JPH11171859A - Vitamin d derivative and its production - Google Patents
Vitamin d derivative and its productionInfo
- Publication number
- JPH11171859A JPH11171859A JP10264190A JP26419098A JPH11171859A JP H11171859 A JPH11171859 A JP H11171859A JP 10264190 A JP10264190 A JP 10264190A JP 26419098 A JP26419098 A JP 26419098A JP H11171859 A JPH11171859 A JP H11171859A
- Authority
- JP
- Japan
- Prior art keywords
- group
- hydroxy
- dihydroxy
- compound
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、新規な３−エピ−
２２−オキサビタミンＤ誘導体、その合成中間体および
それらの製造方法に関する。本発明の３−エピ−２２−
オキサビタミンＤ誘導体は分化誘導作用、増殖抑制作用
を有することが予測され、抗腫瘍剤や抗リウマチ剤、乾
癬治療剤、特には副甲状腺機能亢進症治療薬として有用
であることが期待される。TECHNICAL FIELD The present invention relates to a novel 3-epi-
The present invention relates to a 22-oxavitamin D derivative, a synthetic intermediate thereof, and a method for producing them. 3-Epi-22- of the present invention
The oxavitamin D derivative is expected to have a differentiation-inducing effect and a growth-inhibiting effect, and is expected to be useful as an antitumor agent, an antirheumatic agent, a therapeutic agent for psoriasis, particularly a therapeutic agent for hyperparathyroidism.
【０００２】[0002]
【従来技術】近年、ビタミンＤ類の生理活性が遂次明ら
かにされてきている。ビタミンＤ類、例えば、１α，２
５−ジヒドロキシビタミンＤ3はカルシウム代謝調節作
用、腫瘍細胞等の増殖抑制作用や分化誘導作用、免疫調
節作用など多岐にわたって生理活性を示すことが知られ
ている。例えば、特開昭６１−２６７５５０、特開平６
−８０６２６、特開平６−２５６３００には、特定の側
鎖を有する２２−オキサビタミンＤ誘導体が開示されて
おり、これらの化合物が分化誘導作用や増殖抑制作用を
有することが記載されている。2. Description of the Related Art In recent years, physiological activities of vitamin Ds have been gradually elucidated. Vitamin Ds, for example, 1α, 2
5-dihydroxyvitamin D 3 calcium metabolism regulating action, the growth inhibitory effect and differentiation inducing effect such as tumor cells, are known to exhibit physiological activity over manifold such immunomodulatory effects. For example, Japanese Patent Application Laid-Open No. 61-267550,
-80626 and JP-A-6-256300 disclose 22-oxavitamin D derivatives having a specific side chain, and describe that these compounds have a differentiation-inducing action and a growth-inhibiting action.
【０００３】しかしながら、従来から知られている２２
−オキサビタミンＤ誘導体としては、１位と３位の水酸
基が互いにトランス配置にある誘導体（即ち、１α，３
β−ジヒドロキシ−２２−オキサビタミンＤ誘導体）の
みが報告されているに過ぎず、１位と３位の水酸基が互
いにシス配置にある誘導体（即ち、１α，３α−ジヒド
ロキシ−２２−オキサビタミンＤ誘導体）は現在の所、
報告されていない。[0003] However, the conventionally known 22
-Oxavitamin D derivatives include derivatives in which the hydroxyl groups at the 1- and 3-positions are in the trans configuration to each other (ie, 1α, 3
Only a β-dihydroxy-22-oxavitamin D derivative has been reported, and a derivative in which the 1- and 3-position hydroxyl groups are in a cis configuration with each other (ie, a 1α, 3α-dihydroxy-22-oxavitamin D derivative) ) Is for now,
Not reported.
【０００４】一方、J. Org. Chem. Vol.58, No.7, 199
3, p.1895-1899には、１α位と３α位に水酸基を有する
ビタミンＤ誘導体が開示されている。しかしながら、こ
の文献には２２−オキサビタミンＤ誘導体は開示されて
いない。On the other hand, J. Org. Chem. Vol. 58, No. 7, 199
3, pp. 1895-1899, discloses a vitamin D derivative having a hydroxyl group at the 1α-position and the 3α-position. However, this reference does not disclose a 22-oxavitamin D derivative.
【０００５】[0005]
【発明が解決しようとする課題】本発明の目的の一つ
は、１α位と３α位に水酸基を有する新規な２２−オキ
サビタミンＤ誘導体を提供することである。本発明の別
の目的は、１α位と３α位に水酸基を有する２２−オキ
サビタミンＤ誘導体の合成に有用な新規な中間体化合物
を提供することである。本発明のさらに別の目的は、１
α位と３α位に水酸基を有する２２−オキサビタミンＤ
誘導体を合成するための合成経路を確立することであ
る。An object of the present invention is to provide a novel 22-oxavitamin D derivative having a hydroxyl group at the 1α-position and 3α-position. Another object of the present invention is to provide a novel intermediate compound useful for synthesizing a 22-oxavitamin D derivative having a hydroxyl group at the 1α-position and the 3α-position. Still another object of the present invention is to provide:
22-oxavitamin D having hydroxyl groups at α-position and 3α-position
The purpose is to establish a synthetic route for synthesizing derivatives.
【０００６】[0006]
【課題を解決するための手段】本発明の第１の側面によ
れば、一般式（Ｉ）：According to a first aspect of the present invention, general formula (I):
【化８】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示し、Ｒ2およびＲ3
は、互いに独立して水素原子または保護基を示す）で示
される２２−オキサビタミンＤ誘導体が提供される。Embedded image Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Represents a linear or branched alkyl group of R 2 and R 3
Each independently represent a hydrogen atom or a protecting group).
【０００７】Ｒ1は、好ましくは、一般式（ＩＩ）：R 1 is preferably of the general formula (II):
【化９】 （式中、ｎは１〜３の整数を示し、ｋおよびｌは互いに
独立して０〜２の整数を示す）の基である。Embedded image (Wherein, n represents an integer of 1 to 3, k and 1 each independently represent an integer of 0 to 2).
【０００８】Ｒ1は、特に好ましくは、３−ヒドロキシ
−３−メチルブチル基である。本発明のビタミンＤ誘導
体の２０位の立体配置はＳ配置でもＲ配置でもよいが、
好ましくはＳ配置である。[0008] R 1 is particularly preferably a 3-hydroxy-3-methylbutyl group. The configuration at the 20-position of the vitamin D derivative of the present invention may be S configuration or R configuration,
The S arrangement is preferred.
【０００９】本発明の第２の側面によれば、一般式（Ｉ
ＩＩ）：According to a second aspect of the present invention, the general formula (I
II):
【化１０】 （式中、Ｘは水酸基、塩素原子またはジフェニルホスフ
ィンオキシド基を示し、Ｒ2およびＲ3は、互いに独立し
て水素原子または保護基を示す）で示される化合物が提
供される。一般式（ＩＩＩ）の化合物は新規化合物であ
り、一般式（Ｉ）の２２−オキサビタミンＤ誘導体を合
成するのに有用な合成中間体である。Embedded image (Wherein X represents a hydroxyl group, a chlorine atom or a diphenylphosphine oxide group, and R 2 and R 3 independently represent a hydrogen atom or a protecting group). The compound of the general formula (III) is a novel compound, and is a synthetic intermediate useful for synthesizing the 22-oxavitamin D derivative of the general formula (I).
【００１０】本発明の第３の側面によれば、一般式（Ｉ
Ｖ）：According to a third aspect of the present invention, a compound of the general formula (I
V):
【化１１】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示す）で示される化
合物が提供される。一般式（ＩＶ）の化合物は新規化合
物であり、一般式（Ｉ）の２２−オキサビタミンＤ誘導
体を合成するのに有用な合成中間体である。Embedded image Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Which represents a linear or branched alkyl group). The compound of the general formula (IV) is a novel compound and is a synthetic intermediate useful for synthesizing the 22-oxavitamin D derivative of the general formula (I).
【００１１】本発明の第４の側面によれば、一般式（Ｉ
ＩＩａ）：According to a fourth aspect of the present invention, the general formula (I
IIa):
【化１２】 （式中、Ｒ2およびＲ3は、互いに独立して水素原子また
は保護基を示す）で示される化合物を一般式（ＩＶ）：Embedded image (Wherein R 2 and R 3 independently represent a hydrogen atom or a protecting group) by a compound represented by the general formula (IV):
【化１３】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示す）で示される化
合物と、溶媒中で塩基の存在下において反応させること
を含む、一般式（Ｉ）：Embedded image Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
A linear or branched alkyl group of the formula (I)) in a solvent in the presence of a base.
【化１４】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示し、Ｒ2およびＲ3
は、互いに独立して水素原子または保護基を示す）で示
される２２−オキサビタミンＤ誘導体の製造方法が提供
される。Embedded image Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Represents a linear or branched alkyl group of R 2 and R 3
Each independently represent a hydrogen atom or a protecting group).
【００１２】[0012]
【発明の実施の形態】本明細書中において、Ｒ1は１か
ら３個の水酸基を有するＣ4〜Ｃ10の直鎖または分枝鎖
のアルキル基を示す。Ｒ1の非限定的例としては、３−
ヒドロキシ−３−メチルブチル基、２−ヒドロキシ−３
−メチルブチル基、４−ヒドロキシ−３−メチルブチル
基、２，３−ジヒドロキシ−３−メチルブチル基、２，
４−ジヒドロキシ−３−メチルブチル基、３，４−ジヒ
ドロキシ−３−メチルブチル基、３−ヒドロキシ−３−
エチルペンチル基、２−ヒドロキシ−３−エチルペンチ
ル基、４−ヒドロキシ−３−エチルペンチル基、２，３
−ジヒドロキシ−３−エチルペンチル基、２，４−ジヒ
ドロキシ−３−エチルペンチル基、３，４−ジヒドロキ
シ−３−エチルペンチル基、４−ヒドロキシ−４−メチ
ルペンチル基、３−ヒドロキシ−４−メチルペンチル
基、５−ヒドロキシ−４−メチルペンチル基、３，４−
ジヒドロキシ−４−メチルペンチル基、３，５−ジヒド
ロキシ−４−メチルペンチル基、４，５−ジヒドロキシ
−４−メチルペンチル基、３−ヒドロキシ−３−（ｎ−
プロピル）ヘキシル基、４−ヒドロキシ−３−（ｎ−プ
ロピル）ヘキシル基、２−ヒドロキシ−３−（ｎ−プロ
ピル）ヘキシル基、２，３−ジヒドロキシ−３−（ｎ−
プロピル）ヘキシル基、３，４−ジヒドロキシ−３−
（ｎ−プロピル）ヘキシル基、２，４−ジヒドロキシ−
３−（ｎ−プロピル）ヘキシル基、３−ヒドロキシ−４
−エチルヘキシル基、４−ヒドロキシ−４−エチルヘキ
シル基、５−ヒドロキシ−４−エチルヘキシル基、３，
４−ジヒドロキシ−４−エチルヘキシル基、３，５−ジ
ヒドロキシ−４−エチルヘキシル基、４，５−ジヒドロ
キシ−４−エチルヘキシル基、４−ヒドロキシ−５−メ
チルヘキシル基、５−ヒドロキシ−５−メチルヘキシル
基、６−ヒドロキシ−５−メチルヘキシル基、４，５−
ジヒドロキシ−５−メチルヘキシル基、４，６−ジヒド
ロキシ−５−メチルヘキシル基、５，６−ジヒドロキシ
−５−メチルヘキシル基、５−ヒドロキシ−６−メチル
ヘプチル基、６−ヒドロキシ−６−メチルヘプチル基、
７−ヒドロキシ−６−メチルヘプチル基、５，６−ジヒ
ドロキシ−６−メチルヘプチル基、５，７−ジヒドロキ
シ−６−メチルヘプチル基、６，７−ジヒドロキシ−６
−メチルヘプチル基、４−ヒドロキシ−５−エチルヘプ
チル基、５−ヒドロキシ−５−エチルヘプチル基、６−
ヒドロキシ−５−エチルヘプチル基、４，５−ジヒドロ
キシ−５−エチルヘプチル基、４，６−ジヒドロキシ−
５−エチルヘプチル基、５，６−ジヒドロキシ−５−エ
チルヘプチル基、３−ヒドロキシ−４−（ｎ−プロピ
ル）ヘプチル基、４−ヒドロキシ−４−（ｎ−プロピ
ル）ヘプチル基、５−ヒドロキシ−４−（ｎ−プロピ
ル）ヘプチル基、３，４−ジヒドロキシ−４−（ｎ−プ
ロピル）ヘプチル基、３，５−ジヒドロキシ−４−（ｎ
−プロピル）ヘプチル基および４，５−ジヒドロキシ−
４−（ｎ−プロピル）ヘプチル基が挙げられる。BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, R 1 represents a C 4 -C 10 linear or branched alkyl group having 1 to 3 hydroxyl groups. Non-limiting examples of R 1 include 3-
Hydroxy-3-methylbutyl group, 2-hydroxy-3
-Methylbutyl group, 4-hydroxy-3-methylbutyl group, 2,3-dihydroxy-3-methylbutyl group, 2,
4-dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3-
Ethylpentyl group, 2-hydroxy-3-ethylpentyl group, 4-hydroxy-3-ethylpentyl group, 2,3
-Dihydroxy-3-ethylpentyl group, 2,4-dihydroxy-3-ethylpentyl group, 3,4-dihydroxy-3-ethylpentyl group, 4-hydroxy-4-methylpentyl group, 3-hydroxy-4-methyl Pentyl group, 5-hydroxy-4-methylpentyl group, 3,4-
Dihydroxy-4-methylpentyl group, 3,5-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group, 3-hydroxy-3- (n-
Propyl) hexyl group, 4-hydroxy-3- (n-propyl) hexyl group, 2-hydroxy-3- (n-propyl) hexyl group, 2,3-dihydroxy-3- (n-
Propyl) hexyl group, 3,4-dihydroxy-3-
(N-propyl) hexyl group, 2,4-dihydroxy-
3- (n-propyl) hexyl group, 3-hydroxy-4
-Ethylhexyl group, 4-hydroxy-4-ethylhexyl group, 5-hydroxy-4-ethylhexyl group, 3,
4-dihydroxy-4-ethylhexyl group, 3,5-dihydroxy-4-ethylhexyl group, 4,5-dihydroxy-4-ethylhexyl group, 4-hydroxy-5-methylhexyl group, 5-hydroxy-5-methylhexyl group , 6-hydroxy-5-methylhexyl group, 4,5-
Dihydroxy-5-methylhexyl group, 4,6-dihydroxy-5-methylhexyl group, 5,6-dihydroxy-5-methylhexyl group, 5-hydroxy-6-methylheptyl group, 6-hydroxy-6-methylheptyl Group,
7-hydroxy-6-methylheptyl group, 5,6-dihydroxy-6-methylheptyl group, 5,7-dihydroxy-6-methylheptyl group, 6,7-dihydroxy-6
-Methylheptyl group, 4-hydroxy-5-ethylheptyl group, 5-hydroxy-5-ethylheptyl group, 6-
Hydroxy-5-ethylheptyl group, 4,5-dihydroxy-5-ethylheptyl group, 4,6-dihydroxy-
5-ethylheptyl group, 5,6-dihydroxy-5-ethylheptyl group, 3-hydroxy-4- (n-propyl) heptyl group, 4-hydroxy-4- (n-propyl) heptyl group, 5-hydroxy- 4- (n-propyl) heptyl group, 3,4-dihydroxy-4- (n-propyl) heptyl group, 3,5-dihydroxy-4- (n
-Propyl) heptyl group and 4,5-dihydroxy-
4- (n-propyl) heptyl group.
