13Si2 (3) Mass spectrum (SIMS): m / z 971 (M)+ (4) Specific rotation: [α]D twenty three -2 ° (c1.0, CH3OH) (5) Melting point: No melting point, melting at 72-74 ° C
Melt (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 4.05 (br dt, 3-H), 3.43 (s, 4-OCH3), 3.45
(br d, 5-H), 0.41 (br dd, 7-H), 4,18 (br d, 9-H), 5.
72 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (d
t, 13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H)3), 1.43 (dt,
17-H), 1.66 (br d, 17-H), 4.56 (br dd, 18-H), 4.29
(d, 1'-H), 3.32 (dd, 2'-H), 2.45 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH3)2), 4.87 (d, 1 "-H), 1.52 (dd,
2 "-Hax), 2.23 (d, 2" -Heq), 1.21 (s, 3 "-CH3), 3.25 (s,
3 "-OCH3), 2.76 (d, 4 "-H), 4.45 (dq, 5" -H), 3.64 (dq,
4 "-OCH 2CH3), 3.68 (dq, 4 "-OCH 2CH3)
【0048】実施例5化合物(5)(式(III)において、R3がメチル基で表
され、R4がエチル基で表される化合物)(4"-O-エチル-
3"-O-メチルロイコマイシンV)の製造法 化合物(4) 63 mgに 2M テトラ-n-ブチルアンモニウ
ムフルオリド テトラヒドロフラン溶液 530μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 5.2 mlに滴下しクロ
ロホルム 30 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 50 mlで2回、飽和
食塩水 50 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(50:1))で精製し
て、化合物(5) 24 mgを得た。 化合物(5)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C38H65NO13 (3) マススペクトル (SIMS) : m/z 744 (M+H)+ (4) 比旋光度 : [α]D 24 -60°(c1.0, CH3OH) (5) 明瞭な融点を示さず、89〜92℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.20(br d, 2-H), 2.68(dd, 2-H), 3.76(br
d, 3-H), 3.07(br d, 4-H), 3.52(s, 4-OCH3), 4.08(br
dd, 5-H), 1.88(m, 8-H), 4.07(dd, 9-H), 5.66(dd, 1
0-H), 6.24(dd, 11-H), 6.01(br dd, 12-H), 5.58(ddd,
13-H), 2.10(dt, 14-H), 2.48(br d, 14-H), 5.26(dd
q, 15-H), 1.28(d, 16-H3), 2.31(br dd, 17-H), 2.85
(br dd, 17-H), 9.80(br s, 18-H), 0.99(d, 19-H3),
4.56(d, 1'-H), 2.40(t, 3'-H), 3.45(t, 4'-H), 3.24
(dq, 5'-H), 1.15(d, 6'-H3), 2.57(s, 3'-N(CH3)2),
4.87(d, 1"-H), 1.53(dd, 2"-Hax), 2.22(d, 2"-Heq),
1.21(s, 3"-CH3), 2.76(d, 4"-H),4.39(dq, 5"-H), 1.2
1(d, 6"-H3), 3.22(s, 3"-OCH3), 3.63(dq, 4"-OCH 2C
H3),3.67(dq, 4"-OCH 2CH3)Example 5 Compound (5) (in the formula (III), R 3 represents a methyl group.
And R 4 is an ethyl group) (4 "-O-ethyl-
Method for producing 3 "-O-methylleucomycin V) To 63 mg of compound (4), 530 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added and reacted for 1 hour at 45 ° C. The reaction solution was returned to room temperature. Then, the mixture was added dropwise to 5.2 ml of 5% potassium hydrogen sulfate aqueous solution and extracted twice with 30 ml of chloroform.The chloroform layers were combined and washed twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After that, the organic layer was dried over anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)). 24 mg of compound (5) was obtained Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) Molecular formula: C 38 H 65 NO 13 (3) Mass spectrum (SIMS): m / z 744 (M + H) + (4) Specific rotation: [α] D 24 -60 ° (c1.0, CH 3 OH) (5) Melting around 89 to 92 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz , CDCl 3 ) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.76 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH 3 ), 4.08 (br
dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.26 (dd
q, 15-H), 1.28 (d, 16-H 3 ), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 0.99 (d, 19-H 3 ),
4.56 (d, 1'-H), 2.40 (t, 3'-H), 3.45 (t, 4'-H), 3.24
(dq, 5'-H), 1.15 (d, 6'-H 3 ), 2.57 (s, 3'-N (CH 3 ) 2 ),
4.87 (d, 1 "-H), 1.53 (dd, 2" -Hax), 2.22 (d, 2 "-Heq),
1.21 (s, 3 "-CH 3 ), 2.76 (d, 4" -H), 4.39 (dq, 5 "-H), 1.2
1 (d, 6 "-H 3 ), 3.22 (s, 3" -OCH 3 ), 3.63 (dq, 4 "-OC H 2 C
H 3 ), 3.67 (dq, 4 "-OC H 2 CH 3 )
【0049】実施例6化合物(6)(式(VI)において、R4がプロピル基で表
され、R6がTBDMS基で表される化合物)の製造法 化合物(2)200 mgに無水ジメチルホルムアミド 3.0 m
lを加え溶解し、60%油性水素化ナトリウム 38 mgを加え
室温で撹拌した。気泡の弱まった後、ヨウ化プロピル97
9 mgを加え45℃で30分間撹拌した。反応液を室温に
戻した後、水 100 mlを徐々に加え、クロロホルム 100
mlで抽出した。水層に再度クロロホルム100 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過し濾液を減圧濃縮した。得
られた残渣を分取用TLC(展開系:ヘキサン−酢酸エ
チル(2:1))で精製し、化合物(6) 187 mgを得た。 化合物(6)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C56H107NO13Si3 (3) マススペクトル (FDMS) : m/z 1085 (M+H)
+ (4) 比旋光度 : [α]D 25 -11°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、88〜90℃付近
で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.38(br dd, 2-H), 2.60(dd, 2-H), 4.22(m,
3-H), 3.37(s, 4-OCH3), 3.39(br dd, 5-H), 0.39(br
dd, 7-H), 4,22(m, 9-H), 5.75(dd, 10-H), 6.10(m, 11
-H), 6.10(m, 12-H), 5.61(dt, 13-H), 4.82(ddq, 15-
H), 1.39(dt, 17-H), 4.62(br dd, 18-H), 4.17(d, 1'-
H), 3.43(dd, 2'-H), 2.53(t, 3'-H), 3.35(t, 4'-H),
2.51(s, 3'-N(CH3)2), 5.03(d, 1"-H), 1.76(dd, 2"-Ha
x), 1.97(br d, 2"-Heq), 1.25(s, 3"-CH3), 2.71(d,
4"-H), 4.23(dq, 5"-H), 3.56(t, 4"-OCH2 CH2CH3), 0.9
2(t, 4"-OCH2CH2CH3 )Example 6 Compound (6) (in formula (VI), R 4 represents a propyl group.
A compound in which R 6 is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Propyl iodide 97 after the bubbles have weakened
9 mg was added and it stirred at 45 degreeC for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 187 mg of compound (6). Physicochemical properties of compound (6) (1) Color and shape: Colorless solid (2) Molecular formula: C 56 H 107 NO 13 Si 3 (3) Mass spectrum (FDMS): m / z 1085 (M + H)
+ (4) Specific rotation: [α] D 25 -11 ° (c1.0, CH 3 OH) (5) Melting point: Melting at around 88 to 90 ° C (6) 1 H NMR Spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.38 (br dd, 2-H), 2.60 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH 3 ), 3.39 (br dd, 5-H), 0.39 (br
dd, 7-H), 4,22 (m, 9-H), 5.75 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.61 (dt, 13-H), 4.82 (ddq, 15-
H), 1.39 (dt, 17-H), 4.62 (br dd, 18-H), 4.17 (d, 1'-
H), 3.43 (dd, 2'-H), 2.53 (t, 3'-H), 3.35 (t, 4'-H),
2.51 (s, 3'-N (CH 3 ) 2 ), 5.03 (d, 1 "-H), 1.76 (dd, 2" -Ha
x), 1.97 (br d, 2 "-Heq), 1.25 (s, 3" -CH 3 ), 2.71 (d,
4 "-H), 4.23 (dq, 5" -H), 3.56 (t, 4 "-OC H 2 CH 2 CH 3 ), 0.9
2 (t, 4 "-OCH 2 CH 2 C H 3 )
【0050】実施例7化合物(7)(式(VII)において、R3がメチル基で表
され、R4がプロピル基で表され、R6がTBDMS基で表され
る化合物)の製造法 化合物(6) 187 mgにクロロホルム 9.0 mlを加え溶解
し、m-クロロ過安息香酸 44 mgを加え、室温で5分間撹
拌した。反応液を10%チオ硫酸ナトリウム水溶液 50 ml
に滴下し、クロロホルム 100 mlで抽出した。クロロホ
ルム層を飽和炭酸水素ナトリウム水溶液 100 ml及び飽
和食塩水 100 mlで各2回順次洗浄した後、有機層を無
水硫酸ナトリウムで乾燥し、これを濾過した。濾液を減
圧濃縮して得られた固体 164 mgに無水ジメチルホルム
アミド 1.6 mlを加え溶解し、60%油性水素化ナトリウム
30 mgを加え室温で撹拌した。気泡の弱まった後、ヨウ
化メチル 635 mgを加え45℃で1時間撹拌した。反応
液を室温に戻した後、水 40 mlを徐々に加え、クロロホ
ルム 80 mlで抽出した。水層に再度クロロホルム 80 ml
を加え抽出した。クロロホルム層を合わせ、これを飽和
食塩水 150 mlで2回洗浄した。クロロホルム層を無水
硫酸ナトリウムで乾燥後、これを濾過し濾液を減圧濃縮
した。得られた残渣を分取用TLCにチャージし、2日
間放置後展開して精製し(展開系:クロロホルム−メタ
ノール(20:1))、化合物(7) 44 mgを得た。 化合物(7)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C51H95NO13Si2 (3) マススペクトル (SIMS) : m/z 986 (M+H)+ (4) 比旋光度 : [α]D 24 -3°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、67〜69℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 4.05(br dt, 3-H), 3.43(s, 4-OCH3), 0.42
(br dd, 7-H), 4,18(br d, 9-H), 5.73(dd, 10-H),6.10
(m, 11-H), 6.10(m, 12-H), 5.62(dt, 13-H), 4.80(dd
q, 15-H), 1.31(d,16-H3) ,1.43(dt, 17-H), 1.65(br
d, 17-H), 4.57(br dd, 18-H), 4.30(d, 1'-H), 3.32(d
d, 2'-H), 2.47(t, 3'-H), 3.36(t, 4'-H), 2.56(s, 3'
-N(CH3)2), 4.87(d, 1"-H), 1.54(dd, 2"-Hax), 2.22
(d, 2"-Heq), 1.23(s, 3"-CH3), 2.77(d, 4"-H), 4.45
(dq, 5"-H), 3.25(s, 3"-OCH3), 3.54(dt, 4"-OCH 2CH2C
H3), 3.57(dt, 4"-OCH 2CH2CH3), 1.63(m, 4"-OCH2CH2 CH
3)Example 7 Compound (7) (in formula (VII), R 3 represents a methyl group.
R 4 is represented by a propyl group and R 6 is represented by a TBDMS group.
Compound (6) (187 mg) was added with chloroform (9.0 ml) and dissolved, m-chloroperbenzoic acid (44 mg) was added, and the mixture was stirred at room temperature for 5 minutes. 50 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To a solid (164 mg) obtained by concentrating the filtrate under reduced pressure, 1.6 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride was added.
30 mg was added and stirred at room temperature. After the bubbles were weakened, 635 mg of methyl iodide was added, and the mixture was stirred at 45 ° C for 1 hour. After the reaction solution was returned to room temperature, 40 ml of water was gradually added and extracted with 80 ml of chloroform. 80 ml of chloroform again in the water layer
Was extracted. The chloroform layers were combined and washed twice with 150 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, left standing for 2 days, developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 44 mg of compound (7). Physicochemical properties of compound (7) (1) Color and shape: Colorless solid (2) Molecular formula: C 51 H 95 NO 13 Si 2 (3) Mass spectrum (SIMS): m / z 986 (M + H) + ( 4) Specific rotation: [α] D 24 -3 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 67-69 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz , CDCl 3 ) δ
(ppm): 4.05 (br dt, 3-H), 3.43 (s, 4-OCH 3 ), 0.42
(br dd, 7-H), 4,18 (br d, 9-H), 5.73 (dd, 10-H), 6.10
(m, 11-H), 6.10 (m, 12-H), 5.62 (dt, 13-H), 4.80 (dd
q, 15-H), 1.31 (d, 16-H 3 ), 1.43 (dt, 17-H), 1.65 (br
d, 17-H), 4.57 (br dd, 18-H), 4.30 (d, 1'-H), 3.32 (d
d, 2'-H), 2.47 (t, 3'-H), 3.36 (t, 4'-H), 2.56 (s, 3 '
-N (CH 3 ) 2 ), 4.87 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.22
(d, 2 "-Heq), 1.23 (s, 3" -CH 3 ), 2.77 (d, 4 "-H), 4.45
(dq, 5 "-H), 3.25 (s, 3" -OCH 3 ), 3.54 (dt, 4 "-OC H 2 CH 2 C
H 3 ), 3.57 (dt, 4 "-OC H 2 CH 2 CH 3 ), 1.63 (m, 4" -OCH 2 C H 2 CH
3 )
【0051】実施例8化合物(8)(式(III)において、R3がメチル基で表
され、R4がプロピル基で表される化合物)(3"-O-メチ
ル-4"-O-プロピルロイコマイシンV)の製造法 化合物(7) 41 mgに 2M テトラ-n-ブチルアンモニウ
ムフルオリド テトラヒドロフラン溶液 330μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 3.3 mlに滴下しクロ
ロホルム 20 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 40 mlで2回、飽和
食塩水 40 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(50:1))で精製し
て、化合物(8) 30 mgを得た。 化合物(8)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C39H67NO13 (3) マススペクトル (SIMS) : m/z 758 (M+H)+ (4) 比旋光度 : [α]D 25 -55°(c1.0, CH3OH) (5) 明瞭な融点を示さず、79〜81℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.20(br d, 2-H), 2.68(dd, 2-H), 3.77(br
d, 3-H), 3.07(br d, 4-H), 3.52(s, 4-OCH3), 4.08(br
dd, 5-H), 1.88(m, 8-H), 4.07(dd, 9-H), 5.66(dd, 1
0-H), 6.24(dd, 11-H), 6.01(br dd, 12-H), 5.58(ddd,
13-H), 2.10(dt, 14-H), 2.48(br d, 14-H), 5.26(dd
q, 15-H), 1.28(d, 16-H3), 2.31(br dd, 17-H), 2.85
(br dd, 17-H), 9.80(br s, 18-H), 0.99(d, 19-H3),
4.56(d, 1'-H), 3.16(dd, 2'-H), 2.39(t, 3'-H), 3.45
(t, 4'-H), 3.25(dq, 5'-H), 1.15(d, 6'-H3), 2.55(s,
3'-N(CH 3)2), 4.87(d, 1"-H), 1.54(dd, 2"-Hax), 2.2
1(d, 2"-Heq), 1.22(s, 3"-CH3),2.76(d, 4"-H), 4.40
(dq, 5"-H), 1.21(d, 6"-H3), 3.23(s, 3"-OCH3), 3.52
(dt, 4"-OCH 2CH2CH3), 3.56(dt, 4"-OCH 2CH2CH3), 1.60
(m, 4"-OCH2CH2 CH3), 0.90(t, 4"-OCH2CH2CH3 )Example 8Compound (8) (in formula (III), R 3 represents a methyl group.