【００１３】本明細書中において、Ｒ2およびＲ3は水素
原子または保護基を示す。保護基とは水酸基の保護基を
意味し、例えば、アシル基、置換シリル基、置換または
未置換のアルキル基などが挙げられ、アシル基および置
換シリル基が好ましい。アシル基の例としては、アセチ
ル基、ベンゾイル基、置換アセチル基および置換ベンゾ
イル基、並びにカーボネート型およびカーバメート型が
挙げられ、アセチル基が好ましい。アセチル基およびベ
ンゾイル基上の置換基の例としては、ハロゲン原子、ア
ルキル基、アルケニル基およびアリール基が挙げられ、
フッ素原子、塩素原子、メチル基、フェニル基およびエ
チリデン基が好ましい。置換アセチル基の好ましい例と
しては、クロロアセチル基、トリフルオロアセチル基、
ピバロイル基およびクロトノイル基が挙げられる。置換
ベンゾイル基の好ましい例としては、ｐ−フェニルベン
ゾイル基および２，４，６−トリメチルベンゾイル基が
挙げられる。In the present specification, R 2 and R 3 represent a hydrogen atom or a protecting group. The protecting group means a protecting group for a hydroxyl group, and examples thereof include an acyl group, a substituted silyl group, and a substituted or unsubstituted alkyl group. An acyl group and a substituted silyl group are preferred. Examples of the acyl group include an acetyl group, a benzoyl group, a substituted acetyl group and a substituted benzoyl group, and a carbonate type and a carbamate type, and an acetyl group is preferable. Examples of substituents on acetyl and benzoyl groups include halogen, alkyl, alkenyl and aryl groups,
Preferred are a fluorine atom, a chlorine atom, a methyl group, a phenyl group and an ethylidene group. Preferred examples of the substituted acetyl group include a chloroacetyl group, a trifluoroacetyl group,
Pivaloyl and crotonoyl groups. Preferred examples of the substituted benzoyl group include a p-phenylbenzoyl group and a 2,4,6-trimethylbenzoyl group.
【００１４】置換シリル基の例としては、トリメチルシ
リル基、トリエチルシリル基、トリイソプロピルシリル
基、tert−ブチルジメチルシリル基およびtert−ブチル
ジフェニルシリル基が挙げられ、tert−ブチルジメチル
シリル基が好ましい。置換または未置換のアルキル基の
例としては、メチル基、メトキシメチル基、メチルチオ
メチル基、tert−ブチルチオメチル基、ベンジルオキシ
メチル基、ｐ−メトキシベンジルオキシメチル基、２−
メトキシエトキシメチル基、テトラヒドロピラニル基、
tert−ブチル基、アリル基、ベンジル基、ｐ−メトキシ
ベンジル基、ｏ−またはｐ−ニトロベンジル基が挙げら
れる。Examples of the substituted silyl group include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, with tert-butyldimethylsilyl being preferred. Examples of the substituted or unsubstituted alkyl group include a methyl group, a methoxymethyl group, a methylthiomethyl group, a tert-butylthiomethyl group, a benzyloxymethyl group, a p-methoxybenzyloxymethyl group,
Methoxyethoxymethyl group, tetrahydropyranyl group,
Examples include tert-butyl, allyl, benzyl, p-methoxybenzyl, o- or p-nitrobenzyl.
【００１５】本発明の一般式（Ｉ）で示される２２−オ
キサビタミンＤ誘導体は、一般式（ＩＩＩａ）で示され
る化合物と一般式（ＩＶ）で示される化合物とを、好適
な溶媒中で塩基の存在下において反応させることによっ
て製造することができる。この反応で使用する塩基の例
としては、ｎ−ブチルリチウム、ｓ−ブチルリチウム、
フェニルリチウム等のアルキルリチウム類やリチウムジ
イソプロピルアミド、リチウムジエチルアミド、リチウ
ムテトラメチルピペラジン等のリチウムアミド類やリチ
ウムヘキサメチルジシラザン等が挙げられる。この反応
で使用する溶媒としては、不活性有機溶媒、特にはエー
テル系溶媒、例えば、ＴＨＦ、ジエチルエーテル、ジイ
ソプロピルエーテル、１，４−ジオキサン、ジグライム
（ジエチレングリコールジメチルエーテル）等が挙げら
れる。The 22-oxavitamin D derivative represented by the general formula (I) of the present invention is obtained by converting a compound represented by the general formula (IIIa) and a compound represented by the general formula (IV) into a base in a suitable solvent. Can be produced by reacting in the presence of Examples of bases used in this reaction include n-butyllithium, s-butyllithium,
Examples thereof include alkyllithiums such as phenyllithium, lithium amides such as lithium diisopropylamide, lithium diethylamide, and lithium tetramethylpiperazine, and lithium hexamethyldisilazane. Examples of the solvent used in this reaction include inert organic solvents, particularly ether solvents, for example, THF, diethyl ether, diisopropyl ether, 1,4-dioxane, diglyme (diethylene glycol dimethyl ether) and the like.
【００１６】反応温度は、一般的には−１００℃〜０
℃、好ましくは−８０℃〜−６０℃である。反応時間は
適宜選択することができるが、一般的には、１時間〜２
４時間、好ましくは、３時間〜９時間である。The reaction temperature is generally from -100 ° C to 0 ° C.
° C, preferably -80 ° C to -60 ° C. The reaction time can be appropriately selected, but is generally from 1 hour to 2 hours.
4 hours, preferably 3 hours to 9 hours.
【００１７】本発明の一般式（Ｉ）で示される２２−オ
キサビタミンＤ誘導体の合成のための中間体として使用
することができる、一般式（ＩＩＩ）および一般式（Ｉ
Ｖ）で示される化合物は何れも新規化合物であり、本発
明の別の側面を構成する。一般式（ＩＩＩ）で示される
化合物は、ビタミンＤ誘導体のＡ環部分を構成する化合
物であり、例えば、以下の実施例に記載の合成経路によ
って合成することができる。なお、実施例に記載の合成
経路を、以下に図示する。The general formula (III) and the general formula (I) which can be used as intermediates for the synthesis of the 22-oxavitamin D derivative represented by the general formula (I) of the present invention.
The compounds represented by V) are all novel compounds and constitute another aspect of the present invention. The compound represented by the general formula (III) is a compound constituting the A-ring portion of the vitamin D derivative, and can be synthesized, for example, by a synthetic route described in the following Examples. The synthesis routes described in the examples are illustrated below.
【００１８】[0018]
【化１５】 Embedded image
【００１９】上記の反応経路において化合物１２を得る
時点までは、各化合物は、ビタミンＤ誘導体の３位に相
当する置換基の立体配置に関してエピマー混合物として
得られる。化合物１２のエピマー混合物は次いで、ｉ−
Ｂｕ2ＡｌＨなどの還元剤で処理されて化合物１３およ
び化合物１４の混合物に転換されるが、これらの化合物
１３と化合物１４とは、カラムクロマトグラフィーなど
の通常の単離精製手段によって分離することができる。
本発明の最終目的化合物である１α，３α−ジヒドロキ
シ−２２−オキサビタミンＤ誘導体の立体選択的合成
は、化合物１３と化合物１４とから成る立体異性体混合
物から化合物１３と化合物１４を分離することができる
ことにより可能となる。また、化合物１２を得るための
合成経路は特に限定されるものではない。化合物１２は
公知化合物であり、例えば、J. Org. Chem., 1993, 58,
2523-2529に記載されている方法により得ることができ
る。Up to the point at which compound 12 is obtained in the above reaction route, each compound is obtained as an epimer mixture with respect to the configuration of the substituent corresponding to the 3-position of the vitamin D derivative. The epimer mixture of compound 12 is then i-
The compound 13 and the compound 14 are converted into a mixture of the compound 13 and the compound 14 by treatment with a reducing agent such as Bu 2 AlH. However, the compound 13 and the compound 14 can be separated by ordinary isolation and purification means such as column chromatography. it can.
In the stereoselective synthesis of the 1α, 3α-dihydroxy-22-oxavitamin D derivative, which is the final target compound of the present invention, compound 13 and compound 14 are separated from a stereoisomer mixture of compound 13 and compound 14. It becomes possible by being able to do it. The synthetic route for obtaining compound 12 is not particularly limited. Compound 12 is a known compound, for example, J. Org. Chem., 1993, 58,
It can be obtained by the method described in 2523-2529.
【００２０】一般式（ＩＶ）で示される化合物は、ビタ
ミンＤ誘導体のＣＤ環部分を構成する化合物であり、例
えば、特開昭６１−２６７５５０、特開平６−７２９９
４、特開平６−２５６３００、特表平４−５０３６６９
および特表平４−５０４５７３などに記載の公知の最終
ビタミンＤ誘導体を出発物質として使用して下記のよう
にして製造できる。即ち、最終ビタミンＤ誘導体の水酸
基を保護基で保護した後、オゾンノリシス（オゾン分
解）し、次いでＮａＢＨ4還元することによりアルコー
ル化合物を得ることができる。これを適当な酸化剤（例
えば、ｎ−Ｐｒ4ＮＲｕＯ4）により酸化することにより
一般式（ＩＶ）で示されるケトン化合物を得ることがで
きる。なお、本出願が主張する優先権の基礎となる出願
である特願平９−２５５４７０号の開示は全て引用によ
り本明細書の中に取り込まれる。The compound represented by the general formula (IV) is a compound constituting the CD ring portion of a vitamin D derivative, for example, as described in JP-A-61-267550 and JP-A-6-7299.