And R 4 is a propyl group) (3 "-O-methyl
Method for producing le-4 "-O-propylleucomycin V) Compound (7) 41 mg to 2 M tetra-n-butylammonium
Add 330 μl of mufluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 3.3 ml of a 5% potassium hydrogen sulfate aqueous solution, and
It was extracted twice with 20 ml of Loform. Combine the chloroform layers
And saturate twice with 40 ml of saturated aqueous sodium hydrogen carbonate solution.
After sequentially washing twice with 40 ml of saline solution, the organic layer was dehydrated with sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (50: 1))
Thus, 30 mg of compound (8) was obtained. Physicochemical properties of compound (8) (1) Color and shape: Colorless solid (2) Molecular formula: C39H67NO13 (3) Mass spectrum (SIMS): m / z 758 (M + H)+ (4) Specific rotation: [α]D twenty five -55 ° (c1.0, CH3OH) (5) Melting around 79-81 ℃ without showing clear melting point (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH3), 4.08 (br
dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.26 (dd
q, 15-H), 1.28 (d, 16-H3), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 0.99 (d, 19-H3),
4.56 (d, 1'-H), 3.16 (dd, 2'-H), 2.39 (t, 3'-H), 3.45
(t, 4'-H), 3.25 (dq, 5'-H), 1.15 (d, 6'-H)3), 2.55 (s,
3'-N (CH 3)2), 4.87 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.2
1 (d, 2 "-Heq), 1.22 (s, 3" -CH3), 2.76 (d, 4 "-H), 4.40
(dq, 5 "-H), 1.21 (d, 6" -H3), 3.23 (s, 3 "-OCH3), 3.52
(dt, 4 "-OCH 2CH2CH3), 3.56 (dt, 4 "-OCH 2CH2CH3), 1.60
(m, 4 "-OCH2CH 2 CH3), 0.90 (t, 4 "-OCH2CH2CH 3 )
【0052】実施例9化合物(9)(式(VI)において、R4がブチル基で表さ
れ、R6がTBDMS基で表される化合物)の製造法 化合物(2)200 mgに無水ジメチルホルムアミド 3.0 m
lを加え溶解し、60%油性水素化ナトリウム 38 mgを加え
室温で撹拌した。気泡の弱まった後、臭化ブチル 788 m
gを加え45℃で30分間撹拌した。反応液を室温に戻
した後、水 100mlを徐々に加え、クロロホルム 100 ml
で抽出した。水層に再度クロロホルム 100 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過し濾液を減圧濃縮した。得
られた残渣を分取用TLC(展開系:ヘキサン−酢酸エ
チル(2:1))で精製し、化合物(9) 140 mgを得た。 化合物(9)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C57H109NO13Si3 (3) マススペクトル (FDMS) : m/z 1099 (M)+ (4) 比旋光度 : [α]D 26 -13°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、82〜83℃付近
で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.38(br dd, 2-H), 2.60(dd, 2-H), 4.22(m,
3-H), 3.37(s, 4-OCH3), 3.39(br dd, 5-H), 0.40(br
dd, 7-H), 4,22(m, 9-H), 5.74(dd, 10-H), 6.11(m, 11
-H), 6.11(m, 12-H), 5.61(dt, 13-H), 4.82(ddq, 15-
H), 1.39(dt, 17-H), 1.64(br d, 17-H), 4.62(br dd,
18-H), 4.17(d, 1'-H), 3.43(dd, 2'-H), 2.53(t, 3'-
H), 3.34(t, 4'-H), 2.51(s, 3'-N(CH3)2), 5.03(d, 1"
-H), 1.75(dd, 2"-Hax), 1.97(br d, 2"-Heq), 1.24(s,
3"-CH3), 2.70(d, 4"-H), 4.22(dq, 5"-H), 3.60(dt,
4"-OCH2 CH2CH2CH3), 0.90(t, 4"-OCH2CH2CH2CH3 )Example 9 Compound (9) (in the formula (VI), R 4 represents a butyl group.
R 6 is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Butyl bromide 788 m after air bubbles weaken
g was added and the mixture was stirred at 45 ° C for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water and add 100 ml of chloroform.
It was extracted with. Chloroform 100 ml was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 140 mg of compound (9). Physicochemical properties of compound (9) (1) Color and shape: colorless solid (2) Molecular formula: C 57 H 109 NO 13 Si 3 (3) Mass spectrum (FDMS): m / z 1099 (M) + (4) Specific rotation: [α] D 26 -13 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 82-83 ° C without showing a clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.38 (br dd, 2-H), 2.60 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH 3 ), 3.39 (br dd, 5-H), 0.40 (br
dd, 7-H), 4,22 (m, 9-H), 5.74 (dd, 10-H), 6.11 (m, 11
-H), 6.11 (m, 12-H), 5.61 (dt, 13-H), 4.82 (ddq, 15-
H), 1.39 (dt, 17-H), 1.64 (br d, 17-H), 4.62 (br dd,
18-H), 4.17 (d, 1'-H), 3.43 (dd, 2'-H), 2.53 (t, 3'-
H), 3.34 (t, 4'-H), 2.51 (s, 3'-N (CH 3 ) 2 ), 5.03 (d, 1 "
-H), 1.75 (dd, 2 "-Hax), 1.97 (br d, 2" -Heq), 1.24 (s,
3 "-CH 3 ), 2.70 (d, 4" -H), 4.22 (dq, 5 "-H), 3.60 (dt,
4 "-OC H 2 CH 2 CH 2 CH 3 ), 0.90 (t, 4" -OCH 2 CH 2 CH 2 C H 3 )
【0053】実施例10化合物(10)(式(VII)において、R3がメチル基で
表され、R4がブチル基で表され、R6がTBDMS基で表され
る化合物)の製造法 化合物(9) 140 mgにクロロホルム 7 mlを加え溶解
し、m-クロロ過安息香酸33 mgを加え、室温で5分間撹
拌した。反応液を10%チオ硫酸ナトリウム水溶液35 mlに
滴下し、クロロホルム 70 mlで抽出した。クロロホルム
層を飽和炭酸水素ナトリウム水溶液 70 ml及び飽和食塩
水 70 mlで各2回順次洗浄した後、有機層を無水硫酸ナ
トリウムで乾燥し、これを濾過した。濾液を減圧濃縮し
て固体 141 mgを得た。得られた固体 129 mgに無水ジメ
チルホルムアミド 1.3 mlを加え溶解し、60%油性水素化
ナトリウム 23 mgを加え室温で撹拌した。気泡の弱まっ
た後、ヨウ化メチル 494 mgを加え45℃で1時間撹拌
した。反応液を室温に戻した後、水 30 mlを徐々に加
え、クロロホルム 60 mlで抽出した。水層に再度クロロ
ホルム 60 mlを加え抽出した。クロロホルム層を合わ
せ、これを飽和食塩水120 mlで2回洗浄した。クロロホ
ルム層を無水硫酸ナトリウムで乾燥後、これを濾過し濾
液を減圧濃縮した。得られた残渣を分取用TLCにチャ
ージし、3日間放置後展開して精製し(展開系:クロロ
ホルム−メタノール(20:1))、化合物(10) 80 mgを
得た。 化合物(10)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C52H97NO13Si2 (3) マススペクトル (SIMS) : m/z 999 (M+H)+ (4) 比旋光度 : [α]D 24 -4°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、67〜68℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 4.05(br dt, 3-H), 3.44(s, 4-OCH3), 3.46
(dd, 5-H), 0.42(br dd, 7-H), 4,18(br d, 9-H),5.73
(dd, 10-H), 6.10(m, 11-H), 6.10(m, 12-H), 5.62(dt,
13-H), 4.80(ddq,15-H), 1.30(d, 16-H3), 1.43 (dt,
17-H), 1.66(br d, 17-H), 4.56(br dd, 18-H), 4.29
(d, 1'-H), 3.32(dd, 2'-H), 2.46(t, 3'-H), 3.36(t,
4'-H), 2.55(s, 3'-N(CH3)2), 4.87(d, 1"-H), 1.53(d
d, 2"-Hax), 2.21(d, 2"-Heq), 1.22(s,3"-CH3), 2.76
(d, 4"-H), 4.45(dq, 5"-H), 3.25(s, 3"-OCH3), 3.57
(dt, 4"-OCH 2CH2CH2CH3), 3.61(dt, 4"-OCH 2CH2CH2C
H3), 1.58(m, 4"-OCH2CH2 CH2CH3), 1.36(m, 4"-OCH2CH2
CH2 CH3), 0.99(t, 4"-OCH2CH2CH2CH3 )Example 10 Compound (10) (in formula (VII), R 3 is a methyl group.
R 4 is represented by a butyl group and R 6 is represented by a TBDMS group.
Compound (9) (140 mg) was dissolved in chloroform (7 ml), and m-chloroperbenzoic acid (33 mg) was added. The mixture was stirred at room temperature for 5 minutes. The reaction solution was added dropwise to 35 ml of a 10% sodium thiosulfate aqueous solution and extracted with 70 ml of chloroform. The chloroform layer was washed successively with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 70 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 141 mg of a solid. 1.3 ml of anhydrous dimethylformamide was added to and dissolved in 129 mg of the obtained solid, 23 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 494 mg of methyl iodide was added, and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 30 ml of water was gradually added and the mixture was extracted with 60 ml of chloroform. Chloroform (60 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed with 120 ml of saturated saline twice. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, allowed to stand for 3 days and developed (development system: chloroform-methanol (20: 1)) to obtain 80 mg of compound (10). Physicochemical properties of compound (10) (1) Color and shape: Colorless solid (2) Molecular formula: C 52 H 97 NO 13 Si 2 (3) Mass spectrum (SIMS): m / z 999 (M + H) + ( 4) Specific rotation: [α] D 24 -4 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 67-68 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz , CDCl 3 ) δ
(ppm): 4.05 (br dt, 3-H), 3.44 (s, 4-OCH 3 ), 3.46
(dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br d, 9-H), 5.73
(dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt,
13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H 3 ), 1.43 (dt,
17-H), 1.66 (br d, 17-H), 4.56 (br dd, 18-H), 4.29
(d, 1'-H), 3.32 (dd, 2'-H), 2.46 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH 3 ) 2 ), 4.87 (d, 1 "-H), 1.53 (d
d, 2 "-Hax), 2.21 (d, 2" -Heq), 1.22 (s, 3 "-CH 3 ), 2.76
(d, 4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OCH 3 ), 3.57
(dt, 4 "-OC H 2 CH 2 CH 2 CH 3 ), 3.61 (dt, 4" -OC H 2 CH 2 CH 2 C
H 3 ), 1.58 (m, 4 "-OCH 2 C H 2 CH 2 CH 3 ), 1.36 (m, 4" -OCH 2 CH 2
C H 2 CH 3 ), 0.99 (t, 4 "-OCH 2 CH 2 CH 2 C H 3 )
【0054】実施例11化合物(11)(式(III)において、R3がメチル基で
表され、R4がブチル基で表される化合物)(4"-O-ブチ
ル-3"-O-メチルロイコマイシンV)の製造法 化合物(10) 75 mgに 2M テトラ-n-ブチルアンモニ
ウムフルオリド テトラヒドロフラン溶液 600μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 6.0 mlに滴下しクロ
ロホルム 40 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 80mlで2回、飽和
食塩水 80 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(50:1))で精製し
て、化合物(11) 30 mgを得た。 化合物(11)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C40H69NO13 (3) マススペクトル (SIMS) : m/z 772 (M+H)+ (4) 比旋光度 : [α]D 25 -54°(c1.0, CH3OH) (5) 明瞭な融点を示さず、80〜84℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.20(br d, 2-H), 2.68(dd, 2-H), 3.77(br
d, 3-H), 3.08(br d, 4-H), 3.53(s, 4-OCH3), 4.09(br
dd, 5-H), 1.89(m, 8-H), 4.08(dd, 9-H), 5.67(dd, 1
0-H), 6.25(dd, 11-H), 6.02(br dd, 12-H), 5.59(ddd,
13-H), 2.10(dt, 14-H), 2.49(br d, 14-H), 5.27(dd
q, 15-H), 1.29(d, 16-H3), 2.31(br dd, 17-H), 2.86
(br dd, 17-H), 9.80(br s, 18-H), 4.57(d, 1'-H), 3.
16(dd, 2'-H), 2.39(t, 3'-H), 3.45(t, 4'-H), 3.25(d
q, 5'-H), 1.16(d, 6'-H3), 2.55(s, 3'-N(CH3)2), 4.8
7(d, 1"-H), 1.54(dd, 2"-Hax), 2.21(d, 2"-Heq), 1.2
2(s, 3"-CH3), 2.76(d, 4"-H),4.40(dq, 5"-H), 1.21
(d, 6"-H), 3.23(s, 3"-OCH3), 3.55(dt, 4"-OCH 2CH2C
H 2CH3), 3.60(dt, 4"-OCH 2CH2CH2CH3), 1.60(m, 4"-OCH
2CH2 CH2CH3), 1.36(m, 4"-OCH2CH2CH2 CH3), 0.89(t, 4"
-OCH2CH2CH2CH3 )Example 11Compound (11) (in formula (III), R 3 is a methyl group
A compound in which R 4 is a butyl group) (4 "-O-butyl
Process for the production of le-3 "-O-methylleucomycin V) Compound (10) 75 mg to 2M tetra-n-butylammoni
Add 600 μl of umfluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 6.0 ml of 5% potassium hydrogensulfate aqueous solution and add black.