4, JP-A-6-256300, JP-A-4-503669
It can be produced as follows using a known final vitamin D derivative described in JP-A No. 4-504573 and the like as a starting material. That is, an alcohol compound can be obtained by protecting the hydroxyl group of the final vitamin D derivative with a protecting group, subjecting it to ozone nolysis (ozonolysis), and then reducing it with NaBH 4 . This suitable oxidizing agent (e.g., n-Pr 4 NRuO 4) can be obtained ketone compound represented by the general formula (IV) by oxidation with. The disclosure of Japanese Patent Application No. 9-255470, which is the application on which the priority claimed by the present application is based, is entirely incorporated herein by reference.
【００２１】[0021]
【発明の効果】１α，２５−ジヒドロキシビタミンＤ3
は生体内で代謝されて３−エピ−１α，２５−ジヒドロ
キシビタミンＤ3になることが最近報告されている（Ten
th Workshop on Vitamin D, ストラスブルグ、フラン
ス、１９９７年５月２４〜２９日、ABSTRACTS, p.24
6）。従って、本発明の最終目的化合物である一般式
（Ｉ）で示される１α，３α−ジヒドロキシ−２２−オ
キサビタミンＤ誘導体も、生体において分化誘導作用や
増殖抑制作用を有することが判明している１α，３β−
ジヒドロキシ−２２−オキサビタミンＤ誘導体が代謝さ
れることによって生成される可能性があることが予測さ
れる。従って、本発明の一般式（Ｉ）で示される１α，
３α−ジヒドロキシ−２２−オキサビタミンＤ誘導体も
１α，３β−ジヒドロキシ−２２−オキサビタミンＤ誘
導体と同様に、分化誘導作用や増殖抑制作用を有するこ
とが期待される。即ち、本発明により、分化誘導作用や
増殖抑制作用などの有用な生理活性を有する可能性があ
る新規ビタミンＤ誘導体を提供することができる。ま
た、一般式（ＩＩＩ）および一般式（ＩＶ）で示される
化合物は、一般式（Ｉ）で示される化合物を製造する際
の中間体として重要であり、これらの化合物を使用する
ことにより、一般式（Ｉ）で示される本発明の最終目的
化合物を容易に製造することができる。According to the present invention, 1α, 25-dihydroxyvitamin D 3
Has recently been reported to be metabolized in vivo to 3-epi-1α, 25-dihydroxyvitamin D 3 (Ten
th Workshop on Vitamin D, Strasbourg, France, 24-29 May 1997, ABSTRACTS, p.24
6). Therefore, the 1α, 3α-dihydroxy-22-oxavitamin D derivative represented by the general formula (I), which is the final target compound of the present invention, has also been found to have a differentiation-inducing action and a growth-inhibiting action in living organisms. , 3β-
It is predicted that the dihydroxy-22-oxavitamin D derivative may be produced by metabolism. Therefore, 1α, represented by the general formula (I) of the present invention,
The 3α-dihydroxy-22-oxavitamin D derivative is expected to have a differentiation-inducing effect and a growth-inhibiting effect, like the 1α, 3β-dihydroxy-22-oxavitamin D derivative. That is, according to the present invention, it is possible to provide a novel vitamin D derivative which may have a useful physiological activity such as a differentiation inducing action or a growth inhibiting action. Further, the compounds represented by the general formula (III) and the general formula (IV) are important as intermediates for producing the compound represented by the general formula (I). The final target compound of the present invention represented by the formula (I) can be easily produced.
【００２２】[0022]
【実施例】以下の実施例により本発明をさらに説明する
が、本発明は実施例によって限定されるものではない。
なお、試薬は、特に断りのない限り、市販のものをその
まま用いた。乾燥ＣＨ2Ｃｌ2はＣａＨ2から、ジエチル
エーテルおよびテトラヒドロフラン（ＴＨＦ）はナトリ
ウムベンゾフェノンケチルから蒸留したものを用いた。
カラムクロマトグラフィー用のシリカゲルにはMerck社
製Kieselgel 60（７０−２３０メッシュ、２３０−２４
０メッシュ）を用いた。薄層クロマトグラフ（ＴＬＣ）
はMerck社製Kieselgel 60F254プレート（０．２５ｍｍ
および０．５ｍｍ）を用い、発色には紫外線２５４ｎ
ｍ、ヨウ素、硫酸酸性２％アニスアルデヒドエタノール
溶液、５％リンモリブデン酸エタノール溶液、２，４−
ジニトロフェニルヒドラジン呈色試薬を用いた。核磁気
共鳴スペクトルの測定には、Varian社製Unity plus 50
0、Gemini 300および200を用い、内部標準物質にはテト
ラメチルシランまたはクロロホルムを用いた。赤外吸収
スペクトルの測定には日本分光社製造ＦＴ／ＩＲ２３０
を用い、質量分析の測定には日本電子社製ＪＭＳ−Ｄｘ
３０３を、旋光度の測定には日本分光ＤＩＰ３７０を用
いた。The present invention will be further described with reference to the following examples, but the present invention is not limited to the examples.
Unless otherwise specified, commercially available reagents were used as they were. Dry CH 2 Cl 2 was distilled from CaH 2 , and diethyl ether and tetrahydrofuran (THF) were distilled from sodium benzophenone ketyl.
Silica gel for column chromatography includes Kieselgel 60 (70-230 mesh, 230-24, Merck).
0 mesh). Thin layer chromatography (TLC)
Is a Kieselgel 60F 254 plate manufactured by Merck (0.25 mm
And 0.5 mm), and 254 n
m, iodine, sulfuric acid acidic 2% anisaldehyde ethanol solution, 5% phosphomolybdic acid ethanol solution, 2,4-
Dinitrophenylhydrazine color reagent was used. For the measurement of the nuclear magnetic resonance spectrum, Varian's Unity plus 50
0, Gemini 300 and 200 were used, and tetramethylsilane or chloroform was used as an internal standard substance. For measurement of infrared absorption spectrum, FT / IR230 manufactured by JASCO Corporation
The mass spectrometry was measured using JMS-Dx manufactured by JEOL Ltd.
303, and JASCO DIP370 was used for optical rotation measurement.
【００２３】実施例１：（２Ｓ，３Ｓ）−２，３−エポ
キシ−５−（４−メトキシベンジル）オキシ−１−ペン
タノール（化合物２）の製造Example 1 Preparation of (2S, 3S) -2,3-epoxy-5- (4-methoxybenzyl) oxy-1-pentanol (Compound 2)
【化１６】 アルゴン雰囲気下−２３℃でＬ−（＋）−酒石酸ジイソ
プロピル（４７４．０ｍｇ、２．０３ミリモル）と４Ａ
モレキュラーシーブス（４０５ｍｇ）のＣＨ2Ｃｌ2（１
２ｍｌ）溶液に、Ｔｉ（Ｏ−ｉ−Ｐｒ）4（４６８μ
ｌ、１．５８ミリモル）を加え、１０分間攪拌した。次
いで、５−（４−メトキシベンジル）オキシ−２−ペン
テン−１−オール（化合物１）（５．００ｇ、２２．５
ミリモル）のＣＨ2Ｃｌ2（１１ｍｌ）溶液およびtert−
ブチルペルオキシド（２．９７ＭのＣＨ2Ｃｌ2溶液；１
５ｍｌ、４５．０ミリモル）を滴下し、−１５℃に昇温
した後、２．５日間攪拌した。反応混合物に飽和Ｎａ2
ＳＯ4水溶液とジエチルエーテルを加え、室温で２時間
攪拌し、セライト濾過、濃縮後、シリカゲルカラムクロ
マトグラフィー（ＳｉＯ2＝２５０ｇ、ヘキサン：酢酸
エチル＝３：２）で精製して無色油状の表題化合物２
（４．９２ｇ、２０．７ミリモル、９２％）を得た。Embedded image Diisopropyl L-(+)-tartrate (474.0 mg, 2.03 mmol) and 4A at -23 ° C under an argon atmosphere
Molecular sieves (405 mg) in CH 2 Cl 2 (1
2 ml) solution was added to Ti (Oi-Pr) 4 (468 μm).
1, 1.58 mmol) and stirred for 10 minutes. Then, 5- (4-methoxybenzyl) oxy-2-penten-1-ol (compound 1) (5.00 g, 22.5 g)
CH 2 Cl 2 (11ml) solution and the mmol) tert
Butyl peroxide (2.97 M CH 2 Cl 2 solution; 1
(5 ml, 45.0 mmol) was added dropwise, and the mixture was heated to -15 ° C and stirred for 2.5 days. Saturated Na 2
An aqueous solution of SO 4 and diethyl ether were added, the mixture was stirred at room temperature for 2 hours, filtered through celite, concentrated, and purified by silica gel column chromatography (SiO 2 = 250 g, hexane: ethyl acetate = 3: 2) to give the title compound as a colorless oil. 2
(4.92 g, 20.7 mmol, 92%).
【００２４】1H NMR (300 MHz, CDCl3) 1.70-1.99 (m,
3H), 2.97 (dt, J=2.7, 4.2 Hz, 1H), 3.10 (ddd, J=
2.7, 5.1, 6.6 Hz, 1H), 3.58 (t, J=5.7 Hz, 2H), 3.6
2 (ddd, J=4.2, 7.2, 12.3 Hz, 1H), 3.81 (s, 3H), 3.
90 (ddd, J=2.7, 5.7, 12.3 Hz, 1H), 4.45 (s, 2H),
6.88 (d, J=8.7Hz, 2H), 7.26 (d, J=8.7 Hz, 2H);13 C NMR (75 MHz, CDCl3) 32.0, 53.7, 55.2, 58.5, 6
1.8, 66.5, 72.7, 113.8, 129.2, 130.2, 159.1; FT-IR (neat) 3426, 1512, 1462, 1248, 1176, 1097, 8
19 cm-1; MS(EI) m/z 83 (100), 121, 137, 207, 238 (M+); [α]D 18 -27.7°(c 0.90, CHCl3); HRMS (EI) C13H18O4の計算値 238.1205; 実測値238.122
2; TLC（ヘキサン：酢酸エチル＝１：２、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 1.70-1.99 (m,
3H), 2.97 (dt, J = 2.7, 4.2 Hz, 1H), 3.10 (ddd, J =
2.7, 5.1, 6.6 Hz, 1H), 3.58 (t, J = 5.7 Hz, 2H), 3.6
2 (ddd, J = 4.2, 7.2, 12.3 Hz, 1H), 3.81 (s, 3H), 3.
90 (ddd, J = 2.7, 5.7, 12.3 Hz, 1H), 4.45 (s, 2H),
6.88 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) 32.0, 53.7, 55.2, 58.5, 6
1.8, 66.5, 72.7, 113.8, 129.2, 130.2, 159.1; FT-IR (neat) 3426, 1512, 1462, 1248, 1176, 1097, 8
19 cm -1 ; MS (EI) m / z 83 (100), 121, 137, 207, 238 (M + ); [α] D 18 -27.7 ° (c 0.90, CHCl 3 ); HRMS (EI) C Calculated for 13 H 18 O 4 238.1205; found 238.122
2; TLC (hexane: ethyl acetate = 1: 2, Rf0.5)
【００２５】実施例２：（２Ｓ，３Ｒ）−２，３−エポ
キシ−１−ヨード−５−（４−メトキシベンジル）オキ
シペンタン（化合物３）の製造Example 2 Preparation of (2S, 3R) -2,3-epoxy-1-iodo-5- (4-methoxybenzyl) oxypentane (Compound 3)
【化１７】 実施例１で得た（２Ｓ，３Ｓ）−２，３−エポキシ−５
−（４−メトキシベンジル）オキシ−１−ペンタノール
（４．００ｇ、１６．８ミリモル）のＴＨＦ−ＭｅＣＮ
（４：１、３００ｍｌ）溶液にイミダゾール（８．５８
ｇ、１２６ミリモル）とトリフェニルホスフィン（１
３．２ｇ、５０．４ミリモル）およびヨウ素（１２．８
ｇ、５０．４ミリモル）を加え、室温で３０分攪拌し
た。この反応混合物にジエチルエーテルを加えて希釈し
た後、飽和ＮａＨＣＯ3水溶液、飽和ＮａＨＳＯ3水溶液
および飽和食塩水で洗浄した。有機層をＭｇＳＯ4で乾
燥後、濾過し、濃縮した後、シリカゲルカラムクロマト
グラフィー（ＳｉＯ2＝２５０ｇ、ヘキサン：酢酸エチ
ル＝２０：１）で精製して淡黄色油状の表題化合物３
（５．８８ｇ、１６．９ミリモル、１００％）を得た。Embedded image (2S, 3S) -2,3-epoxy-5 obtained in Example 1
-(4-Methoxybenzyl) oxy-1-pentanol (4.00 g, 16.8 mmol) in THF-MeCN
(4: 1, 300 ml) to a solution of imidazole (8.58).
g, 126 mmol) and triphenylphosphine (1
3.2 g, 50.4 mmol) and iodine (12.8)
g, 50.4 mmol) and stirred at room temperature for 30 minutes. After diluting the reaction mixture with diethyl ether, the mixture was washed with a saturated aqueous solution of NaHCO 3 , a saturated aqueous solution of NaHSO 3 and a saturated saline solution. The organic layer was dried over MgSO 4 , filtered, concentrated, and then purified by silica gel column chromatography (SiO 2 = 250 g, hexane: ethyl acetate = 20: 1) to give the title compound 3 as a pale yellow oil.