It was extracted twice with 40 ml of Loform. Combine the chloroform layers
Let it saturate twice with 80 ml of saturated aqueous sodium hydrogen carbonate solution.
After washing twice with 80 ml of brine, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (50: 1))
Thus, 30 mg of compound (11) was obtained. Physicochemical properties of compound (11) (1) Color and shape: colorless solid (2) molecular formula: C40H69NO13 (3) Mass spectrum (SIMS): m / z 772 (M + H)+ (4) Specific rotation: [α]D twenty five -54 ° (c1.0, CH3OH) (5) Melting at around 80-84 ℃ without showing clear melting point (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.53 (s, 4-OCH3), 4.09 (br
dd, 5-H), 1.89 (m, 8-H), 4.08 (dd, 9-H), 5.67 (dd, 1
0-H), 6.25 (dd, 11-H), 6.02 (br dd, 12-H), 5.59 (ddd,
13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H3), 2.31 (br dd, 17-H), 2.86
(br dd, 17-H), 9.80 (br s, 18-H), 4.57 (d, 1'-H), 3.
16 (dd, 2'-H), 2.39 (t, 3'-H), 3.45 (t, 4'-H), 3.25 (d
q, 5'-H), 1.16 (d, 6'-H3), 2.55 (s, 3'-N (CH3)2), 4.8
7 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.21 (d, 2 "-Heq), 1.2
2 (s, 3 "-CH3), 2.76 (d, 4 "-H), 4.40 (dq, 5" -H), 1.21
(d, 6 "-H), 3.23 (s, 3" -OCH3), 3.55 (dt, 4 "-OCH 2CH2C
H 2CH3), 3.60 (dt, 4 "-OCH 2CH2CH2CH3), 1.60 (m, 4 "-OCH
2CH 2 CH2CH3), 1.36 (m, 4 "-OCH2CH2CH 2 CH3), 0.89 (t, 4 "
-OCH2CH2CH2CH 3 )
【0055】実施例12化合物(12)(式(VI)において、R4がペンチル基で
表され、R6がTBDMS基で表される化合物)の製造法 化合物(2)200 mgに無水ジメチルホルムアミド 3.0 m
lを加え溶解し、60%油性水素化ナトリウム 38 mgを加え
室温で撹拌した。気泡の弱まった後、ヨウ化ペンチル1.
14 gを加え45℃で30分間撹拌した。反応液を室温に
戻した後、水 100 mlを徐々に加え、クロロホルム 100
mlで抽出した。水層に再度クロロホルム100 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過し濾液を減圧濃縮した。得
られた残渣を分取用TLC(展開系:ヘキサン−酢酸エ
チル(2:1))で精製し、化合物(12) 164 mgを得た。 化合物(12)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C58H111NO13Si3 (3) マススペクトル (FDMS) : m/z 1113 (M)+ (4) 比旋光度 : [α]D 26 -13°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、77〜78℃付近
で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.38(br dd, 2-H), 2.61(dd, 2-H), 4.22(m,
3-H), 3.37(s, 4-OCH3), 3.39(br dd, 5-H), 0.40(br
dd, 7-H), 4,22(m, 9-H), 5.74(dd, 10-H), 6.11(m, 11
-H), 6.11(m, 12-H), 5.61(dt, 13-H), 4.83(ddq, 15-
H), 1.39(dt, 17-H), 4.62(br dd, 18-H), 4.17(d, 1'-
H), 3.43(dd, 2'-H), 2.53(t, 3'-H), 3.35(t, 4'-H),
2.51(s, 3'-N(CH3)2), 5.03(d, 1"-H), 1.76(dd, 2"-Ha
x), 1.97(br d, 2"-Heq), 1.24(s, 3"-CH3), 2.70(d,
4"-H), 4.22(dq, 5"-H), 3.59(dt, 4"-OCH2 CH2CH2CH2CH
3)Example 12 Compound (12) (in the formula (VI), R 4 is a pentyl group.
A compound represented by the formula (2) wherein R 6 is a TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles have weakened, pentyl iodide 1.
14 g was added and stirred at 45 ° C. for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 164 mg of compound (12). Physicochemical properties of compound (12) (1) Color and shape: colorless solid (2) Molecular formula: C 58 H 111 NO 13 Si 3 (3) Mass spectrum (FDMS): m / z 1113 (M) + (4) Specific rotation: [α] D 26 -13 ° (c1.0, CH 3 OH) (5) Melting point: No melting point, melting around 77-78 ° C (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.38 (br dd, 2-H), 2.61 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH 3 ), 3.39 (br dd, 5-H), 0.40 (br
dd, 7-H), 4,22 (m, 9-H), 5.74 (dd, 10-H), 6.11 (m, 11
-H), 6.11 (m, 12-H), 5.61 (dt, 13-H), 4.83 (ddq, 15-
H), 1.39 (dt, 17-H), 4.62 (br dd, 18-H), 4.17 (d, 1'-
H), 3.43 (dd, 2'-H), 2.53 (t, 3'-H), 3.35 (t, 4'-H),
2.51 (s, 3'-N (CH 3 ) 2 ), 5.03 (d, 1 "-H), 1.76 (dd, 2" -Ha
x), 1.97 (br d, 2 "-Heq), 1.24 (s, 3" -CH 3 ), 2.70 (d,
4 "-H), 4.22 (dq, 5" -H), 3.59 (dt, 4 "-OC H 2 CH 2 CH 2 CH 2 CH
3 )
【0056】実施例13化合物(13)(式(VII)において、R3がメチル基で
表され、R4がペンチル基で表され、R6がTBDMS基で表さ
れる化合物)の製造法 化合物(12) 148 mgにクロロホルム 7.5 mlを加え溶
解し、m-クロロ過安息香酸 35 mgを加え、室温で5分間
撹拌した。反応液を10%チオ硫酸ナトリウム水溶液 35 m
lに滴下し、クロロホルム 70 mlで抽出した。クロロホ
ルム層を飽和炭酸水素ナトリウム水溶液 70 ml及び飽和
食塩水 70 mlで各2回順次洗浄した後、有機層を無水硫
酸ナトリウムで乾燥し、これを濾過した。濾液を減圧濃
縮して得られた固体 145 mgに無水ジメチルホルムアミ
ド 1.5 mlを加え溶解し、60%油性水素化ナトリウム 26
mgを加え室温で撹拌した。気泡の弱まった後、ヨウ化メ
チル 545 mgを加え45℃で1時間撹拌した。反応液を
室温に戻した後、水 35 mlを徐々に加え、クロロホルム
75 mlで抽出した。水層に再度クロロホルム 75 mlを加
え抽出した。クロロホルム層を合わせ、これを飽和食塩
水 150 mlで2回洗浄した。クロロホルム層を無水硫酸
ナトリウムで乾燥後、これを濾過し濾液を減圧濃縮し
た。得られた残渣を分取用TLCにチャージし、3日間
放置後展開して精製し(展開系:クロロホルム−メタノ
ール(20:1))、化合物(13) 54 mgを得た。 化合物(13)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C53H99NO13Si2 (3) マススペクトル (SIMS) : m/z 1014 (M+H)
+ (4) 比旋光度 : [α]D 25 -2°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、63〜64℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 4.06(br dt, 3-H), 3.44(s, 4-OCH3), 3.45
(dd, 5-H), 0.42(br dd, 7-H), 4,18(br d, 9-H),5.73
(dd, 10-H), 6.10(m, 11-H), 6.10(m, 12-H), 5.62(dt,
13-H), 4.80(ddq,15-H),1.31(d, 16-H3) ,1.43(dt, 17
-H), 1.66(br d, 17-H), 4.57(br dd, 18-H), 4.29(d,
1'-H), 3.32(dd, 2'-H), 2.47(t, 3'-H), 3.36(t, 4'-
H), 2.55(s, 3'-N(CH3)2), 4.87(d, 1"-H), 1.54(dd,
2"-Hax), 2.22(d, 2"-Heq), 1.22(s, 3"-CH3), 2.76(d,
4"-H), 4.45(dq, 5"-H), 3.25(s, 3"-OCH3), 3.54(dt,
4"-OCH 2CH2CH2CH2CH3), 3.60(dt, 4"-OCH 2CH2CH2CH2CH
3)Example 13 Compound (13) (in formula (VII), R 3 is a methyl group.
R 4 is represented by a pentyl group and R 6 is represented by a TBDMS group.
Compound (12) (148 mg) was added with chloroform (7.5 ml) and dissolved, m-chloroperbenzoic acid (35 mg) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution is a 10% aqueous solution of sodium thiosulfate 35 m
It was added dropwise to l and extracted with 70 ml of chloroform. The chloroform layer was washed successively with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 70 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To the solid 145 mg obtained by concentrating the filtrate under reduced pressure, 1.5 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride 26
mg was added and stirred at room temperature. After the bubbles were weakened, 545 mg of methyl iodide was added, and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, gradually add 35 ml of water and add chloroform.
Extracted with 75 ml. Chloroform (75 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 150 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, left standing for 3 days, developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 54 mg of compound (13). Physicochemical properties of compound (13) (1) Color and shape: colorless solid (2) Molecular formula: C 53 H 99 NO 13 Si 2 (3) Mass spectrum (SIMS): m / z 1014 (M + H)
+ (4) Specific rotation: [α] D 25 -2 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 63-64 ° C without showing a clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 4.06 (br dt, 3-H), 3.44 (s, 4-OCH 3 ), 3.45
(dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br d, 9-H), 5.73
(dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt,
13-H), 4.80 (ddq, 15-H), 1.31 (d, 16-H 3 ), 1.43 (dt, 17
-H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.29 (d,
1'-H), 3.32 (dd, 2'-H), 2.47 (t, 3'-H), 3.36 (t, 4'-
H), 2.55 (s, 3'-N (CH 3 ) 2 ), 4.87 (d, 1 "-H), 1.54 (dd,
2 "-Hax), 2.22 (d, 2" -Heq), 1.22 (s, 3 "-CH 3 ), 2.76 (d,
4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OCH 3 ), 3.54 (dt,
4 "-OC H 2 CH 2 CH 2 CH 2 CH 3 ), 3.60 (dt, 4" -OC H 2 CH 2 CH 2 CH 2 CH
3 )
【0057】実施例14化合物(14)(式(III)において、R3がメチル基で
表され、R4がペンチル基で表される化合物)(3"-O-メ
チル-4"-O-ペンチルロイコマイシンV)の製造法 化合物(13) 50 mgに 2M テトラ-n-ブチルアンモニ
ウムフルオリド テトラヒドロフラン溶液 400μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 4.0 mlに滴下しクロ
ロホルム 25 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 50mlで2回、飽和
食塩水 50 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(50:1))で精製し
て、化合物(14) 23 mgを得た。 化合物(14)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C41H71NO13 (3) マススペクトル (SIMS) : m/z 786 (M+H)+ (4) 比旋光度 : [α]D 24 -55°(c1.0, CH3OH) (5) 明瞭な融点を示さず、76〜78℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.19(br d, 2-H), 2.68(dd, 2-H), 3.77(br
d, 3-H), 3.07(br d, 4-H), 3.52(s, 4-OCH3), 4.08(br
dd, 5-H), 1.88(m, 8-H), 4.07(dd, 9-H), 5.66(dd, 1
0-H), 6.24(dd, 11-H), 6.01(br dd, 12-H), 5.58(ddd,
13-H), 2.10(dt, 14-H), 2.48(br d, 14-H), 5.27(dd
q, 15-H), 1.28(d, 16-H3), 2.31(br dd, 17-H), 9.80
(br s, 18-H),0.99(d, 19-H3), 4.57(d, 1'-H), 3.16(d
d, 2'-H), 2.40(t, 3'-H), 3.45(t, 4'-H), 3.25(dq,
5'-H), 1.15(d, 6'-H3), 2.56(s, 3'-N(CH3)2), 4.86
(d, 1"-H), 1.54(dd, 2"-Hax), 2.20(d, 2"-Heq), 1.22
(s, 3"-CH3), 2.75(d, 4"-H), 4.39(dq, 5"-H), 1.20
(d, 6"-H3), 3.23(s, 3"-OCH3), 3.54(dt, 4"-OCH 2CH2C
H2CH2CH3), 3.58(dt, 4"-OCH 2CH2CH2CH2CH3), 0.87(br
t, 4"-OCH2CH2CH2CH2CH3 )Example 14 Compound (14) (in the formula (III), R 3 is a methyl group.
A compound in which R 4 is a pentyl group) (3 "-O-me
Method for producing tyl-4 "-O-pentylleucomycin V) To 50 mg of compound (13), 400 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added, and the mixture was reacted at 45 ° C for 1 hour. The mixture was added dropwise to 4.0 ml of 5% potassium hydrogensulfate aqueous solution and extracted twice with 25 ml of chloroform.The chloroform layers were combined and washed twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After that, the organic layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)). compound (14) 23 mg to give compound (14) physicochemical properties (1) color and shape:. colorless solid (2) molecular formula: C 41 H 71 NO 13 ( 3) mass spectrum (SIMS) m / z 786 (M + H ) + (4) Specific rotation: [α] D 24 -55 ° (c1.0, CH 3 OH) (5) showed no clear melting point, at around 76 to 78 ° C. Melt (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.19 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH 3 ), 4.08 (br
dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.27 (dd
q, 15-H), 1.28 (d, 16-H 3 ), 2.31 (br dd, 17-H), 9.80
(br s, 18-H), 0.99 (d, 19-H 3 ), 4.57 (d, 1'-H), 3.16 (d
d, 2'-H), 2.40 (t, 3'-H), 3.45 (t, 4'-H), 3.25 (dq,
5'-H), 1.15 (d , 6'-H 3), 2.56 (s, 3'-N (CH 3) 2), 4.86
(d, 1 "-H), 1.54 (dd, 2" -Hax), 2.20 (d, 2 "-Heq), 1.22
(s, 3 "-CH 3 ), 2.75 (d, 4" -H), 4.39 (dq, 5 "-H), 1.20
(d, 6 "-H 3 ), 3.23 (s, 3" -OCH 3 ), 3.54 (dt, 4 "-OC H 2 CH 2 C
H 2 CH 2 CH 3 ), 3.58 (dt, 4 "-OC H 2 CH 2 CH 2 CH 2 CH 3 ), 0.87 (br
t, 4 "-OCH 2 CH 2 CH 2 CH 2 C H 3 )
【0058】実施例15化合物(15)(式(VI)において、R4がイソアミル基
で表され、R6がTBDMS基で表される化合物)の製造法 化合物(2)1.00 gに無水ジメチルホルムアミド 15 ml
を加え溶解し、60%油性水素化ナトリウム 192 mgを加え
室温で撹拌した。気泡の弱まった後、ヨウ化イソアミル
5.70 gを加え45℃で1時間撹拌した。反応液を室温
に戻した後、水 250 mlを徐々に加え、クロロホルム 25
0 mlで抽出した。水層に再度クロロホルム 250 mlを加
え抽出した。クロロホルム層を合わせ、これを飽和食塩
水 500mlで2回洗浄した。クロロホルム層を無水硫酸ナ
トリウムで乾燥後、これを濾過し濾液を減圧濃縮した。
得られた残渣をシリカゲルカラムクロマトグラフィー
(150 g:ヘキサン−酢酸エチル(2:1))で精製して、化
合物(15) 715 mgを得た。 化合物(15)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C58H111NO13Si3 (3) マススペクトル (FDMS) : m/z 1113 (M)+ (4) 比旋光度 : [α]D 25 -13°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、84〜86℃付近
で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.37(br dd, 2-H), 2.59(dd, 2-H), 4.20(m,
3-H), 3.36(s, 4-OCH3), 3.38(br dd, 5-H), 0.38(br
dd, 7-H), 4,20(m, 9-H), 5.73(dd, 10-H), 6.10(m, 11
-H), 6.10(m, 12-H), 5.60(dt, 13-H), 4.81(ddq, 15-
H), 1.38(dt, 17-H), 1.62(br d,17-H), 4.60(br dd, 1
8-H), 4.16(d, 1'-H), 3.42(dd, 2'-H), 2.52(t, 3'-
H), 3.34(t, 4'-H), 2.50(s, 3'-N(CH3)2), 5.01(d, 1"
-H), 1.74(dd, 2"-Hax), 1.95(br d, 2"-Heq), 1.23(s,
3"-CH3), 2.69(d, 4"-H), 4.20(dq, 5"-H), 3.59(dt,
4"-OCH 2CH2CH(CH3)2), 3.63(dt, 4"-OCH 2CH2CH(CH3)2),
1.49(m, 4"-OCH2CH2 CH(CH3)2),1.68(m, 4"-OCH2CH2CH
(CH3)2)Example 15Compound (15) (in formula (VI), R 4 is an isoamyl group
And a compound in which R 6 is a TBDMS group) Compound (2) 1.00 g and anhydrous dimethylformamide 15 ml
And dissolve, and add 192 mg of 60% oily sodium hydride.
Stir at room temperature. After the bubbles have weakened, isoamyl iodide
5.70 g was added and stirred at 45 ° C. for 1 hour. Room temperature
Then, add 250 ml of water gradually, and add 25 ml of chloroform.
It was extracted with 0 ml. Add 250 ml of chloroform again to the aqueous layer.
I extracted it. Combine the chloroform layers and add this to saturated sodium chloride.
It was washed twice with 500 ml of water. The chloroform layer was washed with anhydrous sodium sulfate.
After drying with thorium, this was filtered and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(150 g: hexane-ethyl acetate (2: 1))
Compound (15) 715 mg was obtained. Physicochemical properties of compound (15) (1) Color and shape: colorless solid (2) molecular formula: C58H111NO13Si3 (3) Mass spectrum (FDMS): m / z 1113 (M)+ (4) Specific rotation: [α]D twenty five -13 ° (c1.0, CH3OH) (5) Melting point: No clear melting point, around 84-86 ℃
Melting with (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.37 (br dd, 2-H), 2.59 (dd, 2-H), 4.20 (m,
3-H), 3.36 (s, 4-OCH3), 3.38 (br dd, 5-H), 0.38 (br
dd, 7-H), 4,20 (m, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.60 (dt, 13-H), 4.81 (ddq, 15-
H), 1.38 (dt, 17-H), 1.62 (br d, 17-H), 4.60 (br dd, 1
8-H), 4.16 (d, 1'-H), 3.42 (dd, 2'-H), 2.52 (t, 3'-
H), 3.34 (t, 4'-H), 2.50 (s, 3'-N (CH3)2), 5.01 (d, 1 "
-H), 1.74 (dd, 2 "-Hax), 1.95 (br d, 2" -Heq), 1.23 (s,
3 "-CH3), 2.69 (d, 4 "-H), 4.20 (dq, 5" -H), 3.59 (dt,
4 "-OCH 2CH2CH (CH3)2), 3.63 (dt, 4 "-OCH 2CH2CH (CH3)2),
1.49 (m, 4 "-OCH2CH 2 CH (CH3)2), 1.68 (m, 4 "-OCH2CH2CH
(CH3)2)
【0059】実施例16化合物(16)(式(VII)において、R3がメチル基で
表され、R4がイソアミル基で表され、R6がTBDMS基で表
される化合物)の製造法 化合物(15) 1.42 gにクロロホルム 71 mlを加え溶
解し、m-クロロ過安息香酸 328 mgを加え、室温で5分
間撹拌した。反応液を10%チオ硫酸ナトリウム水溶液 15
0 mlに滴下し、クロロホルム 500 mlで抽出した。クロ
ロホルム層を飽和炭酸水素ナトリウム水溶液 500 ml及
び飽和食塩水 500 mlで各2回順次洗浄した後、有機層
を無水硫酸ナトリウムで乾燥し、これを濾過した。濾液
を減圧濃縮して得られた固体 1.42 gに無水ジメチルホ
ルムアミド 14 mlを加え溶解し、60%油性水素化ナトリ
ウム 251 mgを加え室温で撹拌した。気泡の弱まった
後、ヨウ化メチル 5.39 gを加え45℃で1時間撹拌し
た。反応液を室温に戻した後、水 500 mlを徐々に加
え、クロロホルム 500 mlで抽出した。水層に再度クロ
ロホルム500 mlを加え抽出した。クロロホルム層を合わ
せ、これを飽和食塩水 500 mlで2回洗浄した。クロロ
ホルム層を無水硫酸ナトリウムで乾燥後、これを濾過し
濾液を減圧濃縮し 1.55 gの油状物質を得た。得られた
油状物質 190 mgにメタノール 12 mlを加え溶解し、シ
リカゲル 16.0 gに吸着させた後、メタノールを減圧留
去し、一夜放置した。シリカゲルに吸着している物質を
混合溶媒(クロロホルム−メタノール(5:1))にて抽出
し、溶媒を減圧留去した。得られた残渣をシリカゲルカ
ラムクロマトグラフィー(12 g:クロロホルム−メタノ
ール(50:1))にて精製し、化合物(16) 103 mgを得
た。 化合物(16)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C53H99NO13Si2 (3) マススペクトル (SIMS) : m/z 1014 (M+H)
+ (4) 比旋光度 : [α]D 25 -2°(c1.0, CH3OH) (5) 融点 : 明瞭な融点を示さず、68〜70℃で熔
融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.42(dd, 2-H), 4.05(br dt, 3-H), 3.44(s,
4-OCH3), 3.46(dd, 5-H), 0.42(br dd, 7-H), 4,18(br
d, 9-H), 5.73(dd, 10-H), 6.10(m, 11-H), 6.10(m, 1
2-H), 5.62(dt, 13-H), 4.80(ddq, 15-H), 1.31(d, 16-
H3) ,1.43(dt, 17-H), 1.66(br d, 17-H),4.57(br dd,
18-H), 4.30(d, 1'-H), 3.32(dd, 2'-H), 2.46(t, 3'-
H), 3.36(t,4'-H), 2.55(s, 3'-N(CH3)2), 4.87(d, 1"-
H), 1.54(dd, 2"-Hax), 2.21(d, 2"-Heq), 1.22(s, 3"-
CH3), 2.76(d, 4"-H), 4.45(dq, 5"-H), 3.25(s, 3"-OC
H3),3.57(dt, 4"-OCH 2CH2CH(CH3)2), 3.63(dt, 4"-OCH 2
CH2CH(CH3)2)Example 16 Compound (16) (in the formula (VII), R 3 is a methyl group.
R 4 is an isoamyl group and R 6 is a TBDMS group.
The compound) of Preparation Compound (15) in 1.42 g was dissolved by adding 71 ml of chloroform, m- chloroperbenzoic acid 328 mg was added and stirred for 5 minutes at room temperature. The reaction solution is a 10% aqueous solution of sodium thiosulfate 15
The mixture was added dropwise to 0 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 500 ml of water was gradually added, and the mixture was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 190 mg of the obtained oily substance, 12 ml of methanol was added and dissolved, and after adsorbing on 16.0 g of silica gel, methanol was distilled off under reduced pressure, and the mixture was left overnight. The substance adsorbed on silica gel was extracted with a mixed solvent (chloroform-methanol (5: 1)), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (12 g: chloroform-methanol (50: 1)) to obtain 103 mg of compound (16). Physicochemical properties of compound (16) (1) Color and shape: Colorless solid (2) Molecular formula: C 53 H 99 NO 13 Si 2 (3) Mass spectrum (SIMS): m / z 1014 (M + H)
+ (4) Specific rotation: [α] D 25 -2 ° (c1.0, CH 3 OH) (5) Melting point: Melting at 68-70 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.42 (dd, 2-H), 4.05 (br dt, 3-H), 3.44 (s,
4-OCH 3 ), 3.46 (dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br
d, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 1
2-H), 5.62 (dt, 13-H), 4.80 (ddq, 15-H), 1.31 (d, 16-
H 3 ), 1.43 (dt, 17-H), 1.66 (br d, 17-H), 4.57 (br dd,
18-H), 4.30 (d, 1'-H), 3.32 (dd, 2'-H), 2.46 (t, 3'-
H), 3.36 (t, 4'-H), 2.55 (s, 3'-N (CH 3 ) 2 ), 4.87 (d, 1 "-
H), 1.54 (dd, 2 "-Hax), 2.21 (d, 2" -Heq), 1.22 (s, 3 "-
CH 3 ), 2.76 (d, 4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OC
H 3 ), 3.57 (dt, 4 "-OC H 2 CH 2 CH (CH 3 ) 2 ), 3.63 (dt, 4" -OC H 2
CH 2 CH (CH 3 ) 2 )
【0060】実施例17化合物(16)(式(VII)において、R3がメチル基で
表され、R4がイソアミル基で表され、R6がTBDMS基で表
される化合物)の製造法 化合物(15) 1.42 gにクロロホルム 71 mlを加え溶
解し、m-クロロ過安息香酸 328 mgを加え、室温で5分
間撹拌した。反応液を 10%チオ硫酸ナトリウム水溶液 1
50 mlに滴下し、クロロホルム 500 mlで抽出した。クロ
ロホルム層を飽和炭酸水素ナトリウム水溶液 500 ml及
び飽和食塩水 500 mlで各2回順次洗浄した後、有機層
を無水硫酸ナトリウムで乾燥し、これを濾過した。濾液
を減圧濃縮して得られた固体 1.42 gに無水ジメチルホ
ルムアミド 14 mlを加え溶解し、60%油性水素化ナトリ
ウム 251 mgを加え室温で撹拌した。気泡の弱まった
後、ヨウ化メチル 5.39 gを加え45℃で1時間撹拌し
た。反応液を室温に戻した後、水500 mlを徐々に加え、
クロロホルム 500 mlで抽出した。水層に再度クロロホ
ルム 500 mlを加え抽出した。クロロホルム層を合わ
せ、これを飽和食塩水 500 mlで2回洗浄した。クロロ
ホルム層を無水硫酸ナトリウムで乾燥後、これを濾過し
濾液を減圧濃縮し 1.55 gの油状物質を得た。本油状物
質 190 mgにメタノール 19 mlと 0.025規定塩酸 19 ml
を順次加え溶解し、45℃で2時間反応させた。反応液
を室温に戻した後、飽和炭酸水素ナトリウム水溶液 150
mlに滴下しクロロホルム 150 mlで2回抽出した。クロ
ロホルム層を合わせ、飽和食塩水 300 mlで2回洗浄し
た後、有機層を無水硫酸ナトリウムで乾燥し、これを濾
過した。濾液を減圧濃縮して得られた残渣を分取用TL
C(展開系:クロロホルム−メタノール(30:1))で精製
して、化合物(16) 98 mgを得た。Example 17 Compound (16) (in the formula (VII), R 3 is a methyl group.
R 4 is an isoamyl group and R 6 is a TBDMS group.
The compound) of Preparation Compound (15) in 1.42 g was dissolved by adding 71 ml of chloroform, m- chloroperbenzoic acid 328 mg was added and stirred for 5 minutes at room temperature. Add 10% aqueous sodium thiosulfate solution to the reaction mixture 1
The mixture was added dropwise to 50 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, gradually add 500 ml of water,
It was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 190 mg of this oily substance, 19 ml of methanol and 19 ml of 0.025N hydrochloric acid were added.
Were sequentially added and dissolved, and the mixture was reacted at 45 ° C. for 2 hours. After returning the reaction solution to room temperature, a saturated aqueous solution of sodium hydrogencarbonate 150
The mixture was added dropwise to 150 ml and extracted twice with 150 ml of chloroform. The chloroform layers were combined and washed twice with 300 ml of saturated saline, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is TL for preparative separation.
Purification with C (developing system: chloroform-methanol (30: 1)) yielded 98 mg of compound (16).