(5.88 g, 16.9 mmol, 100%).
【００２６】1H NMR (300 MHz, CDCl3) 1.73-1.95 (m,
2H), 2.98 (ddd, J=1.8, 5.1, 6.3Hz, 1H), 3.06 (dd
d, J=1.8, 6.6, 8.7 Hz, 1H), 3.07 (dd, J=6.3, 12.6
Hz,1H), 3.22 (dd, J=8.7, 12.6 Hz, 1H), 3.57 (t, J=
5.7 Hz, 2H), 3.81 (s, 3H), 6.89 (d, J=9.0 Hz, 2H),
7.27 (d, J=9.0 Hz, 2H);13 C NMR (75 MHz, CDCl3) 5.0, 32.2, 55.3, 58.3, 60.
3, 66.4, 72.8, 113.8, 129.3, 130.2, 159.2; FT-IR (neat) 2948, 2859, 1612, 1512, 1460, 1361, 1
301, 1249, 1174, 1100, 1033, 889, 1033, 820 cm-1; MS(EI) m/z 121 (100), 221, 348 (M+); [α]D 19 +4.3°(c 1.04, CHCl3); HRMS (EI) C13H17O3Iの計算値 348.0222; 実測値348.02
16; TLC (ヘキサン：酢酸エチル＝５：１、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 1.73-1.95 (m,
2H), 2.98 (ddd, J = 1.8, 5.1, 6.3Hz, 1H), 3.06 (dd
d, J = 1.8, 6.6, 8.7 Hz, 1H), 3.07 (dd, J = 6.3, 12.6
Hz, 1H), 3.22 (dd, J = 8.7, 12.6 Hz, 1H), 3.57 (t, J =
5.7 Hz, 2H), 3.81 (s, 3H), 6.89 (d, J = 9.0 Hz, 2H),
7.27 (d, J = 9.0 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) 5.0, 32.2, 55.3, 58.3, 60.
3, 66.4, 72.8, 113.8, 129.3, 130.2, 159.2; FT-IR (neat) 2948, 2859, 1612, 1512, 1460, 1361, 1
301, 1249, 1174, 1100, 1033, 889, 1033, 820 cm -1 ; MS (EI) m / z 121 (100), 221, 348 (M + ); [α] D 19 + 4.3 ° (c 1.04 , CHCl 3 ); HRMS (EI) calcd for C 13 H 17 O 3 I 348.0222; found 348.02
16; TLC (hexane: ethyl acetate = 5: 1, Rf0.5)
【００２７】実施例３：（３Ｓ）−５−（４−メトキシ
ベンジル）オキシ−１−ペンテン−３−オール（化合物
４）の製造Example 3 Preparation of (3S) -5- (4-methoxybenzyl) oxy-1-penten-3-ol (Compound 4)
【化１８】 実施例２で得た（２Ｓ，３Ｒ）−２，３−エポキシ−１
−ヨード−５−（４−メトキシベンジル）オキシペンタ
ン（５．３９ｇ、１５．５ミリモル）のメタノール（２
００ｍｌ）溶液に活性化亜鉛粉末（３．０４ｇ、４６．
５ミリモル）および酢酸（８ｍｌ）を加え、超音波照射
下３７℃で１時間反応させた。反応混合物をジエチルエ
ーテルで希釈し、セライト濾過で沈殿物を除去後、濾液
を５％塩酸、飽和ＮａＨＣＯ3水溶液および飽和食塩水
で洗浄した。有機層をＭｇＳＯ4で乾燥し、濾過、濃縮
後、シリカゲルカラムクロマトグラフィー（ＳｉＯ2＝
９０ｇ、ヘキサン：酢酸エチル＝７：２）で精製して無
色油状の表題化合物４（３．１８ｇ、１４．３ミリモ
ル、９２％）を得た。Embedded image (2S, 3R) -2,3-epoxy-1 obtained in Example 2
Of iodo-5- (4-methoxybenzyl) oxypentane (5.39 g, 15.5 mmol) in methanol (2
Activated zinc powder (3.04 g, 46.00 ml) solution.
5 mmol) and acetic acid (8 ml) were added and reacted at 37 ° C. for 1 hour under ultrasonic irradiation. The reaction mixture was diluted with diethyl ether, and the precipitate was removed by filtration through Celite. Then, the filtrate was washed with 5% hydrochloric acid, a saturated aqueous solution of NaHCO 3 and a saturated saline solution. The organic layer was dried over MgSO 4 , filtered, concentrated, and then subjected to silica gel column chromatography (SiO 2 =
Purification by 90 g, hexane: ethyl acetate = 7: 2) gave the title compound 4 (3.18 g, 14.3 mmol, 92%) as a colorless oil.
【００２８】1H NMR (300 MHz, CDCl3) 1.73-1.92 (m,
2H), 2.98 (d, J= 3.6 Hz, 1H), 3.56-3.73 (m, 2H),
3.81 (s, 3H), 4.28-4.38 (m, 1H), 4.45 (s, 2H), 5.1
0 (dt, J=1.2, 10.8 Hz, 1H), 5.27 (dt, J=1.2, 17.4
Hz, 1H), 5.87 (ddd, J=5.4,10.8, 17.4 Hz, 1H), 6.88
(d, J=8.7 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H);13 C NMR (75 MHz, CDCl3) 36.1, 55.4, 68.1, 72.3, 7
3.1, 113.9, 114.7, 129.5, 129.8, 140.3, 159.3; FT-IR (neat) 3427, 1612, 1513, 1461, 1363, 1249, 1
095, 1033, 821 cm-1; MS(EI) m/z 121 (100), 222 (M+); [α]D 20 +8.5°(c 0.98, CHCl3); HRMS (EI) C13H18O3の計算値 222.1256; 実測値222.124
9; TLC (ヘキサン：酢酸エチル＝２：１、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 1.73-1.92 (m,
2H), 2.98 (d, J = 3.6 Hz, 1H), 3.56-3.73 (m, 2H),
3.81 (s, 3H), 4.28-4.38 (m, 1H), 4.45 (s, 2H), 5.1
0 (dt, J = 1.2, 10.8 Hz, 1H), 5.27 (dt, J = 1.2, 17.4
Hz, 1H), 5.87 (ddd, J = 5.4,10.8, 17.4 Hz, 1H), 6.88
(d, J = 8.7 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) 36.1, 55.4, 68.1, 72.3, 7
3.1, 113.9, 114.7, 129.5, 129.8, 140.3, 159.3; FT-IR (neat) 3427, 1612, 1513, 1461, 1363, 1249, 1
095, 1033, 821 cm -1 ; MS (EI) m / z 121 (100), 222 (M + ); [α] D 20 + 8.5 ° (c 0.98, CHCl 3 ); HRMS (EI) C 13 H 18 O 3 Calculated 222.1256; Found 222.124
9; TLC (hexane: ethyl acetate = 2: 1, Rf0.5)
【００２９】実施例４：（３Ｓ）−３−（tert−ブチル
ジメチルシリル）オキシ−５−（４−メトキシベンジ
ル）オキシ−１−ペンテン（化合物５）の製造Example 4: Preparation of (3S) -3- (tert-butyldimethylsilyl) oxy-5- (4-methoxybenzyl) oxy-1-pentene (compound 5)
【化１９】 アルゴン雰囲気下０℃で実施例３で得た（３Ｓ）−５−
（４−メトキシベンジル）オキシ−１−ペンテン−３−
オール（５．１５ｇ、３３．１ミリモル）のＣＨ2Ｃｌ2
（１００ｍｌ）溶液にトリエチルアミン（５．０ｍｌ、
３５．９ミリモル）、４−ジメチルアミノピリジン（１
６９．０ｍｇ、１．３８ミリモル）およびtert−ブチル
ジメチルシリルクロライド（９７％；５．１５ｇ、３
３．１ミリモル）を加えた後、室温に昇温し１６時間攪
拌した。反応混合物に飽和ＮａＨＣＯ3溶液を加え、酢
酸エチルで抽出し、抽出液をＭｇＳＯ4で乾燥、濾過、
濃縮後、フラッシュシリカゲルカラムクロマトグラフィ
ー（ＳｉＯ2＝１２０ｇ、ヘキサン：酢酸エチル＝１
０：１）で精製して無色油状の表題化合物５（４．３３
ｇ、１２．９ミリモル、９３％）を得た。Embedded image (3S) -5 obtained in Example 3 at 0 ° C. under an argon atmosphere.
(4-methoxybenzyl) oxy-1-pentene-3-
All (5.15 g, 33.1 mmol) CH 2 Cl 2
(100 ml) solution in triethylamine (5.0 ml,
35.9 mmol), 4-dimethylaminopyridine (1
69.0 mg, 1.38 mmol) and tert-butyldimethylsilyl chloride (97%; 5.15 g, 3
After adding 3.1 mmol), the mixture was heated to room temperature and stirred for 16 hours. To the reaction mixture was added a saturated NaHCO 3 solution, extracted with ethyl acetate, and the extract was dried over MgSO 4 , filtered,
After concentration, flash silica gel column chromatography (SiO 2 = 120 g, hexane: ethyl acetate = 1)
0: 1) to give the title compound 5 (4.33) as a colorless oil.
g, 12.9 mmol, 93%).
【００３０】1H NMR (300 MHz, CDCl3) 0.03 (s, 3H),
0.05 (s, 3H), 0.89 (s, 9H), 1.77 (q, J= 7.7 Hz, 2
H), 3.43-3.60 (m, 2H), 3.81 (s, 3H), 4.28 (q, J=6.
6 Hz, 1H), 4.38 (d, J=11.0 Hz, 1H), 4.45 (d, J=11.
0 Hz, 1H), 5.01 (dt, J=2.0, 10.0 Hz, 1H), 5.14 (d
t, J=2.0, 17.0 Hz, 1H), 5.80 (ddd, J=6.6, 10.0, 1
7.0 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (d, J=8.
7 Hz, 2H);13 C NMR (75 MHz, CDCl3) -4.8, -4.3, 18.3, 26.0, 3
8.2, 55.4, 66.5, 70.9, 72.7, 113.7, 113.8, 129.4,
130.7, 141.7, 159.2; FT-IR (neat) 1620, 1515, 1405, 1360, 1300, 1250, 1
090, 1040, 920, 840cm-1; MS(EI) m/z 122 (100), 279, 336 (M+); [α]D 18 +2.0°(c 0.99, CHCl3); HRMS (EI) C19H32O3Siの計算値 336.2121; 実測値336.2
066; TLC (ヘキサン：酢酸エチル＝１０：１、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 0.03 (s, 3H),
0.05 (s, 3H), 0.89 (s, 9H), 1.77 (q, J = 7.7 Hz, 2
H), 3.43-3.60 (m, 2H), 3.81 (s, 3H), 4.28 (q, J = 6.