【0061】実施例18化合物(17)(式(III)において、R3がメチル基で
表され、R4がイソアミル基で表される化合物)(4"-O-
イソアミル-3"-O-メチルロイコマイシンV)の製造法 化合物(16) 1.07 gに 2M テトラ-n-ブチルアンモニ
ウムフルオリド テトラヒドロフラン溶液 8.4 mlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 50 mlに滴下しクロロ
ホルム 300 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 600mlで2回、飽和
食塩水 600 mlで2回順次洗浄した後、有機層を無水硫
酸ナトリウムで乾燥し、これを濾過した。濾液を減圧濃
縮して得られた残渣をシリカゲルカラムクロマトグラフ
ィー(100 g:クロロホルム−メタノール(50:1))で精
製して、化合物(17)380 mgを得た。 化合物(17)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C41H71NO13 (3) マススペクトル (EIMS) : m/z 785 (M)+ (4) 比旋光度 : [α]D 26 -71°(c1.0, CH3OH) (5) 明瞭な融点を示さず、101〜106℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.22(br d, 2-H), 2.71(dd, 2-H), 3.80(br
d, 3-H), 3.10(br d, 4-H), 3.55(s, 4-OCH3), 4.12(br
dd, 5-H), 1.91(m, 8-H), 4.11(dd, 9-H), 5.69(dd, 1
0-H), 6.27(dd, 11-H), 6.04(br dd, 12-H), 5.62(ddd,
13-H), 2.13(dt,14-H), 2.52(br d, 14-H), 5.30(ddq,
15-H), 1.31(d, 16-H3), 2.34(br dd, 17-H), 2.88(br
dd, 17-H), 9.81(br s, 18-H), 0.99(d, 19-H3), 4.60
(d, 1'-H), 3.18(dd, 2'-H), 2.41(t, 3'-H), 3.48(t,
4'-H), 3.28(dq, 5'-H), 1.18(d, 6'-H3), 2.57(s, 3'-
N(CH 3)2), 4.90(d, 1"-H), 1.57(dd, 2"-Hax), 2.23(d,
2"-Heq), 1.25(s, 3"-CH3),2.79(d, 4"-H), 4.43(dq,
5"-H), 1.23(d, 6"-H3), 3.26(s, 3"-OCH3), 3.60(dt,
4"-OCH 2CH2CH(CH3)2), 3.64(dt, 4"-OCH 2CH2CH(CH3)2),
1.52(m, 4"-OCH2CH2 CH(CH3)2), 1.70(m, 4"-OCH2CH2CH
(CH3)2), 0.89(d, 4"-OCH2CH2CH(CH3)2 )Example 18Compound (17) (in the formula (III), R 3 is a methyl group.
Represented by R 4 is an isoamyl group) (4 "-O-
Method for producing isoamyl-3 "-O-methylleucomycin V) Compound (16) 1.07 g to 2M tetra-n-butylammoni
Add 8.4 ml of umfluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 50 ml of 5% potassium hydrogensulfate aqueous solution and add chloro.
It was extracted twice with 300 ml of form. Combine the chloroform layers
And saturate with 600 ml of saturated aqueous sodium hydrogen carbonate solution twice.
After sequentially washing twice with 600 ml of saline solution, the organic layer was dehydrated.
It was dried over sodium acidate and filtered. The filtrate is concentrated under reduced pressure.
Silica gel column chromatograph of the residue obtained by shrinking
(100 g: chloroform-methanol (50: 1))
The compound (17) (380 mg) was obtained. Physicochemical properties of compound (17) (1) Color and shape: colorless solid (2) molecular formula: C41H71NO13 (3) Mass spectrum (EIMS): m / z 785 (M)+ (4) Specific rotation: [α]D 26 -71 ° (c1.0, CH3OH) (5) Melting at around 101-106 ℃ without showing clear melting point (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.22 (br d, 2-H), 2.71 (dd, 2-H), 3.80 (br
d, 3-H), 3.10 (br d, 4-H), 3.55 (s, 4-OCH3), 4.12 (br
dd, 5-H), 1.91 (m, 8-H), 4.11 (dd, 9-H), 5.69 (dd, 1
0-H), 6.27 (dd, 11-H), 6.04 (br dd, 12-H), 5.62 (ddd,
13-H), 2.13 (dt, 14-H), 2.52 (br d, 14-H), 5.30 (ddq,
15-H), 1.31 (d, 16-H3), 2.34 (br dd, 17-H), 2.88 (br
dd, 17-H), 9.81 (br s, 18-H), 0.99 (d, 19-H)3), 4.60
(d, 1'-H), 3.18 (dd, 2'-H), 2.41 (t, 3'-H), 3.48 (t,
4'-H), 3.28 (dq, 5'-H), 1.18 (d, 6'-H3), 2.57 (s, 3'-
N (CH 3)2), 4.90 (d, 1 "-H), 1.57 (dd, 2" -Hax), 2.23 (d,
2 "-Heq), 1.25 (s, 3" -CH3), 2.79 (d, 4 "-H), 4.43 (dq,
5 "-H), 1.23 (d, 6" -H3), 3.26 (s, 3 "-OCH3), 3.60 (dt,
4 "-OCH 2CH2CH (CH3)2), 3.64 (dt, 4 "-OCH 2CH2CH (CH3)2),
1.52 (m, 4 "-OCH2CH 2 CH (CH3)2), 1.70 (m, 4 "-OCH2CH2CH
(CH3)2), 0.89 (d, 4 "-OCH2CH2CH (CH 3 ) 2 )
【0062】実施例19化合物(18)(式(VII)において、R3がエチル基で
表され、R4がイソアミル基で表され、R6がTBDMS基で表
される化合物)の製造法 化合物(15)190 mgに無水ジメチルホルムアミド 1.0
mlを加え溶解し、60%油性水素化ナトリウム 34 mgを加
え室温で撹拌した。気泡の弱まった後、ヨウ化エチル 7
96 mgを加え45℃で3時間撹拌した。反応液を室温に
戻した後、水 100 mlを徐々に加え、クロロホルム 100
mlで抽出した。水層に再度クロロホルム100 mlを加え抽
出した。クロロホルム層を合わせ、これを飽和食塩水 1
00 mlで2回洗浄した。クロロホルム層を無水硫酸ナト
リウムで乾燥後、これを濾過した。濾液を減圧濃縮して
粗 9,18,2'-トリ-O-TBDMS-3"-O-エチル-4"-O-イソアミ
ルロイコマイシンV-3,18-アセタール 114 mgを得た。こ
れにクロロホルム 5.7 mlを加え溶解し、m-クロロ過安
息香酸 26 mgを加え、室温で5分間撹拌した。反応液を
10%チオ硫酸ナトリウム水溶液 30 mlに滴下し、クロロ
ホルム 60 mlで抽出した。クロロホルム層を飽和炭酸水
素ナトリウム水溶液 60 ml及び飽和食塩水 60 mlで各2
回順次洗浄した後、有機層を無水硫酸ナトリウムで乾燥
し、これを濾過した。濾液を減圧濃縮して得られた残渣
を分取用TLCにチャージし、3日間放置後展開して精
製し(展開系:クロロホルム−メタノール(20:1))、化
合物(18) 56 mgを得た。 化合物(18)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C54H101NO13Si2 (3) マススペクトル (FDMS) : m/z 1028 (M+H)
+ (4) 比旋光度 : [α]D 26 -11°(c1.0, CH3OH) (5) 融点 : 66〜67℃ (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.41(dd, 2-H), 4.05(br dt, 3-H), 3.44(s,
4-OCH3), 0.42(br dd, 7-H), 4,19(br d, 9-H),5.73(d
d, 10-H), 6.10(m, 11-H), 6.10(m, 12-H), 5.62(dt, 1
3-H), 4.80(ddq,15-H), 1.31(d, 16-H3), 1.44(dt, 17-
H), 1.66(br d, 17-H), 4.57(br dd, 18-H), 4.29(d,
1'-H), 3.33(dd, 2'-H), 2.45(t, 3'-H), 3.31(t, 4'-
H), 3.24(dq, 5'-H), 2.55(s, 3'-N(CH3)2), 4.84(d,
1"-H), 1.54(dd, 2"-Hax), 2.21(d, 2"-Heq), 1.23(s,
3"-CH3), 2.74(d, 4"-H), 4.46(dq, 5"-H), 3.45(dq,
3"-OCH 2CH3), 3.50(dq, 3"-OCH 2CH3), 1.14(t, 3"-OCH2
CH3 ), 3.54(dt, 4"-OCH 2CH2CH(CH3)2), 3.66(dt, 4"-OC
H 2CH2CH(CH3)2)Example 19 Compound (18) (in formula (VII), R 3 is an ethyl group
R 4 is an isoamyl group and R 6 is a TBDMS group.
Compounds) of Preparation compound (15) in anhydrous dimethylformamide 1.0 190 mg
ml was added and dissolved, 34% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles have weakened, ethyl iodide 7
96 mg was added and it stirred at 45 degreeC for 3 hours. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 114 mg of crude 9,18,2'-tri-O-TBDMS-3 "-O-ethyl-4" -O-isoamylleucomycin V-3,18-acetal. Chloroform (5.7 ml) was added to and dissolved in this, m-chloroperbenzoic acid (26 mg) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution
The mixture was added dropwise to 30 ml of a 10% aqueous sodium thiosulfate solution and extracted with 60 ml of chloroform. The chloroform layer was diluted with 60 ml of saturated aqueous sodium hydrogencarbonate solution and 60 ml of saturated saline solution each for 2 times.
After being washed successively, the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was charged in a preparative TLC, left standing for 3 days and developed (development system: chloroform-methanol (20: 1)) to obtain 56 mg of compound (18). It was Physicochemical properties of compound (18) (1) Color and shape: colorless solid (2) Molecular formula: C 54 H 101 NO 13 Si 2 (3) Mass spectrum (FDMS): m / z 1028 (M + H)
+ (4) Specific rotation: [α] D 26 -11 ° (c1.0, CH 3 OH) (5) Melting point: 66-67 ° C (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.41 (dd, 2-H), 4.05 (br dt, 3-H), 3.44 (s,
4-OCH 3 ), 0.42 (br dd, 7-H), 4,19 (br d, 9-H), 5.73 (d
d, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt, 1
3-H), 4.80 (ddq, 15-H), 1.31 (d, 16-H 3 ), 1.44 (dt, 17-
H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.29 (d,
1'-H), 3.33 (dd, 2'-H), 2.45 (t, 3'-H), 3.31 (t, 4'-
H), 3.24 (dq, 5'-H), 2.55 (s, 3'-N (CH 3 ) 2 ), 4.84 (d,
1 "-H), 1.54 (dd, 2" -Hax), 2.21 (d, 2 "-Heq), 1.23 (s,
3 "-CH 3 ), 2.74 (d, 4" -H), 4.46 (dq, 5 "-H), 3.45 (dq,
3 "-OC H 2 CH 3 ), 3.50 (dq, 3" -OC H 2 CH 3 ), 1.14 (t, 3 "-OCH 2
C H 3 ), 3.54 (dt, 4 "-OC H 2 CH 2 CH (CH 3 ) 2 ), 3.66 (dt, 4" -OC
H 2 CH 2 CH (CH 3 ) 2 )
【0063】実施例20化合物(19)(式(III)において、R3がエチル基で
表され、R4がイソアミル基で表される化合物)(3"-O-
エチル-4"-O-イソアミルロイコマイシンV)の製造法 化合物(18) 56 mgに 2M テトラ-n-ブチルアンモニ
ウムフルオリド テトラヒドロフラン溶液 430μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 4.3 mlに滴下しクロ
ロホルム 25 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 50mlで2回、飽和
食塩水 50 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(30:1))で精製し
て、化合物(19)23 mgを得た。 化合物(19)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C42H73NO13 (3) マススペクトル (EIMS) : m/z 799 (M)+ (4) 比旋光度 : [α]D 26 -70°(c1.0, CH3OH) (5) 明瞭な融点を示さず、98〜100℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.20(br d, 2-H), 2.69(dd, 2-H), 3.77(br
d, 3-H), 3.08(br d, 4-H), 3.53(s, 4-OCH3), 4.09(br
dd, 5-H), 1.88(m, 8-H), 4.08(dd, 9-H), 5.66(dd, 1
0-H), 6.25(dd, 11-H), 6.01(br dd, 12-H), 5.59(ddd,
13-H), 2.10(dt, 14-H), 2.49(br d, 14-H), 5.27(dd
q, 15-H), 1.29(d, 16-H3), 2.31(br dd, 17-H), 2.86
(br dd, 17-H), 9.80(br s, 18-H), 0.97(d, 19-H3),
4.56(d, 1'-H), 3.16(dd, 2'-H), 2.38(t, 3'-H), 3.40
(t, 4'-H), 3.24(dq, 5'-H), 1.15(d, 6'-H3), 2.55(s,
3'-N(CH 3)2), 4.83(d, 1"-H), 1.55(dd, 2"-Hax), 2.2
0(d, 2"-Heq), 1.22(s, 3"-CH3),2.73(d, 4"-H), 4.41
(dq, 5"-H), 1.21(d, 6"-H3), 3.42(dq, 3"-OCH 2CH3),
3.47(dq, 3"-OCH 2CH3), 1.11(t, 3"-OCH2CH3 ), 3.56(d
t, 4"-OCH 2CH2CH(CH3)2), 3.64(dt, 4"-OCH 2CH2CH(CH3)
2), 1.49(m, 4"-OCH2CH2 CH(CH3)2), 1.65(m, 4"-OCH 2CH
2CH(CH3)2), 0.87(d, 4"-OCH2CH2CH(CH3)2 )Example 20Compound (19) (in formula (III), R 3 is an ethyl group
Represented by R 4 is an isoamyl group) (3 "-O-
Method for producing ethyl-4 "-O-isoamyl leucomycin V) Compound (18) 56 mg to 2M tetra-n-butylammoni
Add 430 μl of um fluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 4.3 ml of 5% potassium hydrogensulfate aqueous solution and add black.
Extracted twice with 25 ml Loform. Combine the chloroform layers
And saturate with 50 ml of saturated aqueous sodium hydrogen carbonate solution twice.
After sequentially washing twice with 50 ml of brine, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (30: 1))
Thus, 23 mg of compound (19) was obtained. Physicochemical properties of compound (19) (1) Color and shape: Colorless solid (2) Molecular formula: C42H73NO13 (3) Mass spectrum (EIMS): m / z 799 (M)+ (4) Specific rotation: [α]D 26 -70 ° (c1.0, CH3OH) (5) Melting at around 98-100 ° C without showing clear melting point (6)11 H NMR spectrum (400MHz, CDCl3) δ
(ppm): 2.20 (br d, 2-H), 2.69 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.53 (s, 4-OCH3), 4.09 (br
dd, 5-H), 1.88 (m, 8-H), 4.08 (dd, 9-H), 5.66 (dd, 1
0-H), 6.25 (dd, 11-H), 6.01 (br dd, 12-H), 5.59 (ddd,
13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H3), 2.31 (br dd, 17-H), 2.86
(br dd, 17-H), 9.80 (br s, 18-H), 0.97 (d, 19-H3),
4.56 (d, 1'-H), 3.16 (dd, 2'-H), 2.38 (t, 3'-H), 3.40
(t, 4'-H), 3.24 (dq, 5'-H), 1.15 (d, 6'-H3), 2.55 (s,
3'-N (CH 3)2), 4.83 (d, 1 "-H), 1.55 (dd, 2" -Hax), 2.2
0 (d, 2 "-Heq), 1.22 (s, 3" -CH3), 2.73 (d, 4 "-H), 4.41
(dq, 5 "-H), 1.21 (d, 6" -H3), 3.42 (dq, 3 "-OCH 2CH3),
3.47 (dq, 3 "-OCH 2CH3), 1.11 (t, 3 "-OCH2CH 3 ), 3.56 (d
t, 4 "-OCH 2CH2CH (CH3)2), 3.64 (dt, 4 "-OCH 2CH2CH (CH3)
2), 1.49 (m, 4 "-OCH2CH 2 CH (CH3)2), 1.65 (m, 4 "-OCH 2CH
2CH(CH3)2), 0.87 (d, 4 "-OCH2CH2CH (CH 3 ) 2 )
【0064】実施例21化合物(20)(式(VII)において、R3がプロピル基
で表され、R4がイソアミル基で表され、R6がTBDMS基で
表される化合物)の製造法 化合物(15)410 mgに無水ジメチルホルムアミド 820
μlを加え溶解し、60%油性水素化ナトリウム 74 mgを加
え室温で撹拌した。気泡の弱まった後、ヨウ化プロピル
1.88 gを加え45℃で4時間撹拌した。反応液を室温
に戻した後、水200 mlを徐々に加え、クロロホルム 200
mlで抽出した。水層に再度クロロホルム 200 mlを加え
抽出した。クロロホルム層を合わせ、これを飽和食塩水
400 mlで2回洗浄した。クロロホルム層を無水硫酸ナ
トリウムで乾燥後、これを濾過した。濾液を減圧濃縮し
て得られた固体 420 mgを分取用TLC(展開系:ヘキ
サン−酢酸エチル(4:1))で精製して、9,18,2'-トリ-O-
TBDMS-4"-O-イソアミル-3"-O-プロピルロイコマイシンV
-3,18-アセタール 147 mgを得た。これにクロロホルム
6.5 mlを加え溶解し、m-クロロ過安息香酸 24 mgを加
え、室温で5分間撹拌した。反応液を10%チオ硫酸ナト
リウム水溶液 25 mlに滴下し、クロロホルム100 mlで抽
出した。クロロホルム層を飽和炭酸水素ナトリウム水溶
液 100 ml及び飽和食塩水 100 mlで各2回順次洗浄した
後、有機層を無水硫酸ナトリウムで乾燥し、これを濾過
した。濾液を減圧濃縮して得られた残渣を分取用TLC
にチャージし、3日間放置後展開して精製し(展開系:
クロロホルム−メタノール(20:1))、化合物(20) 8
1 mgを得た。 化合物(20)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C55H103NO13Si2 (3) マススペクトル (FDMS) : m/z 1042(M+H)
+ (4) 比旋光度 : [α]D 24 -17°(c1.0, CHC
l3) (5) 明瞭な融点を示さず、57〜63℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.43(dd, 2-H), 4.07(br d, 3-H), 3.27(br
d, 4-H), 3.46(s, 4-OCH3), 3.48(br dd, 5-H), 4.21(d
d, 9-H), 5.75(dd, 10-H), 6.12(m, 11-H), 6.12(m, 12
-H), 5.64(ddd, 13-H), 4.83(ddq, 15-H), 1.33(d, 16-
H3), 1.49(br dd, 17-H), 4.59(br s, 18-H), 4.31(d,
1'-H), 3.36(dd, 2'-H), 2.48(t, 3'-H), 3.25(dq, 5'-
H), 2.58(s,3'-N(CH3)2), 4.85(d, 1"-H), 1.57(dd, 2"
-Hax), 2.21(d, 2"-Heq), 1.24(s,3"-CH3), 2.77(d, 4"
-H), 4.46(dq, 5"-H), 1.22(d, 6"-H3), 3.42(dt, 3"-O
CH 2CH2CH3), 0.88(t, 3"-OCH2CH2CH3 ), 3.59(dt, 4"-OC
H 2CH2CH(CH3)2), 3.68(dt,4"-OCH 2CH2CH(CH3)2), 0.90
(d, 4"-OCH2CH2CH(CH3)2 )Example 21 Compound (20) (in the formula (VII), R 3 is a propyl group)
, R 4 is an isoamyl group, and R 6 is a TBDMS group.
Preparation compound of the compound represented by) (15) 410 anhydrous mg dimethylformamide 820
μl was added and dissolved, 60% oily sodium hydride (74 mg) was added, and the mixture was stirred at room temperature. Propyl iodide after the bubbles have weakened
1.88 g was added and the mixture was stirred at 45 ° C. for 4 hours. After returning the reaction solution to room temperature, slowly add 200 ml of water and add chloroform 200
extracted with ml. 200 ml of chloroform was added again to the aqueous layer for extraction. Combine the chloroform layers and add this to saturated saline.
It was washed twice with 400 ml. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. 420 mg of a solid obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (developing system: hexane-ethyl acetate (4: 1)) to obtain 9,18,2'-tri-O-.
TBDMS-4 "-O-isoamyl-3" -O-propylleucomycin V
147 mg of -3,18-acetal was obtained. Chloroform
6.5 ml was added and dissolved, 24 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was added dropwise to 25 ml of 10% aqueous sodium thiosulfate solution and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is preparative TLC
And leave it for 3 days before developing and refining (Development system:
Chloroform-methanol (20: 1)), compound (20) 8
1 mg was obtained. Physicochemical properties of compound (20) (1) Color and shape: colorless solid (2) Molecular formula: C 55 H 103 NO 13 Si 2 (3) Mass spectrum (FDMS): m / z 1042 (M + H)
+ (4) Specific rotation: [α] D 24 -17 ° (c1.0, CHC
l 3 ) (5) Melting around 57-63 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.43 (dd, 2-H), 4.07 (br d, 3-H), 3.27 (br
d, 4-H), 3.46 (s, 4-OCH 3 ), 3.48 (br dd, 5-H), 4.21 (d
d, 9-H), 5.75 (dd, 10-H), 6.12 (m, 11-H), 6.12 (m, 12
-H), 5.64 (ddd, 13-H), 4.83 (ddq, 15-H), 1.33 (d, 16-
H 3 ), 1.49 (br dd, 17-H), 4.59 (br s, 18-H), 4.31 (d,
1'-H), 3.36 (dd, 2'-H), 2.48 (t, 3'-H), 3.25 (dq, 5'-
H), 2.58 (s, 3'-N (CH 3 ) 2 ), 4.85 (d, 1 "-H), 1.57 (dd, 2"
-Hax), 2.21 (d, 2 "-Heq), 1.24 (s, 3" -CH 3 ), 2.77 (d, 4 "
-H), 4.46 (dq, 5 "-H), 1.22 (d, 6" -H 3 ), 3.42 (dt, 3 "-O
C H 2 CH 2 CH 3 ), 0.88 (t, 3 "-OCH 2 CH 2 C H 3 ), 3.59 (dt, 4" -OC
H 2 CH 2 CH (CH 3 ) 2 ), 3.68 (dt, 4 "-OC H 2 CH 2 CH (CH 3 ) 2 ), 0.90
(d, 4 "-OCH 2 CH 2 CH (C H 3 ) 2 )
【0065】実施例22化合物(21)(式(III)において、R3がプロピル基
で表され、R4がイソアミル基で表される化合物)(4"-O
-イソアミル-3"-O-プロピルロイコマイシンV)の製造法 化合物(20) 37 mgに 2M テトラ-n-ブチルアンモニ
ウムフルオリド テトラヒドロフラン溶液 280μl を加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 3 mlに滴下しクロロ
ホルム 20 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 50 mlで2回、飽和
食塩水 50 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(6.0 g:クロロホルム−メタノール(50:1))で精製
して、化合物(21)9.8 mgを得た。 化合物(21)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C43H75NO13 (3) マススペクトル (SIMS) : m/z 814 (M+H)+ (4) 比旋光度 : [α]D 24 -73°(c1.0, CH3O
H) (5) 明瞭な融点を示さず、88〜93℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.22(br d, 2-H), 2.70(dd, 2-H), 3.79(br
d, 3-H), 3.10(br d, 4-H), 3.55(s, 4-OCH3), 4.10(br
dd, 5-H), 1.91(m, 8-H), 4.11(dd, 9-H), 5.68(dd, 1
0-H), 6.26(dd, 11-H), 6.04(br dd, 12-H), 5.61(ddd,
13-H), 2.12(dt,14-H), 2.51(br d, 14-H), 5.29(ddq,
15-H), 1.30(d, 16-H3), 2.33(br dd, 17-H), 2.88(br
dd, 17-H),9.80(br s, 18-H), 0.98(d, 19-H3), 4.58
(d, 1'-H), 3.18(dd, 2'-H), 2.40(t, 3'-H), 3.41(t,
4'-H), 3.26(dq, 5'-H), 1.17(d, 6'-H3), 2.56(s, 3'-
N(CH3)2), 4.84(d, 1"-H), 1.57(dd, 2"-Hax), 2.21(d,
2"-Heq), 1.23(s, 3"-CH3),2.76(d, 4"-H), 4.41(dq,
5"-H), 1.22(d, 6"-H3), 3.28(dt, 3"-OCH 2CH2CH3),3.3
9(dt, 3"-OCH 2CH2CH3), 0.87(t, 3"-OCH2CH2CH3 ), 3.58
(dt, 4"-OCH 2CH2CH(CH3)2), 3.66(dt, 4"-OCH 2CH2CH(CH
3)2), 1.68(m, 4"-OCH2CH2CH(CH3)2), 0.89(d, 4"-OCH2
CH2CH(CH3)2 )Example 22 Compound (21) (in the formula (III), R 3 is a propyl group)
And a compound in which R 4 is an isoamyl group) (4 "-O
Method for producing -isoamyl- 3 "-O-propylleucomycin V) To 37 mg of compound (20) was added 280 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution, and the mixture was reacted at 45 ° C for 1 hour. After returning to room temperature, the mixture was added dropwise to 3 ml of 5% potassium hydrogen sulfate aqueous solution and extracted twice with 20 ml of chloroform.The chloroform layers were combined, twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After washing sequentially, the organic layer was dried over anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (6.0 g: chloroform-methanol (50: 1)). ., compounds (21) to obtain a 9.8 mg physicochemical properties of the compound (21) (1) color and shape: colorless solid (2) molecular formula: C 43 H 75 NO 13 ( 3) mass spectrometry (SIMS): m / z 814 (M + H) + (4) Specific rotation: [α] D 24 -73 ° (c1.0, CH 3 O
H) (5) Melting in the vicinity of 88 to 93 ℃ without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.22 (br d, 2-H), 2.70 (dd, 2-H), 3.79 (br
d, 3-H), 3.10 (br d, 4-H), 3.55 (s, 4-OCH 3 ), 4.10 (br
dd, 5-H), 1.91 (m, 8-H), 4.11 (dd, 9-H), 5.68 (dd, 1
0-H), 6.26 (dd, 11-H), 6.04 (br dd, 12-H), 5.61 (ddd,
13-H), 2.12 (dt, 14-H), 2.51 (br d, 14-H), 5.29 (ddq,
15-H), 1.30 (d, 16-H 3 ), 2.33 (br dd, 17-H), 2.88 (br
dd, 17-H), 9.80 (br s, 18-H), 0.98 (d, 19-H 3 ), 4.58
(d, 1'-H), 3.18 (dd, 2'-H), 2.40 (t, 3'-H), 3.41 (t,
4'-H), 3.26 (dq, 5'-H), 1.17 (d, 6'-H 3 ), 2.56 (s, 3'-
N (CH 3 ) 2 ), 4.84 (d, 1 "-H), 1.57 (dd, 2" -Hax), 2.21 (d,
2 "-Heq), 1.23 (s, 3" -CH 3 ), 2.76 (d, 4 "-H), 4.41 (dq,
5 "-H), 1.22 (d, 6" -H 3 ), 3.28 (dt, 3 "-OC H 2 CH 2 CH 3 ), 3.3
9 (dt, 3 "-OC H 2 CH 2 CH 3 ), 0.87 (t, 3" -OCH 2 CH 2 C H 3 ), 3.58
(dt, 4 "-OC H 2 CH 2 CH (CH 3 ) 2 ), 3.66 (dt, 4" -OC H 2 CH 2 CH (CH
3 ) 2 ), 1.68 (m, 4 "-OCH 2 CH 2 C H (CH 3 ) 2 ), 0.89 (d, 4" -OCH 2
CH 2 CH (C H 3 ) 2 )
【0066】実施例23化合物(22)(式(VII)において、R3がメチル基で
表され、R4がメチル基で表され、R6がTBDMS基で表され
る化合物)の製造法 化合物(2) 200 mgにクロロホルム 10 mlを加え溶解
し、m-クロロ過安息香酸 50 mgを加え、室温で5分間撹
拌した。反応液を10%チオ硫酸ナトリウム水溶液 50 ml
に滴下し、クロロホルム 100 mlで抽出した。クロロホ
ルム層を飽和炭酸水素ナトリウム水溶液 100 ml及び飽
和食塩水 100 mlで各2回順次洗浄した後、有機層を無
水硫酸ナトリウムで乾燥し、これを濾過した。濾液を減
圧濃縮して得られた固体 200 mgに無水ジメチルホルム
アミド 2.0 mlを加え溶解し、60%油性水素化ナトリウム
60 mgを加え室温で撹拌した。気泡の弱まった後、ヨウ
化メチル 1.2 gを加え45℃で1時間撹拌した。反応液
を室温に戻した後、水 100 mlを徐々に加え、クロロホ
ルム 100 mlで抽出した。水層に再度クロロホルム 100m
lを加え抽出した。クロロホルム層を合わせ、これを飽
和食塩水 100 mlで2回洗浄した。クロロホルム層を無
水硫酸ナトリウムで乾燥後、これを濾過し濾液を減圧濃
縮した。得られた残渣を分取用TLCにチャージし、2
日間放置後展開して精製し(展開系:クロロホルム−メ
タノール(20:1))、化合物(22) 55 mgを得た。 化合物(22)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C49H91NO13Si2 (3) マススペクトル (FDMS) : m/z 958 (M+H)+ (4) 比旋光度 : [α]D 26 -4°(c1.0, CH3OH) (5) 融点 : 76℃ (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 4.05(br dt, 3-H), 3.44(s, 4-OCH3), 3.46
(br d, 5-H), 0.41(br dd, 7-H), 4,18(br d, 9-H), 5.