6 Hz, 1H), 4.38 (d, J = 11.0 Hz, 1H), 4.45 (d, J = 11.
0 Hz, 1H), 5.01 (dt, J = 2.0, 10.0 Hz, 1H), 5.14 (d
t, J = 2.0, 17.0 Hz, 1H), 5.80 (ddd, J = 6.6, 10.0, 1
7.0 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.
7 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) -4.8, -4.3, 18.3, 26.0, 3
8.2, 55.4, 66.5, 70.9, 72.7, 113.7, 113.8, 129.4,
130.7, 141.7, 159.2; FT-IR (neat) 1620, 1515, 1405, 1360, 1300, 1250, 1
090, 1040, 920, 840cm -1 ; MS (EI) m / z 122 (100), 279, 336 (M + ); [α] D 18 + 2.0 ° (c 0.99, CHCl 3 ); HRMS (EI) Calculated for C 19 H 32 O 3 Si 336.2121; found 336.2
066; TLC (hexane: ethyl acetate = 10: 1, Rf0.5)
【００３１】実施例５：（３Ｓ）−３−（tert−ブチル
ジメチルシリル）オキシ−４−ペンテン−１−オール
（化合物６）の製造Example 5: Preparation of (3S) -3- (tert-butyldimethylsilyl) oxy-4-penten-1-ol (compound 6)
【化２０】 実施例４で得た（３Ｓ）−３−（tert−ブチルジメチル
シリル）オキシ−５−（４−メトキシベンジル）オキシ
−１−ペンテン（５３１．４ｍｇ、１．５８ミリモル）
の含水ＣＨ2Ｃｌ2（５ｍｌ）にＤＤＱ（５３９．２ｍ
ｇ、２．３８ミリモル）を加え１５分間攪拌した。この
反応混合物に飽和ＮａＨＣＯ3水溶液（５ｍｌ）を加
え、ＣＨ2Ｃｌ2（２５ｍｌ×３）で抽出した。抽出液を
飽和ＮａＨＣＯ3水溶液（２０ｍｌ）で洗浄し、ＭｇＳ
Ｏ4で乾燥、濾過、濃縮した後、シリカゲルカラムクロ
マトグラフィー（ＳｉＯ2＝３０ｇ、ヘキサン：酢酸エ
チル＝１０：１）で精製して淡黄色油状の表題化合物６
（３７７．２ｍｇ、１．８９ミリモル、quant.）を得
た。Embedded image (3S) -3- (tert-butyldimethylsilyl) oxy-5- (4-methoxybenzyl) oxy-1-pentene obtained in Example 4 (531.4 mg, 1.58 mmol)
DDQ (539.2 m) in water-containing CH 2 Cl 2 (5 ml).
g, 2.38 mmol) and stirred for 15 minutes. To the reaction mixture was added a saturated aqueous solution of NaHCO 3 (5 ml), and the mixture was extracted with CH 2 Cl 2 (25 ml × 3). The extract was washed with a saturated aqueous NaHCO 3 solution (20 ml),
After drying over O 4 , filtration and concentration, the residue was purified by silica gel column chromatography (SiO 2 = 30 g, hexane: ethyl acetate = 10: 1) to give the title compound 6 as a pale yellow oil.
(377.2 mg, 1.89 mmol, quant.).
【００３２】1H NMR (300 MHz, CDCl3) 0.06 (s, 3H),
0.10 (s, 3H), 0.91 (s, 9H), 1.65-1.78 (m, 1H), 1.
79-1.91 (m, 1H), 2.46 (br t, J= 5.4 Hz, 1H), 3.66-
3.76(m, 1H), 3.78-3.88 (m, 1H), 4.42 (br q, J=6.0
Hz, 1H), 5.11 (dt, J=1.8,9.3 Hz, 1H), 5.23 (dt, J=
1.8, 17.4 Hz, 1H), 5.85 (ddd, J=5.7, 9.3, 17.4Hz,
1H);13 C NMR (75 MHz, CDCl3) -5.0, -4.3, 18.2, 25.9, 3
9.2, 60.2, 73.3, 114.5, 140.7; FT-IR (neat) 3350, 1643, 1467, 1362, 1254, 1087, 1
024, 922, 838 cm-1; MS(EI) m/z 75 (100), 159, 160, 171, 217 (M+); [α]D 20 +3.3°(c 0.94, CHCl3); HRMS (EI) C9H19OSiの計算値 171.1205; 実測値171.120
4; TLC (ヘキサン：酢酸エチル＝４：１、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 0.06 (s, 3H),
0.10 (s, 3H), 0.91 (s, 9H), 1.65-1.78 (m, 1H), 1.
79-1.91 (m, 1H), 2.46 (br t, J = 5.4 Hz, 1H), 3.66-
3.76 (m, 1H), 3.78-3.88 (m, 1H), 4.42 (br q, J = 6.0
Hz, 1H), 5.11 (dt, J = 1.8,9.3 Hz, 1H), 5.23 (dt, J =
1.8, 17.4 Hz, 1H), 5.85 (ddd, J = 5.7, 9.3, 17.4Hz,
1H); 13 C NMR (75 MHz, CDCl 3 ) -5.0, -4.3, 18.2, 25.9, 3
9.2, 60.2, 73.3, 114.5, 140.7; FT-IR (neat) 3350, 1643, 1467, 1362, 1254, 1087, 1
024, 922, 838 cm -1 ; MS (EI) m / z 75 (100), 159, 160, 171, 217 (M + ); [α] D 20 + 3.3 ° (c 0.94, CHCl 3 ); HRMS (EI) C 9 H 19 OSi calculated 171.1205; found 171.120
4; TLC (hexane: ethyl acetate = 4: 1, Rf0.5)
【００３３】実施例６：（３Ｓ）−３−（tert−ブチル
ジメチルシリル）オキシ−４−ペンテナール（化合物
７）の製造Example 6: Preparation of (3S) -3- (tert-butyldimethylsilyl) oxy-4-pentenal (compound 7)
【化２１】 アルゴン雰囲気下−６３℃で塩化オキザリル（０．９ｍ
ｌ、１９．３２ミリモル）を加え３０分間攪拌後、実施
例５で得た（３Ｓ）−３−（tert−ブチルジメチルシリ
ル）オキシ−４−ペンテン−１−オール（１．１１４
ｇ、５．１６ミリモル）のＣＨ2Ｃｌ2（５ｍｌ）溶液を
滴下した。４０分間攪拌後、反応液にトリエチルアミン
（５．７５ｍｌ、４１．２５ミリモル）を加え反応温度
を室温まで徐々に上げた。反応混合物に０．１ＭのＨＣ
ｌを加え、酢酸エチルで希釈した後、有機層を水および
飽和食塩水で洗浄し、ＭｇＳＯ4で乾燥、濾過、濃縮し
淡黄色油状の表題化合物７（１．０７７ｇ、５．０３ミ
リモル、９７％）を得た。これはさらに精製することな
くそのまま次の反応に用いた。Embedded image Oxalyl chloride (0.9m
After stirring for 30 minutes, (3S) -3- (tert-butyldimethylsilyl) oxy-4-penten-1-ol (1.114) obtained in Example 5 was added.
g, 5.16 mmol) in CH 2 Cl 2 (5 ml) was added dropwise. After stirring for 40 minutes, triethylamine (5.75 ml, 41.25 mmol) was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. 0.1M HC in the reaction mixture
After diluting with ethyl acetate, the organic layer was washed with water and saturated saline, dried over MgSO 4 , filtered and concentrated to give the title compound 7 as a pale yellow oil (1.077 g, 5.03 mmol, 97 %). This was used for the next reaction without further purification.
【００３４】1H NMR (300 MHz, CDCl3) 0.06 (s, 3H),
0.07 (s, 3H), 0.88 (s, 9H), 2.5(ddd, J= 2.1, 4.8,
15.6 Hz, 1H), 2.62 (ddd, J= 2.7, 6.6, 15.6 Hz, 1
H),4.65 (br q, J=5.1 Hz, 1H), 5.13 (dt, J=1.5, 10.
5 Hz, 1H), 5.27 (dt, J=1.5, 17.1 Hz, 1H), 5.88 (dd
d, J=5.7, 10.5, 17.1 Hz, 1H), 9.79 (br t, J=2.5Hz,
1H); MS(EI) m/z 75 (100), 157, 171, 185 (N-CHO); TLC (ヘキサン：酢酸エチル＝２：１、Rf0.5） 1 H NMR (300 MHz, CDCl 3 ) 0.06 (s, 3H),
0.07 (s, 3H), 0.88 (s, 9H), 2.5 (ddd, J = 2.1, 4.8,
15.6 Hz, 1H), 2.62 (ddd, J = 2.7, 6.6, 15.6 Hz, 1
H), 4.65 (br q, J = 5.1 Hz, 1H), 5.13 (dt, J = 1.5, 10.
5 Hz, 1H), 5.27 (dt, J = 1.5, 17.1 Hz, 1H), 5.88 (dd
d, J = 5.7, 10.5, 17.1 Hz, 1H), 9.79 (br t, J = 2.5Hz,
1H); MS (EI) m / z 75 (100), 157, 171, 185 (N-CHO); TLC (hexane: ethyl acetate = 2: 1, Rf0.5)
【００３５】実施例７：メチル（５ＲおよびＳ，７Ｓ）
−７−（tert−ブチルジメチルシリル）オキシ−５−ヒ
ドロキシ−３−オキソ−８−ノナノエート（化合物８）
の製造Example 7: Methyl (5R and S, 7S)
-7- (tert-Butyldimethylsilyl) oxy-5-hydroxy-3-oxo-8-nonanoate (compound 8)
Manufacturing of
【化２２】 アルゴン雰囲気下−７８℃に冷却したリチウムジイソプ
ロピルアミドのＴＨＦ溶液（０．７Ｍ；２８．７ミリモ
ル，４１ｍｌ）にアセト酢酸メチル（１．４ｍｌ、１３
ミリモル）を加えその温度で１時間攪拌した後、実施例
６で得た（３Ｓ）−３−（tert−ブチルジメチルシリ
ル）オキシ−４−ペンテナール（１．０７７ｇ、５．０
３ミリモル）のＴＨＦ（５ｍｌ）溶液を滴下し、さらに
１．５時間攪拌した。反応混合物にＮＨ4Ｃｌ水を加
え、酢酸エチルで抽出し、抽出液をＮＨ4Ｃｌ水で洗浄
し、ＭｇＳＯ4で乾燥、濾過、濃縮して淡黄色油状物
（１．７６２ｇ）を得た。これを精製することなくその
まま次の反応に用いたが、一部分取用薄層シリカゲルク
ロマトグラフィー（ヘキサン：酢酸エチル＝５：２）で
精製し表題化合物８を得た。Embedded image Methyl acetoacetate (1.4 ml, 13 ml) was added to a THF solution of lithium diisopropylamide (0.7 M; 28.7 mmol, 41 ml) cooled to -78 ° C under an argon atmosphere.
(3 mmol)) and stirred at that temperature for 1 hour, and then (3S) -3- (tert-butyldimethylsilyl) oxy-4-pentenal obtained in Example 6 (1.077 g, 5.0).
(3 mmol) in THF (5 ml) was added dropwise, and the mixture was further stirred for 1.5 hours. The reaction mixture was added with aqueous NH 4 Cl and extracted with ethyl acetate. The extract was washed with aqueous NH 4 Cl, dried over MgSO 4 , filtered and concentrated to give a pale yellow oil (1.762 g). This was used for the next reaction without purification, but was purified by partially preparative thin-layer silica gel chromatography (hexane: ethyl acetate = 5: 2) to obtain the title compound 8.
【００３６】1H NMR (300 MHz, CDCl3) 0.06 (s, 3H),
0.010 (s, 3H), 0.90 (s, 4.5H),0.91 (s, 4.5H), 1.5
2-1.79 (m, 2H), 2.58-2.78 (m, 2H), 3.51 (s, 1H),
3.52(s, 1H), 3.74 (s, 3H), 4.20-4.28 (m, 0.5H), 4.
38 (br quint., J=6.6 Hz,1H), 4.46-4.56 (m, 0.5H),
[5.08 (br d, J= 10.5 Hz), 5.12 (br d, J=12.0 Hz),
5.18 (br d, J=17.1 Hz), 5.25 (br d, J=17.1 Hz), 2
H], 5.74-5.92 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ) 0.06 (s, 3H),
0.010 (s, 3H), 0.90 (s, 4.5H), 0.91 (s, 4.5H), 1.5
2-1.79 (m, 2H), 2.58-2.78 (m, 2H), 3.51 (s, 1H),
3.52 (s, 1H), 3.74 (s, 3H), 4.20-4.28 (m, 0.5H), 4.