72(dd, 10-H), 6.10(m, 11-H), 6.10(m, 12-H), 5.62(d
t, 13-H), 4.80(ddq, 15-H),1.30(d, 16-H3), 1.43(dt,
17-H), 1.66(br d, 17-H), 4.57(br dd, 18-H), 4.30
(d,1'-H), 3.33(dd, 2'-H), 2.46(t, 3'-H), 3.36(t,
4'-H), 2.55(s,3'-N(CH3)2), 4.87(d, 1"-H), 1.52(dd,
2"-Hax), 2.22(d, 2"-Heq), 1.23(s,3"-CH3), 2.56(d,
4"-H), 4.44(dq, 5"-H), 3.24(s,3"-OCH3), 3.53(s,
4"-OCH3)Example 23 Compound (22) (in the formula (VII), R 3 is a methyl group.
R 4 is represented by a methyl group and R 6 is represented by a TBDMS group.
Compound (2) (200 mg) was dissolved in chloroform (10 ml), m-chloroperbenzoic acid (50 mg) was added, and the mixture was stirred at room temperature for 5 minutes. 50 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To 200 mg of the solid obtained by concentrating the filtrate under reduced pressure, 2.0 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride was added.
60 mg was added and stirred at room temperature. After the bubbles were weakened, 1.2 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 100 ml of water was gradually added and extracted with 100 ml of chloroform. Chloroform 100m again in the water layer
l was added for extraction. The chloroform layers were combined and washed twice with 100 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Charge the resulting residue to a preparative TLC, 2
After standing for 1 day, it was developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 55 mg of compound (22). Physicochemical properties of compound (22) (1) Color and shape: colorless solid (2) Molecular formula: C 49 H 91 NO 13 Si 2 (3) Mass spectrum (FDMS): m / z 958 (M + H) + ( 4) Specific rotation: [α] D 26 -4 ° (c1.0, CH 3 OH) (5) Melting point: 76 ° C (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 4.05 (br dt, 3-H), 3.44 (s, 4-OCH 3 ), 3.46
(br d, 5-H), 0.41 (br dd, 7-H), 4,18 (br d, 9-H), 5.
72 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (d
t, 13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H 3 ), 1.43 (dt,
17-H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.30
(d, 1'-H), 3.33 (dd, 2'-H), 2.46 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH 3 ) 2 ), 4.87 (d, 1 "-H), 1.52 (dd,
2 "-Hax), 2.22 (d, 2" -Heq), 1.23 (s, 3 "-CH 3 ), 2.56 (d,
4 "-H), 4.44 (dq, 5" -H), 3.24 (s, 3 "-OCH 3 ), 3.53 (s,
4 "-OCH 3 )
【0067】実施例24化合物(23)(式(III)において、R3がメチル基で
表され、R4がメチル基で表される化合物)(3",4"-ジ-O
-メチルロイコマイシンV)の製造法 化合物(22)55 mgに 2M テトラ-n-ブチルアンモニウ
ムフルオリド テトラヒドロフラン溶液 460μlを加
え、45℃で1時間反応させた。反応液を室温に戻した
後、5%硫酸水素カリウム水溶液 4.6 mlに滴下しクロ
ロホルム 25 mlで2回抽出した。クロロホルム層を合わ
せ、飽和炭酸水素ナトリウム水溶液 50 mlで2回、飽和
食塩水 50 mlで2回順次洗浄した後、有機層を無水硫酸
ナトリウムで乾燥し、これを濾過した。濾液を減圧濃縮
して得られた残渣をシリカゲルカラムクロマトグラフィ
ー(10 g:クロロホルム−メタノール(50:1))で精製し
て、化合物(23) 12 mgを得た。 化合物(23)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C37H63NO13 (3) マススペクトル (SIMS) : m/z 730 (M+H)+ (4) 比旋光度 : [α]D 25 -53°(c1.0, CH3OH) (5) 明瞭な融点を示さず、99〜101℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.20(br d, 2-H), 2.68(dd, 2-H), 3.77(br
d, 3-H), 3.08(br d, 4-H), 3.52(s, 4-OCH3), 4.09(br
dd, 5-H), 1.87(m, 8-H), 4.08(dd, 9-H), 5.66(dd, 1
0-H), 6.25(dd, 11-H), 6.02(br dd, 12-H), 5.59(ddd,
13-H), 2.10(dt, 14-H), 2.49(br d, 14-H), 5.27(dd
q, 15-H), 1.29(d, 16-H3), 2.31(br dd, 17-H), 2.85
(br dd, 17-H), 9.80(br s, 18-H), 4.57(d, 1'-H), 2.
40(t, 3'-H), 3.46(t, 4'-H), 3.24(dq, 5'-H), 1.16
(d, 6'-H3), 2.57(s, 3'-N(CH3)2), 4.88(d, 1"-H), 1.
53(dd, 2"-Hax), 2.22(d,2"-Heq), 1.22(s, 3"-CH3),
2.66(d, 4"-H), 4.37(dq, 5"-H), 1.21(d, 6"-H3), 3.2
2(s, 3"-OCH3), 3.52(s, 4"-OCH3)Example 24 Compound (23) (in the formula (III), R 3 is a methyl group.
Compound in which R 4 is a methyl group) (3 ", 4" -di-O
-Methylleucomycin V) Production Method To 55 mg of compound (22), 460 μl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added, and reacted at 45 ° C. for 1 hour. After the reaction solution was returned to room temperature, it was added dropwise to 4.6 ml of 5% potassium hydrogensulfate aqueous solution and extracted twice with 25 ml of chloroform. The chloroform layers were combined, washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate twice and 50 ml of a saturated saline solution in this order, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)) to obtain 12 mg of compound (23). Physicochemical properties of compound (23) (1) Color and shape: Colorless solid (2) Molecular formula: C 37 H 63 NO 13 (3) Mass spectrum (SIMS): m / z 730 (M + H) + (4) Specific rotation: [α] D 25 -53 ° (c1.0, CH 3 OH) (5) Melting around 99-101 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.52 (s, 4-OCH 3 ), 4.09 (br
dd, 5-H), 1.87 (m, 8-H), 4.08 (dd, 9-H), 5.66 (dd, 1
0-H), 6.25 (dd, 11-H), 6.02 (br dd, 12-H), 5.59 (ddd,
13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H 3 ), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 4.57 (d, 1'-H), 2.
40 (t, 3'-H), 3.46 (t, 4'-H), 3.24 (dq, 5'-H), 1.16
(d, 6'-H 3 ), 2.57 (s, 3'-N (CH 3 ) 2 ), 4.88 (d, 1 "-H), 1.
53 (dd, 2 "-Hax), 2.22 (d, 2" -Heq), 1.22 (s, 3 "-CH 3 ),
2.66 (d, 4 "-H), 4.37 (dq, 5" -H), 1.21 (d, 6 "-H 3 ), 3.2
2 (s, 3 "-OCH 3 ), 3.52 (s, 4" -OCH 3 )
【0068】実施例25化合物(17)(式(III)において、R3がメチル基で
表され、R4がイソアミル基で表される化合物)(4"-O-
イソアミル-3"-O-メチルロイコマイシンV)の製造法 化合物(15) 1.42 gにクロロホルム 71 mlを加え溶
解し、m-クロロ過安息香酸 328 mgを加え、室温で5分
間撹拌した。反応液を10%チオ硫酸ナトリウム水溶液 15
0 mlに滴下し、クロロホルム 500 mlで抽出した。クロ
ロホルム層を飽和炭酸水素ナトリウム水溶液 500 ml及
び飽和食塩水 500 mlで各2回順次洗浄した後、有機層
を無水硫酸ナトリウムで乾燥し、これを濾過した。濾液
を減圧濃縮して得られた固体 1.42 gに無水ジメチルホ
ルムアミド 14 mlを加え溶解し、60%油性水素化ナトリ
ウム 251 mgを加え室温で撹拌した。気泡の弱まった
後、ヨウ化メチル 5.39 gを加え45℃で1時間撹拌し
た。反応液を室温に戻した後、水 500 mlを徐々に加
え、クロロホルム 500 mlで抽出した。水層に再度クロ
ロホルム500 mlを加え抽出した。クロロホルム層を合わ
せ、これを飽和食塩水 500 mlで2回洗浄した。クロロ
ホルム層を無水硫酸ナトリウムで乾燥後、これを濾過し
濾液を減圧濃縮し 1.55 gの油状物質を得た。本油状物
質 38 mgにアセトニトリル2.7 mlと 0.025規定塩酸 2.7
mlを順次加え溶解し、45℃で4時間反応させた。反
応液を室温に戻した後、飽和炭酸水素ナトリウム水溶液
25 mlに滴下し、クロロホルム 25 mlで2回抽出した。
クロロホルム層を合わせ、飽和食塩水 50 mlで2回洗浄
した後、有機層を無水硫酸ナトリウムで乾燥し、これを
濾過した。濾液を減圧濃縮して得られた残渣を分取用T
LC(展開系:ヘキサン−アセトン−クロロホルム−メ
タノール−濃アンモニア水(4:4:5:1:0.1))で精製し
て、化合物(17)10 mgを得た。Example 25 Compound (17) (in the formula (III), R 3 is a methyl group.
Represented by R 4 is an isoamyl group) (4 "-O-
Method for producing isoamyl-3 "-O-methylleucomycin V) To 1.42 g of compound (15), 71 ml of chloroform was added and dissolved, 328 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 5 minutes. 10% sodium thiosulfate solution 15
The mixture was added dropwise to 0 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 500 ml of water was gradually added, and the mixture was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 38 mg of this oily substance, 2.7 ml of acetonitrile and 0.025N hydrochloric acid 2.7
ml was sequentially added and dissolved, and the mixture was reacted at 45 ° C. for 4 hours. After returning the reaction solution to room temperature, saturated aqueous sodium hydrogen carbonate solution
The mixture was added dropwise to 25 ml and extracted twice with 25 ml of chloroform.
The chloroform layers were combined and washed twice with 50 ml of saturated saline, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is used for preparative T
It was purified by LC (developing system: hexane-acetone-chloroform-methanol-concentrated aqueous ammonia (4: 4: 5: 1: 0.1)) to obtain 10 mg of compound (17).
【0069】実施例26化合物(24)(式(I)において、R1がプロピオニル
基で表され、R2が水素原子で表され、R3がメチル基で表
され、R4がイソアミル基で表される化合物)(4"-O-イ
ソアミル-3"-O-メチル-9-O-プロピオニルロイコマイシ
ンV)の製造法 化合物(17) 100 mgに乾燥トルエン
5.0 mlを加え溶解し、ピリジン 55 μl及び塩化アセチ
ル 44 μlを順次加えた後、室温で45分間撹拌した。
反応混合物に飽和炭酸水素ナトリウム水溶液 10 mlを徐
々に加え、クロロホルム 20 mlで抽出し、飽和食塩水 1
0 mlで2回洗浄した後、無水硫酸ナトリウムで乾燥後こ
れを濾過した。濾液を減圧濃縮して得られた残渣にメタ
ノール 10 mlを加え溶解し、室温で一昼夜放置した。こ
れを減圧濃縮して得られた残渣を分取用TLC(展開
系:クロロホルム-メタノール(10:1))で精製して、化
合物(24) 51 mgを得た。 化合物(24)の理化学的性状 (1) 色および形状 : 無色固体 (2) 分子式 : C44H75NO14 (3) マススペクトル (EIMS) : m/z 841 (M)+ (4) 比旋光度 : [α]D 30 -63°(c1.0, CH3OH) (5) 明瞭な融点を示さず、97〜100℃付近で熔融 (6) 1H NMRスペクトル (400MHz, CDCl3) δ
(ppm) : 2.19(br d, 2-H), 2.68(dd, 2-H), 3.76(br
d, 3-H), 3.06(br d, 4-H), 3.51(s, 4-OCH3), 4.11(br
dd, 5-H), 2.28(br t, 6-H), 0.94(br dt, 7-H), 1.58
(br dt, 7-H), 5.15(dd, 9-H), 2.25(q, 9-OCOCH 2CH3),
1.07(t, 9-OCOCH2CH3 ), 5.58(dd, 10-H),6.36(dd, 11-
H), 6.00(br dd, 12-H), 5.62(ddd, 13-H), 2.09(dt, 1
4-H), 2.47(br d, 14-H), 5.26(ddq, 15-H), 1.27(d, 1
6-H3), 2.39(br dd, 17-H), 2.80(br dd, 17-H), 9.77
(br s, 18-H), 0.94(d, 19-H3), 4.55(d, 1'-H), 3.13
(br dd, 2'-H), 2.38(t, 3'-H), 3.44(t, 4'-H), 3.24
(dq, 5'-H), 1.15(d, 6'-H3), 2.54(s, 3'-N(CH3)2),
4.86(d, 1"-H), 1.53(dd, 2"-Hax), 2.20(d, 2"-Heq),
1.21(s, 3"-CH3), 2.75(d, 4"-H), 4.39(dq, 5"-H), 1.
19(d, 6"-H3), 3.22(s, 3"-OCH3), 3.57(dt, 4"-OCH 2CH
2CH(CH3)2), 3.60(dt, 4"-OCH 2CH2CH(CH3)2), 1.49(m,
4"-OCH2CH2 CH(CH3)2), 1.65(m, 4"-OCH2CH2CH(CH3)2),
0.86(d, 4"-OCH2CH2CH(CH3)2 )Example 26 Compound (24) (in the formula (I), R 1 is propionyl
Group, R 2 is a hydrogen atom, and R 3 is a methyl group.
And R 4 is an isoamyl group) (4 "-O-
Soamyl-3 "-O-methyl-9-O-propionyl leucomyc
V) Production method Compound (17) 100 mg dry toluene
5.0 ml was added and dissolved, 55 μl of pyridine and 44 μl of acetyl chloride were added successively, and the mixture was stirred at room temperature for 45 minutes.
Saturated aqueous sodium hydrogen carbonate solution (10 ml) was gradually added to the reaction mixture, and the mixture was extracted with chloroform (20 ml) and saturated brine (1).
The extract was washed twice with 0 ml, dried over anhydrous sodium sulfate, and filtered. To the residue obtained by concentrating the filtrate under reduced pressure was added 10 ml of methanol to dissolve it, and the mixture was allowed to stand at room temperature for 24 hours. The residue obtained by concentration under reduced pressure was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to obtain 51 mg of compound (24). Physicochemical properties of compound (24) (1) Color and shape: colorless solid (2) Molecular formula: C 44 H 75 NO 14 (3) Mass spectrum (EIMS): m / z 841 (M) + (4) Specific rotation Degree: [α] D 30 -63 ° (c1.0, CH 3 OH) (5) Melting around 97-100 ° C without showing clear melting point (6) 1 H NMR spectrum (400MHz, CDCl 3 ) δ
(ppm): 2.19 (br d, 2-H), 2.68 (dd, 2-H), 3.76 (br
d, 3-H), 3.06 (br d, 4-H), 3.51 (s, 4-OCH 3 ), 4.11 (br
dd, 5-H), 2.28 (br t, 6-H), 0.94 (br dt, 7-H), 1.58
(br dt, 7-H), 5.15 (dd, 9-H), 2.25 (q, 9-OCOC H 2 CH 3 ),
1.07 (t, 9-OCOCH 2 C H 3 ), 5.58 (dd, 10-H), 6.36 (dd, 11-
H), 6.00 (br dd, 12-H), 5.62 (ddd, 13-H), 2.09 (dt, 1
4-H), 2.47 (br d, 14-H), 5.26 (ddq, 15-H), 1.27 (d, 1
6-H 3 ), 2.39 (br dd, 17-H), 2.80 (br dd, 17-H), 9.77
(br s, 18-H), 0.94 (d, 19-H 3 ), 4.55 (d, 1'-H), 3.13
(br dd, 2'-H), 2.38 (t, 3'-H), 3.44 (t, 4'-H), 3.24
(dq, 5'-H), 1.15 (d, 6'-H 3 ), 2.54 (s, 3'-N (CH 3 ) 2 ),
4.86 (d, 1 "-H), 1.53 (dd, 2" -Hax), 2.20 (d, 2 "-Heq),
1.21 (s, 3 "-CH 3 ), 2.75 (d, 4" -H), 4.39 (dq, 5 "-H), 1.
19 (d, 6 "-H 3 ), 3.22 (s, 3" -OCH 3 ), 3.57 (dt, 4 "-OC H 2 CH
2 CH (CH 3 ) 2 ), 3.60 (dt, 4 "-OC H 2 CH 2 CH (CH 3 ) 2 ), 1.49 (m,
4 "-OCH 2 C H 2 CH (CH 3 ) 2 ), 1.65 (m, 4" -OCH 2 CH 2 C H (CH 3 ) 2 ),
0.86 (d, 4 "-OCH 2 CH 2 CH (C H 3 ) 2 )
【0070】[0070]
【発明の効果】第一の本発明の効果とするところは、有
用な新規16員環マクロリド誘導体の造出にある。即ち
本発明で得られる一般式(I)で表される化合物
(5)、(8)、(11)、(14)、(17)、(1
9)、(21)、(23)、(24)は、何れも臨床上
重要なグラム陽性菌に対して強い抗菌力を有している。
表1並びに表2に、数種の本発明化合物と、比較の為に
ロイコマイシンA7(LM-A7)並びにミオカマイシン(MO
M)の抗菌活性を示した。The first effect of the present invention is to create a useful novel 16-membered ring macrolide derivative. That is, the compounds (5), (8), (11), (14), (17), (1) represented by the general formula (I) obtained in the present invention
All of 9), (21), (23) and (24) have strong antibacterial activity against clinically important Gram-positive bacteria.
Tables 1 and 2 show several compounds of the present invention and leucomycin A 7 (LM-A 7 ) and myocamycin (MO) for comparison.
M) showed antibacterial activity.
【0071】[0071]
【表1】 [Table 1]
【0072】[0072]
【表2】 表1並びに表2に示す様に、特に化合物(11)、(1
4)、(17)は、MOMよりも明らかに優れたin vitro
の抗菌活性を有し、さらに天然のロイコマイシン類16
員環マクロリドにおいては強い抗菌活性を有する部類に
属するLM-A7と比較しても、Haemophilus influenzae菌
を除き、同等以上の際立った抗菌活性を有している。[Table 2] As shown in Table 1 and Table 2, in particular, compounds (11) and (1
4) and (17) are clearly superior to MOM in vitro
With natural antibacterial activity and natural leucomycin 16
The member-membered macrolide has the same or more prominent antibacterial activity, except for Haemophilus influenzae , even when compared to LM-A 7 which belongs to a class having strong antibacterial activity.
【0073】また本発明で得られる一般式(I)で表さ
れる化合物は、ラクトン環の3位が遊離の水酸基であ
り、かつマイカロース部分の4"位にプロピオニル基が結
合したロイコマイシンA7と比較して、ラット血漿中にお
いて抗菌活性がより長く持続するという性質を有してい
る。この安定性は、本発明で得られる化合物におけるマ
イカロース部分の水酸基がアシル基によりエステル結合
しているのではなく、何れの水酸基もアルキル基により
エーテル結合していることに直接関与している。ところ
で、ミオカマイシンに関する研究報告によれば、マイカ
ロース部分の代謝のパターンはヒト及びラットにおいて
概ね類似していることが報告されている(薬学雑誌, 10
2(8), 781(1982))。それゆえ本発明による誘導体、特
に化合物(11)、(14)、(17)等は、ヒトの血
液内においてもその強い抗菌活性が比較的長く持続され
ることが容易に示唆される。Further, the compound represented by the general formula (I) obtained in the present invention is a leucomycin A in which the 3-position of the lactone ring is a free hydroxyl group and the propionyl group is bonded to the 4 "-position of the mycarose moiety. It has the property that the antibacterial activity lasts longer in rat plasma as compared with 7. This stability is due to the fact that the hydroxyl group of the mycarose moiety in the compound obtained in the present invention is ester-bonded with an acyl group. However, according to the research report on myocamycin, the patterns of metabolism of the mycarose moiety are generally similar in humans and rats. Have been reported (pharmaceutical journal, 10
2 (8), 781 (1982)). Therefore, it is easily suggested that the derivatives according to the present invention, especially the compounds (11), (14), (17) and the like, retain their strong antibacterial activity in human blood for a relatively long time.
【0074】第二の本発明の効果とするところは、一般
式(I)で表される新規16員環マクロリド誘導体を製
造する為に重要な合成中間体であり、同時にそれ自体抗
菌剤として極めて有用な新規16員環マクロリド誘導体
である一般式(III)で表される化合物を、一般式(I
I)で表される天然に存在する公知の16員環マクロリ
ド抗生物質を出発原料として、5工程ないしは6工程で
効率良く調製する新規製造法を提供する事にある。以前
本発明者らが、ミデカマイシンA3とエリスロマイシンを
出発原料として本発明化合物(17)を調製した際は、
グリコシル化反応を含む8工程の化学反応と2段階の微
生物変換を実施して、ミデカマイシンA3からの全収率は
1%以下であった。しかしながら本発明の新規製造法に
よれば、例えばロイコマイシンA7を出発原料として全収
率10%前後で化合物(17)を合成する事が可能とな
った。The second effect of the present invention is that it is an important synthetic intermediate for producing the novel 16-membered ring macrolide derivative represented by the general formula (I), and at the same time, it is extremely useful as an antibacterial agent. A compound represented by the general formula (III), which is a useful novel 16-membered ring macrolide derivative, can be prepared by
Another object of the present invention is to provide a novel production method for efficiently preparing a naturally occurring known 16-membered macrolide antibiotic represented by I) in 5 to 6 steps as a starting material. Previously, when the present inventors prepared the compound (17) of the present invention using midecamycin A 3 and erythromycin as starting materials,
Eight-step chemical reaction including glycosylation reaction and two-step microbial conversion were performed, and the total yield from midecamycin A 3 was less than 1%. However, according to the novel production method of the present invention, it has become possible to synthesize compound (17) using leucomycin A 7 as a starting material in a total yield of about 10%.
【0075】また現在までのところ、化合物(19)、
(21)の如くマイカロース部分の3"位の3級水酸基に
メチル基以外のアルキル基が導入された化合物は、天然
物或いは誘導体の別を問わず全く知られていない。それ
故、これらの化合物を新しく提供する事で、それらの生
化学的評価を進める事により、16員環マクロリド誘導
体の構造と活性の相関及び構造とそれらの薬動力学との
相関を解明する重要な情報を供与する。To date, compound (19),
A compound in which an alkyl group other than a methyl group is introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose moiety as in (21) is not known at all regardless of whether it is a natural product or a derivative. Providing new compounds provides important information to elucidate the structure-activity relationship of 16-membered macrolide derivatives and the relationship between their structure and their pharmacokinetics by promoting their biochemical evaluation. .
【0076】第三の本発明の効果とするところは、当該
新規製造法を提供した事により、今までは比較的穏和な
反応条件によってのみ化学修飾されていた16員環マク
ロリド化合物を、さらに苛酷な反応条件で化学修飾する
事を可能にした。即ち、本新規製造法は、マイカロース
部分の2つの水酸基にそれぞれアルキル基を導入する方
法論を提供したに留まらず、アシル化等に比較して一層
苛酷な反応条件を用いて中性糖部分を抜本的に化学修飾
し得る方法論をも提供している。従って、本新規製造法
を用いる事によって、マイカロース部分の水酸基が修飾
された全く新しい構造の新規16員環マクロリド誘導体
を造出する事が可能である。The third effect of the present invention is that the 16-membered macrolide compound, which has been chemically modified only by relatively mild reaction conditions until now, is provided by providing the novel production method. It was possible to chemically modify under various reaction conditions. That is, this new production method not only provides a methodology for introducing an alkyl group into each of the two hydroxyl groups of the mycarose moiety, but also uses a reaction condition that is more severe than that of acylation or the like to convert the neutral sugar moiety into a neutral sugar moiety. It also provides a methodology that can be radically chemically modified. Therefore, by using this new production method, it is possible to create a novel 16-membered ring macrolide derivative having a completely new structure in which the hydroxyl group of the mycalose moiety is modified.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 原 修 神奈川県横浜市港北区師岡町760番地 明 治製菓株式会社薬品総合研究所内 (72)発明者 柴原 聖至 神奈川県横浜市港北区師岡町760番地 明 治製菓株式会社薬品総合研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Hara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Seiji Shibahara 760 Shimohara-cho, Kohoku-ku, Yokohama-shi, Kanagawa Address Meiji Seika Co., Ltd. Pharmaceutical Research Institute
Claims (10)
〜3の直鎖のアルキル基)であり、R2は水素原子又は式
CORの基(但しRは前記と同じ意味を持つ)であり、R3は
炭素数1〜4の直鎖のアルキル基、置換された又は置換
されていないアリル基であり、R4は置換された又は置換
されていない炭素数1〜10の直鎖又は分枝鎖のアルキ
ル基、アルケニル基又はアラルキル基]で表される化合
物、又はその薬学的に許容し得る塩。1. The following formula (I): [In the formula, R 1 is a hydrogen atom or a group of the formula COR (where R is a carbon number 1
~ 3 straight chain alkyl group), R 2 is a hydrogen atom or a formula
A COR group (wherein R has the same meaning as above), R 3 is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R 4 is a substituted group. Or a non-substituted linear or branched alkyl group, alkenyl group or aralkyl group having 1 to 10 carbon atoms], or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がメチル基で
表され、R4がメチル基で表される化合物、又はその薬学
的に許容し得る塩。2. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is a methyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がメチル基で
表され、R4がエチル基で表される化合物、又はその薬学
的に許容し得る塩。3. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is an ethyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がメチル基で
表され、R4がプロピル基で表される化合物、又はその薬
学的に許容し得る塩。4. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is a propyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がメチル基で
表され、R4がブチル基で表される化合物、又はその薬学
的に許容し得る塩。5. In the formula (I) according to claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is a butyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がメチル基で
表され、R4がペンチル基で表される化合物、又はその薬
学的に許容し得る塩。6. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is a pentyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がエチル基で
表され、R4がイソアミル基で表される化合物、又はその
薬学的に許容し得る塩。7. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is an ethyl group, and R 4 is an isoamyl group. Or a pharmaceutically acceptable salt thereof.
原子で表され、R2が水素原子で表され、R3がプロピル基
で表され、R4がイソアミル基で表される化合物、又はそ
の薬学的に許容し得る塩。8. In the formula (I) of claim 1, R 1 is a hydrogen atom, R 2 is a hydrogen atom, R 3 is a propyl group, and R 4 is an isoamyl group. Or a pharmaceutically acceptable salt thereof.
ピオニル基で表され、R2が水素原子で表され、R3がメチ
ル基で表され、R4がイソアミル基で表される化合物、又
はその薬学的に許容し得る塩。9. In the formula (I) of claim 1, R 1 is a propionyl group, R 2 is a hydrogen atom, R 3 is a methyl group, and R 4 is an isoamyl group. Or a pharmaceutically acceptable salt thereof.
シル基]で表される化合物、又はその塩を出発原料とし
て用いて、次の式(III) 【化3】 [式中、R3は炭素数1〜4の直鎖のアルキル基、置換さ
れた又は置換されていないアリル基であり、R4は置換さ
れた又は置換されていない炭素数1〜10の直鎖又は分
枝鎖のアルキル基、アルケニル基又はアラルキル基]で
表される化合物、又はその塩を得るための新規製造法。10. The following formula (II): [Wherein R 5 is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms] or a salt thereof as a starting material, and the compound represented by the following formula (III): ] [In the formula, R 3 is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R 4 is a substituted or unsubstituted C 1 to 10 straight-chain group. Chain or branched alkyl group, alkenyl group or aralkyl group] or a salt thereof.
Priority Applications (1)
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---|---|---|---|
JP19438494A JPH07109288A (en) | 1993-08-20 | 1994-08-18 | Novel 16-membered macrolide derivative and novel production process thereof |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP20673193 | 1993-08-20 | ||
JP5-206731 | 1993-08-20 | ||
JP19438494A JPH07109288A (en) | 1993-08-20 | 1994-08-18 | Novel 16-membered macrolide derivative and novel production process thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH07109288A true JPH07109288A (en) | 1995-04-25 |
Family
ID=26508474
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP19438494A Pending JPH07109288A (en) | 1993-08-20 | 1994-08-18 | Novel 16-membered macrolide derivative and novel production process thereof |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH07109288A (en) |
-
1994
- 1994-08-18 JP JP19438494A patent/JPH07109288A/en active Pending
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