38 (br quint., J = 6.6 Hz, 1H), 4.46-4.56 (m, 0.5H),
[5.08 (br d, J = 10.5 Hz), 5.12 (br d, J = 12.0 Hz),
5.18 (br d, J = 17.1 Hz), 5.25 (br d, J = 17.1 Hz), 2
H], 5.74-5.92 (m, 1H)
【００３７】実施例８：メチル（５ＲおよびＳ，７Ｓ）
−５，７−ジ（tert−ブチルジメチルシリル）オキシ−
３−オキソ−８−ノナノエート（化合物９）の製造Example 8: Methyl (5R and S, 7S)
-5,7-di (tert-butyldimethylsilyl) oxy-
Production of 3-oxo-8-nonanoate (Compound 9)
【化２３】 アルゴン雰囲気下−７８℃で実施例７で得たメチル（５
ＲおよびＳ，７Ｓ）−７−（tert−ブチルジメチルシリ
ル）オキシ−５−ヒドロキシ−３−オキソ−８−ノナノ
エートを含む粗生成物（１．７ｇ）のＣＨ2Ｃｌ2（５０
ｍｌ）溶液にトリエチルアミン（１．１ｍｌ、７．８９
ミリモル）とtert−ブチルジメチルシリルトリフレート
（１．４２ｍｌ、６．１８ミリモル）を加え２０分間攪
拌した。この反応混合物に飽和ＮａＨＣＯ3水を加えア
ルカリ性とし、酢酸エチルで抽出した。抽出液を飽和食
塩水で洗浄し、ＭｇＳＯ4で乾燥、濾過、濃縮後、カラ
ムクロマトグラフィー（ＳｉＯ2＝１００ｇ；ヘキサ
ン：酢酸エチル＝１５：１）で精製して無色油状の表題
化合物９（６２６ｍｇ、１．４１ミリモル、化合物７か
ら２８％）と無色油状のメチル（５ＲおよびＳ，７Ｓ）
−３，５，７−トリ（tert−ブチルジメチルシリル）オ
キシノナ−２，８−ジエノエート（化合物１０）（９０
２ｍｇ、１．６２ミリモル、化合物７から３２％）を得
た。Embedded image Methyl (5) obtained in Example 7 at -78 ° C under an argon atmosphere.
The crude product (1.7 g) containing R and S, 7S) -7- (tert-butyldimethylsilyl) oxy-5-hydroxy-3-oxo-8-nonanoate in CH 2 Cl 2 (50
ml) solution in triethylamine (1.1 ml, 7.89).
Mmol) and tert-butyldimethylsilyl triflate (1.42 ml, 6.18 mmol) were added and stirred for 20 minutes. The reaction mixture was basified by adding saturated aqueous NaHCO 3 and extracted with ethyl acetate. The extract was washed with brine, dried over MgSO 4 , filtered, concentrated, and purified by column chromatography (SiO 2 = 100 g; hexane: ethyl acetate = 15: 1) to give the title compound 9 as a colorless oil (626 mg). 1.41 mmol, 28% from compound 7) and methyl (5R and S, 7S) as a colorless oil
-3,5,7-tri (tert-butyldimethylsilyl) oxynona-2,8-dienoate (compound 10) (90
2 mg, 1.62 mmol, 32% from compound 7).
【００３８】化合物１０（５８６．４ｍｇ、１．０５ミ
リモル）のメタノール（５８ｍｌ）溶液にシリカゲル
（５．９０ｇ）を加え５日間攪拌した。反応混合物を酢
酸エチルで希釈し、綿栓濾過でシリカゲルを除去後、濃
縮した。残渣をシリカゲルクロマトグラフィー（ＳｉＯ
2＝１５ｇ、ヘキサン：酢酸エチル＝３０：１）で精製
して無色油状の表題化合物９（３１３．７ｍｇ、０．７
０７ミリモル、６７％）をＣ−５位の１：１エピマー混
合物として得た。Silica gel (5.90 g) was added to a solution of compound 10 (586.4 mg, 1.05 mmol) in methanol (58 ml), and the mixture was stirred for 5 days. The reaction mixture was diluted with ethyl acetate, filtered through a cotton plug to remove silica gel, and then concentrated. The residue is purified by silica gel chromatography (SiO
2 = 15 g, hexane: ethyl acetate = 30: 1) to give the title compound 9 as a colorless oil (313.7 mg, 0.7
(07 mmol, 67%) as a 1: 1 mixture of epimers at the C-5 position.
【００３９】1H NMR (300 MHz, CDCl3) 0.00-0.10 (m,
12H), ［0.86 (s), 0.87 (s), 0.88 (s), 0.89 (s), 1
8H], 0.57-1.82 (m, 2H), [2.69 (d, J=3.9 Hz), 2.70
(d,J=6.0 Hz), 2.73 (d, J=3.9 Hz), 2H], [3.47 (s),
3.48 (s), 2H], 4.07-4.35(m, 2H), [5.04 (br d, J=1
6.5 Hz), 5.05 (br d, J= 10.2 Hz), 1H], [5.14 (br
d, J=17.4 Hz), 5.16 (bd d, J=15.9 Hz), 1H], 5.72-
5.87 (m, 1H) 1 H NMR (300 MHz, CDCl 3 ) 0.00-0.10 (m,
12H), [0.86 (s), 0.87 (s), 0.88 (s), 0.89 (s), 1
8H], 0.57-1.82 (m, 2H), [2.69 (d, J = 3.9 Hz), 2.70
(d, J = 6.0 Hz), 2.73 (d, J = 3.9 Hz), 2H], [3.47 (s),
3.48 (s), 2H], 4.07-4.35 (m, 2H), [5.04 (br d, J = 1
6.5 Hz), 5.05 (br d, J = 10.2 Hz), 1H], [5.14 (br
d, J = 17.4 Hz), 5.16 (bd d, J = 15.9 Hz), 1H], 5.72-
5.87 (m, 1H)
【００４０】実施例９：メチル（Ｚ，５ＲおよびＳ，７
Ｓ）−５，７−ビス（tert−ブチルジメチルシリル）オ
キシ−３−（トリフルオロメタンスルホニル）オキシノ
ナ−２，８−ジエノエート（化合物１１ａ）およびメチ
ル（Ｅ，５ＲおよびＳ，７Ｓ）−５，７−ビス（tert−
ブチルジメチルシリル）オキシ−３−（トリフルオロメ
タンスルホニル）オキシノナ−２，８−ジエノエート
（化合物１１ｂ）の製造Example 9: Methyl (Z, 5R and S, 7
S) -5,7-bis (tert-butyldimethylsilyl) oxy-3- (trifluoromethanesulfonyl) oxynona-2,8-dienoate (compound 11a) and methyl (E, 5R and S, 7S) -5,7 -Bis (tert-
Production of butyldimethylsilyl) oxy-3- (trifluoromethanesulfonyl) oxynona-2,8-dienoate (Compound 11b)
【化２４】 アルゴン雰囲気下−５℃で実施例８で得たメチル（５Ｒ
およびＳ，７Ｓ）−５，７−ジ（tert−ブチルジメチル
シリル）オキシ−３−オキソ−８−ノネノエート（３９
３．１ｍｇ、０．８８５ミリモル）のＴＨＦ（４．７ｍ
ｌ）溶液に水素化ナトリウム（６０％；４１．１ｍｇ、
１．０３ミリモル）を加え１時間攪拌した後、２−
［Ｎ，Ｎ−ビス（トリフルオロメチルスルホニル）アミ
ノ］ピリジン（３３３．２ｍｇ、１．０５ミリモル）を
加え、室温でさらに１９．５時間攪拌した。反応混合物
に０℃で水（１ｍｌ）を加えた後、ジエチルエーテル
（８０ｍｌ）で希釈し、水（８０ｍｌ）、１０％クエン
酸水溶液（８０ｍｌ）、１０％ＮａＯＨ（８０ｍｌ）お
よび飽和食塩水（８０ｍｌ）で順次洗浄した。有機層を
ＭｇＳＯ4で乾燥、濾過、濃縮した後、フラッシュシリ
カゲルカラムクロマトグラフィー（ＳｉＯ2＝４０ｇ；
ヘキサン：酢酸エチル＝５０：１）で精製して無色油状
の表題化合物１１ａ（３２０．７ｍｇ、０．５５７ミリ
モル、６３％）と無色油状の表題化合物１１ｂ（２７．
９ｍｇ、０．０４８４ミリモル、６％）をそれぞれＣ−
５位の１：１エピマー混合物として得た。なお、この
際、原料の化合物９（７１.６ｍｇ、０．１６１ミリモ
ル、１８％）も回収した。Embedded image The methyl obtained in Example 8 (5R
And S, 7S) -5,7-di (tert-butyldimethylsilyl) oxy-3-oxo-8-nonenoate (39
3.1 mg, 0.885 mmol) of THF (4.7 m
1) Add sodium hydride (60%; 41.1 mg,
1.03 mmol) and stirred for 1 hour.
[N, N-bis (trifluoromethylsulfonyl) amino] pyridine (333.2 mg, 1.05 mmol) was added, and the mixture was further stirred at room temperature for 19.5 hours. After water (1 ml) was added to the reaction mixture at 0 ° C., the mixture was diluted with diethyl ether (80 ml), water (80 ml), 10% aqueous citric acid solution (80 ml), 10% NaOH (80 ml) and saturated saline (80 ml). ). The organic layer was dried over MgSO 4 , filtered and concentrated, and then flash silica gel column chromatography (SiO 2 = 40 g;
Purification with hexane: ethyl acetate = 50: 1) and colorless oily title compound 11a (320.7 mg, 0.557 mmol, 63%) and colorless oily title compound 11b (27.
9 mg, 0.0484 mmol, 6%), respectively.
Obtained as a 5: 1 1: 1 epimer mixture. At this time, the starting compound 9 (71.6 mg, 0.161 mmol, 18%) was also recovered.
【００４１】化合物１１ａ；1H NMR (300 MHz, CDCl3)
[0.01 (s), 0.03 (s), 0.05 (s),0.07 (s), 12H], [0.
086 (s), 0.088 (s), 0.89 (s), 18H], 1.62-1.88 (m,
2H), [2.47 (dd, J=8.1, 15.3 Hz), 2.53 (dd, J=5.3,
15.3 Hz), 1H], 2.63 (dd,J=5.1, 15.3 Hz, 0.5H], 2.7
5 (dd, J=4.2, 15.3 Hz, 0.5 Hz), [3.75 (s), 3.76
(s), 1H], 4.06 (quint., J=3.3 Hz, 1H), 4.15 (q, J=
6.3 Hz, 0.5H), 4.27(q, J= 4.8 Hz, 0.5H), [5.09 (br
d, J=10.5 Hz), 5.14 (bd d, J=16.8 Hz), 5.17 (br
d, J= 16.8 Hz), 2H)], [5.70-5.84 (m), 5.81 (s), 2
H]Compound 11a; 1 H NMR (300 MHz, CDCl 3 )
[0.01 (s), 0.03 (s), 0.05 (s), 0.07 (s), 12H], [0.
086 (s), 0.088 (s), 0.89 (s), 18H], 1.62-1.88 (m,
2H), (2.47 (dd, J = 8.1, 15.3 Hz), 2.53 (dd, J = 5.3,
15.3 Hz), 1H], 2.63 (dd, J = 5.1, 15.3 Hz, 0.5H], 2.7
5 (dd, J = 4.2, 15.3 Hz, 0.5 Hz), (3.75 (s), 3.76
(s), 1H], 4.06 (quint., J = 3.3 Hz, 1H), 4.15 (q, J =
6.3 Hz, 0.5H), 4.27 (q, J = 4.8 Hz, 0.5H), (5.09 (br
d, J = 10.5 Hz), 5.14 (bd d, J = 16.8 Hz), 5.17 (br
d, J = 16.8 Hz), 2H)], [5.70-5.84 (m), 5.81 (s), 2
H]
【００４２】化合物１１ｂ；1H NMR (300 MHz, CDCl3)
[0.016 (s), 0.022 (s), 0.034 (s), 0.051 (s), 0.05
5 (s), 0.062 (s), 0.069 (s), 12H], 0.085 (s, 9H),
[0.87 (s), 0.89 (s), 9H], 1.62-1.89 (m, 2H), 2.96
(dd, J=5.4, 14.4 Hz, 0.5H), 3.09 (dd, J=5.4, 14.4
Hz, 0.5H), [3.26 (dd, J=6.0, 14.4 Hz), 3.28 (dd,J=
6.0, 14.4 Hz), 1 Hz], [3.74 (s), 3.75 (s), 3H],
[5.07 (br d, J=10.2 Hz), 1H], 5.78 (ddd, J=5.4, 1
0.2, 16.8 Hz, 1H), [5.98 (s), 5.99 (s), 1H]Compound 11b; 1 H NMR (300 MHz, CDCl 3 )
[0.016 (s), 0.022 (s), 0.034 (s), 0.051 (s), 0.05
5 (s), 0.062 (s), 0.069 (s), 12H], 0.085 (s, 9H),
[0.87 (s), 0.89 (s), 9H], 1.62-1.89 (m, 2H), 2.96
(dd, J = 5.4, 14.4 Hz, 0.5H), 3.09 (dd, J = 5.4, 14.4
Hz, 0.5H), [3.26 (dd, J = 6.0, 14.4 Hz), 3.28 (dd, J =
6.0, 14.4 Hz), 1 Hz], [3.74 (s), 3.75 (s), 3H],
[5.07 (br d, J = 10.2 Hz), 1H], 5.78 (ddd, J = 5.4, 1
0.2, 16.8 Hz, 1H), [5.98 (s), 5.99 (s), 1H]
【００４３】実施例１０：メチル（Ｚ，３Ｓ−，５Ｒお
よびＳ）−［３，５−ビス（tert−ブチルジメチルシリ
ル）オキシ−２−メチレンシクロヘキシリデン］アセテ
ート（化合物１２）の製造Example 10: Preparation of methyl (Z, 3S-, 5R and S)-[3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] acetate (Compound 12)
【化２５】 アルゴン雰囲気下、実施例９で得たメチル（Ｚ，５Ｒお
よびＳ，７Ｓ）−５，７−ビス（tert−ブチルジメチル
シリル）オキシ−３−（トリフルオロメタンスルホニ
ル）オキシノナ−２，８−ジエノエート（３５５．５ｍ
ｇ、０．６１７ミリモル）とＡｇ2Ｏ（１５７．６ｍ
ｇ、０．６７６ミリモル）およびテトラキストリフェニ
ルホスフィンパラジウム（７２．３ｍｇ、０．０６２６
ミリモル）をＴＨＦ（３５ｍｌ）に懸濁し、６０℃で２
４時間攪拌した。反応混合物をシリカゲルカラム（Ｓｉ
Ｏ2＝８ｇ）を通して濾過し、濾液を濃縮後、フラッシ
ュシリカゲルカラムクロマトグラフィー（ＳｉＯ2＝３
８ｇ；ヘキサン：酢酸エチル＝５０：１）で精製して無
色油状の表題化合物１２（２０６．０ｍｇ、０．４８３
ミリモル、７８％）をＣ−５位の１：１エピマー混合物
として得た。これは混合物のまま次の反応に用いたが、
一部分取用薄層シリカゲルクロマトグラフィーで精製し
各種機器データを集めた。Embedded image Under an argon atmosphere, methyl (Z, 5R and S, 7S) -5,7-bis (tert-butyldimethylsilyl) oxy-3- (trifluoromethanesulfonyl) oxynona-2,8-dienoate obtained in Example 9 ( 355.5m
g, 0.617 mmol) and Ag 2 O (157.6 m
g, 0.676 mmol) and tetrakistriphenylphosphine palladium (72.3 mg, 0.0626)
Mmol) in THF (35 ml) and 2
Stir for 4 hours. The reaction mixture is applied to a silica gel column (Si
O 2 = 8 g), and the filtrate was concentrated and then flash silica gel column chromatography (SiO 2 = 3).
8 g; hexane: ethyl acetate = 50: 1) to give the title compound 12 as a colorless oil (206.0 mg, 0.483).
Mmol, 78%) as a 1: 1 epimeric mixture at the C-5 position. This was used as a mixture for the next reaction,
Purification was performed by thin-layer silica gel chromatography, and various instrument data were collected.
【００４４】化合物５Ｒ−１２；1H NMR (300 MHz) 0.
06 (s, 6H), 0.09 (s, 3H), 0.10 (s, 3H), 0.87 (s, 9
H), 0.94 (s, 9H), 1.57 (q, J= 11.7 Hz, 1H), 2.15-
2.27(m, 2H), 2.38-2.50 (m, 1H), 3.63 (s, 3H), 3.64
-3.80 (m, 1H), 4.06-4.12 (m, 1H), 4.96 (t, J=2.1 H
z, 1H), 5.25 (t, J=2.1 Hz, 1H), 5.67 (d, J=2.1 Hz,
1H); FT-IR (neet) 1729, 1643, 1255, 1079, 874, 835, 776
cm-1; MS(EI) m/z 369 (100), 411, 426 (M+);Compound 5R-12; 1 H NMR (300 MHz)
06 (s, 6H), 0.09 (s, 3H), 0.10 (s, 3H), 0.87 (s, 9
H), 0.94 (s, 9H), 1.57 (q, J = 11.7 Hz, 1H), 2.15-
2.27 (m, 2H), 2.38-2.50 (m, 1H), 3.63 (s, 3H), 3.64
-3.80 (m, 1H), 4.06-4.12 (m, 1H), 4.96 (t, J = 2.1 H
z, 1H), 5.25 (t, J = 2.1 Hz, 1H), 5.67 (d, J = 2.1 Hz,
1H); FT-IR (neet) 1729, 1643, 1255, 1079, 874, 835, 776
cm -1 ; MS (EI) m / z 369 (100), 411, 426 (M + );
【００４５】化合物５Ｓ−１２；1H NMR (300 MHz) 0.
05 (s, 6H), 0.09 (s, 6H), 0.89 (s, 9H), 0.90 (s, 9
H), 1.76 (ddd, J= 3.0, 9.0, 12.1 Hz, 1H), 1.93 (d
t, J=5.1, 12.1 Hz, 1H), 2.26 (dd, J=5.6, 13.1 Hz,
1H), 2.34 (br d, J=13.1 Hz,1H), 3.63 (s, 3H), 4.24
(m, 1H), 4.53 (dd, J=4.2, 8.7 Hz, 1H), 4.98 (t,J=
1.0 Hz, 1H), 5.18 (t, J=1.0 Hz, 1H), 5.63 (br s, 1
H); FT-IR (neet) 1722, 1641, 1253, 1077, 876, 834, 776
cm-1; MS(EI) m/z 369 (100), 411, 426 (M+);Compound 5S-12; 1 H NMR (300 MHz)
05 (s, 6H), 0.09 (s, 6H), 0.89 (s, 9H), 0.90 (s, 9
H), 1.76 (ddd, J = 3.0, 9.0, 12.1 Hz, 1H), 1.93 (d
t, J = 5.1, 12.1 Hz, 1H), 2.26 (dd, J = 5.6, 13.1 Hz,
1H), 2.34 (br d, J = 13.1 Hz, 1H), 3.63 (s, 3H), 4.24
(m, 1H), 4.53 (dd, J = 4.2, 8.7 Hz, 1H), 4.98 (t, J =
1.0 Hz, 1H), 5.18 (t, J = 1.0 Hz, 1H), 5.63 (br s, 1
H); FT-IR (neet) 1722, 1641, 1253, 1077, 876, 834, 776
cm -1 ; MS (EI) m / z 369 (100), 411, 426 (M + );
【００４６】実施例１１：（Ｚ，３Ｓ，５Ｒ）−２−
［３，５−ビス（tert−ブチルジメチルシリル）オキシ
−２−メチレンシクロヘキシリデン］エタノール（化合
物１３）および（Ｚ，３Ｓ，５Ｓ）−２−［３，５−ビ
ス（tert−ブチルジメチルシリル）オキシ−２−メチレ
ンシクロヘキシリデン］エタノール（化合物１４）の製
造Embodiment 11: (Z, 3S, 5R) -2-
[3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] ethanol (compound 13) and (Z, 3S, 5S) -2- [3,5-bis (tert-butyldimethylsilyl) ) Oxy-2-methylenecyclohexylidene] ethanol (Compound 14)
【化２６】 アルゴン雰囲気下、実施例１０で得たメチル（Ｚ，３Ｓ
−，５ＲおよびＳ）−［３，５−ビス（tert−ブチルジ
メチルシリル）オキシ−２−メチレンシクロヘキシリデ
ン］アセテート（２０６．０ｍｇ、０．４８３ミリモ
ル）のＣＨ2Ｃｌ2（４．４ｍｌ）溶液を−７８℃に冷却
し、ｉ−Ｂｕ2ＡｌＨ（１．０Ｍトルエン溶液；１．３
ｍｌ、１．３ミリモル）をゆっくりと滴下した後、３０
分間攪拌した。この反応混合物に１０％水酸化ナトリウ
ム水溶液を３滴加え攪拌しながら室温まで昇温後、セラ
イト濾過し、濾液にＣＨ2Ｃｌ2（４０ｍｌ）と１０％ク
エン酸水溶液（２０ｍｌ）を加え分液した。その水層を
さらにＣＨ2Ｃｌ2（２０ｍｌ×２）で抽出し、有機層を
合わせ、ＭｇＳＯ4で乾燥、濾過、濃縮後、シリカゲル
カラムクロマトグラフィー（ＳｉＯ2＝６ｇ、ＣＨ2Ｃｌ
2）で精製して無色固体の既知の表題化合物１３（７
６．６ｍｇ、０．１９２ミリモル、４０％）と無色油状
の表題化合物１４（７７．１ｍｇ、０．１９４ミリモ
ル、４０％）を得た。化合物１３の各種スペクトルデー
タは標品のそれと一致した。Embedded image In an argon atmosphere, the methyl (Z, 3S
-, 5R and S) - [3,5-bis (tert- butyldimethylsilyl) oxy-2-methylene-cyclohexylidene] acetate (206.0mg, CH 2 Cl 2 of 0.483 mmol) (4.4 ml) The solution was cooled to −78 ° C., and i-Bu 2 AlH (1.0 M toluene solution; 1.3
ml, 1.3 mmol) was slowly added dropwise.
Stirred for minutes. Three drops of a 10% aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was heated to room temperature with stirring, filtered through celite, and CH 2 Cl 2 (40 ml) and a 10% aqueous citric acid solution (20 ml) were added to the filtrate to separate the layers. . The aqueous layer was further extracted with CH 2 Cl 2 (20 ml × 2), and the organic layers were combined, dried over MgSO 4 , filtered, concentrated, and then subjected to silica gel column chromatography (SiO 2 = 6 g, CH 2 Cl 2).
2 ) The title compound 13 (7) was purified as a colorless solid by purification.
6.6 mg, 0.192 mmol, 40%) and the title compound 14 (77.1 mg, 0.194 mmol, 40%) as a colorless oil. Various spectral data of the compound 13 agreed with those of the sample.
【００４７】化合物１４；1H NMR (300 MHz) 0.06 (s,
6H), 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 0.
93 (s, 9H), 1.56 (q, J=11.7 Hz, 1H), 2.15-2.21 (m,
2H), 2.42 (ddd, J=2.4, 5.1, 12.9 Hz, 1H), 3.73 (t
t, J=2.1, 11.1 Hz, 1H), 4.14 (br d, J=12.6 Hz, 1
H), 4.28 (dd, J=8.4, 12.6Hz, 1H), 4.76 (t, J=2.4 H
z, 1H), 5.33 (t, J=2.4 Hz, 1H), 5.55 (ddd, J=1.8,
5.1, 7.5 Hz, 1H);13 C NMR (75 MHz) -4.9, -4.6, 18.2, 18.5, 25.9, 46.
4, 46.5, 60.0, 68.3,70.1, 109.9, 126.9, 138.4, 14
7.4; FT-IR (neat) 3353, 1467, 1254, 1080, 836 cm-1; MS(EI) m/z 73 (100), 341, 380, 398 (M+); [α]D 20 -65.6°(c 0.69, CHCl3); HRMS (EI) C21H42O3Si2の計算値 398.2672; 実測値398.
2647; TLC (CH2Cl2, Rf 0.2; ヘキサン：酢酸エチル＝４：
１、Rf0.5)Compound 14; 1 H NMR (300 MHz) 0.06 (s,
6H), 0.07 (s, 3H), 0.08 (s, 3H), 0.89 (s, 9H), 0.
93 (s, 9H), 1.56 (q, J = 11.7 Hz, 1H), 2.15-2.21 (m,
2H), 2.42 (ddd, J = 2.4, 5.1, 12.9 Hz, 1H), 3.73 (t
t, J = 2.1, 11.1 Hz, 1H), 4.14 (br d, J = 12.6 Hz, 1
H), 4.28 (dd, J = 8.4, 12.6Hz, 1H), 4.76 (t, J = 2.4 H
z, 1H), 5.33 (t, J = 2.4 Hz, 1H), 5.55 (ddd, J = 1.8,
5.1, 7.5 Hz, 1H); 13 C NMR (75 MHz) -4.9, -4.6, 18.2, 18.5, 25.9, 46.
4, 46.5, 60.0, 68.3,70.1, 109.9, 126.9, 138.4, 14
7.4; FT-IR (neat) 3353, 1467, 1254, 1080, 836 cm -1 ; MS (EI) m / z 73 (100), 341, 380, 398 (M + ); [α] D 20 -65.6 ° (c 0.69, CHCl 3 ); HRMS (EI) Calculated for C 21 H 42 O 3 Si 2 398.2672; found 398.
2647; TLC (CH 2 Cl 2 , Rf 0.2; hexane: ethyl acetate = 4:
1, Rf0.5)
【００４８】実施例１２：（Ｚ，３Ｓ，５Ｓ）−２−
［３，５−ビス（tert−ブチルジメチルシリル）オキシ
−２−メチレンシクロヘキシリデン］−１−クロロエタ
ン（化合物１５）の製造Embodiment 12: (Z, 3S, 5S) -2-
Production of [3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] -1-chloroethane (Compound 15)
【化２７】 アルゴン雰囲気下０℃に冷却したＮ−クロロスクシミド
（１８１．０ｍｇ、１．３６ミリモル）のＣＨ2Ｃｌ
2（４．４ｍｌ）溶液にジメチルスルフィド（１００μ
ｌ、１．３６ミリモル）を加え４０分間攪拌した。この
反応混合物のうち１．２ｍｌを、別に調製した（Ｚ，３
Ｓ，５Ｓ）−２−［３，５−ビス（tert−ブチルジメチ
ルシリル）オキシ−２−メチレンシクロヘキシリデン］
エタノール（化合物１４）（７４．１ｍｇ、０．１８６
ミリモル）のＣＨ2Ｃｌ2（０．６ｍｌ）溶液にシリンジ
を用いて−２０℃でゆっくりと滴下した。４５分間−２
０℃で攪拌後、３０分かけて反応温度を室温まで上げ
た。反応混合物にヘキサン（２０ｍｌ）を加え、有機層
を水（２０ｍｌ）と飽和塩化ナトリウム水（２０ｍｌ）
で洗浄し、ＭｇＳＯ4で乾燥、濾過、濃縮後、淡黄色油
状の表題化合物１５（７０．６ｍｇ、０．１７０ミリモ
ル、９１％）を得た。Embedded image N-chlorosuccinimide (181.0 mg, 1.36 mmol) in CH 2 Cl cooled to 0 ° C. under an argon atmosphere
2 Dimethyl sulfide (100 μl) was added to the (4.4 ml) solution.
1, 1.36 mmol) and stirred for 40 minutes. 1.2 ml of this reaction mixture was separately prepared (Z, 3
S, 5S) -2- [3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene]
Ethanol (compound 14) (74.1 mg, 0.186
(Mmol) of CH 2 Cl 2 (0.6 ml) was slowly added dropwise at −20 ° C. using a syringe. 45 minutes -2
After stirring at 0 ° C., the reaction temperature was raised to room temperature over 30 minutes. Hexane (20 ml) was added to the reaction mixture, and the organic layer was combined with water (20 ml) and saturated aqueous sodium chloride (20 ml).
After drying over MgSO 4 , filtration and concentration, the title compound 15 (70.6 mg, 0.170 mmol, 91%) was obtained as a pale yellow oil.
【００４９】1H NMR (300 MHz) 0.07 (s, 6H), 0.08
(s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 0.93 (s, 9H),
1.56 (q, J=11.4 Hz, 1H), 2.18 (m, 2H), 2.43 (ddd,
J=2.1, 4.8, 12.9 Hz, 1H), 3.71 (tt, J=4.5, 11.1 H
z, 1H), 3.94 (ddt, J=2.1, 4.5, 11.7 Hz, 1H), 4.10
(dd, J=1.5, 11.1 Hz, 1H), 4.18 (dd, J=8.1, 11.1 H
z, 1H), 4.96 (t, J=2.1 Hz, 1H), 5.39 (t, J=2.1 Hz,
1H), 5.57 (dt, J=2.1,8.1 Hz, 1H);13 C NMR (75 MHz) -4.8, -4.6, 18.2, 18.5, 25.9, 41.
5, 46.4, 46.5, 68.1,70.0, 110.1, 123.2, 141.1, 14
6.9; FT-IR (neat) 1467, 1377, 1255, 1078, 835 cm-1; MS(EI) m/z 57, 73 (100), 381, 401, 416 (M+); HRMS (EI) C20H38O2Si2Clの計算値 401.2099; 実測値40
1.2065; TLC (ヘキサン：酢酸エチル＝２０：１、Rf0.5） 1 H NMR (300 MHz) 0.07 (s, 6H), 0.08
(s, 3H), 0.09 (s, 3H), 0.89 (s, 9H), 0.93 (s, 9H),
1.56 (q, J = 11.4 Hz, 1H), 2.18 (m, 2H), 2.43 (ddd,
J = 2.1, 4.8, 12.9 Hz, 1H), 3.71 (tt, J = 4.5, 11.1 H
z, 1H), 3.94 (ddt, J = 2.1, 4.5, 11.7 Hz, 1H), 4.10
(dd, J = 1.5, 11.1 Hz, 1H), 4.18 (dd, J = 8.1, 11.1 H
z, 1H), 4.96 (t, J = 2.1 Hz, 1H), 5.39 (t, J = 2.1 Hz,
1H), 5.57 (dt, J = 2.1,8.1 Hz, 1H); 13 C NMR (75 MHz) -4.8, -4.6, 18.2, 18.5, 25.9, 41.
5, 46.4, 46.5, 68.1, 70.0, 110.1, 123.2, 141.1, 14
6.9; FT-IR (neat) 1467, 1377, 1255, 1078, 835 cm -1 ; MS (EI) m / z 57, 73 (100), 381, 401, 416 (M + ); HRMS (EI) C 20 H 38 O 2 Calculated for Si 2 Cl 401.2099; found 40
1.2065; TLC (hexane: ethyl acetate = 20: 1, Rf0.5)
【００５０】実施例１３：（Ｚ，３Ｓ，５Ｓ）−２−
［［３，５−ビス（tert−ブチルジメチルシリル）オキ
シ−２−メチレンシクロヘキシリデン］エチル］ジフェ
ニルホスフィンオキシド（化合物１６）の製造Embodiment 13: (Z, 3S, 5S) -2-
Production of [[3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] ethyl] diphenylphosphine oxide (Compound 16)
【化２８】 アルゴン雰囲気下ジフェニルホスフィン（１３５．５ｍ
ｇ、０．７２８ミリモル）のＴＨＦ（２．４ｍｌ）溶液
を０℃に冷却し、ｎ−ＢｕＬｉ（１．５８Ｍのヘキサン
溶液；４６０μｌ、０．７２７ミリモル）をゆっくりと
滴下し１０分間攪拌した後、−５０℃に冷却し、実施例
１２で得た（Ｚ，３Ｓ，５Ｓ）−２−［３，５−ビス
（tert−ブチルジメチルシリル）オキシ−２−メチレン
シクロヘキシリデン］−１−クロロエタン（６７．５ｍ
ｇ、０．１６２ミリモル）のＴＨＦ（１ｍｌ）溶液を滴
下しさらに１０分間攪拌した。この反応混合物に水を３
滴加え、攪拌しながら室温にした後、ＣＨＣｌ3（７．
４ｍｌ）と５％Ｈ2Ｏ2（５．４ｍｌ）を加えて１．５時
間攪拌した。反応混合物にＣＨＣｌ3（１５ｍｌ）を加
え分液した後、その有機層を飽和ＮａＨＳＯ3水溶液
（２０ｍｌ）および水（２０ｍｌ）で洗浄し、ＭｇＳＯ
4で乾燥、濾過、濃縮後、シリカゲルカラムクロマトグ
ラフィー（ＳｉＯ2＝２５ｇ、ヘキサン：酢酸エチル＝
２：１）で精製して無色油状粘性の表題化合物１６（６
８．０ｍｇ、０．１１７ミリモル、７２％）を得た。Embedded image Diphenylphosphine (135.5 m
g, 0.728 mmol) in THF (2.4 ml) was cooled to 0 ° C., n-BuLi (1.58 M hexane solution; 460 μl, 0.727 mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes. , Cooled to −50 ° C., and obtained in Example 12 (Z, 3S, 5S) -2- [3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] -1-chloroethane (67.5m
g, 0.162 mmol) in THF (1 ml) was added dropwise and stirred for another 10 minutes. Water is added to the reaction mixture for 3 hours.
Add dropwise, bring to room temperature with stirring, and add CHCl 3 (7.
4 ml) and 5% H 2 O 2 (5.4 ml) were added and stirred for 1.5 hours. After CHCl 3 (15 ml) was added to the reaction mixture and the layers were separated, the organic layer was washed with a saturated aqueous solution of NaHSO 3 (20 ml) and water (20 ml).
After drying with 4 , filtration and concentration, silica gel column chromatography (SiO 2 = 25 g, hexane: ethyl acetate =
2: 1) to give the title compound 16 (6
8.0 mg, 0.117 mmol, 72%).
【００５１】1H NMR (500 MHz) 0.03 (s, 6H), 0.04
(s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 0.92 (s, 9H),
1.45 (q, J=11.5 Hz, 1H), 2.05-2.15 (m, 2H), 2.37
(ddd,J=2.0, 4.5, 12.0 Hz, 1H), 3.15 (dddd, J=2.5,
5.5, 15.0, 18.0 Hz, 1H), 3.32 (br dt, J=10.0, 15.0
Hz, 1H), 3.40 (tt, J=4.0, 11.5 Hz, 1H), 3.53 (dd
t, J=2.0, 5.0, 9.0 Hz), 4.76 (t, J=2.5 Hz, 1H), 5.
28 (t, J=2.5 Hz, 1H),5.49 (ddt, J=2.0, 5.0, 7.5 H
z), 7.42-7.76 (m, 6H), 7.64-7.76 (m, 4H);13 C NMR -4.8, -4.7, -4.6, -4.5, 25.8, 25.9, 31.1,
32.2, 46.6, 46.8, 68.3, 69.22, 109.7, 115.7; FT-IR (neat) 1471, 1437, 1253, 1120, 1073, 835 cm
-1; MS(EI) m/z 525 (100), 582 (M+); [α]D 22 -38.0°(c 1.02, CHCl3); HRMS (EI) C33H51O3Si2Pの計算値 582.3115; 実測値58
2.3088; TLC (ヘキサン：酢酸エチル＝１：１、Rf0.5) 1 H NMR (500 MHz) 0.03 (s, 6H), 0.04
(s, 3H), 0.05 (s, 3H), 0.86 (s, 9H), 0.92 (s, 9H),
1.45 (q, J = 11.5 Hz, 1H), 2.05-2.15 (m, 2H), 2.37
(ddd, J = 2.0, 4.5, 12.0 Hz, 1H), 3.15 (dddd, J = 2.5,
5.5, 15.0, 18.0 Hz, 1H), 3.32 (br dt, J = 10.0, 15.0
Hz, 1H), 3.40 (tt, J = 4.0, 11.5 Hz, 1H), 3.53 (dd
t, J = 2.0, 5.0, 9.0 Hz), 4.76 (t, J = 2.5 Hz, 1H), 5.
28 (t, J = 2.5 Hz, 1H), 5.49 (ddt, J = 2.0, 5.0, 7.5 H
z), 7.42-7.76 (m, 6H), 7.64-7.76 (m, 4H); 13 C NMR -4.8, -4.7, -4.6, -4.5, 25.8, 25.9, 31.1,
32.2, 46.6, 46.8, 68.3, 69.22, 109.7, 115.7; FT-IR (neat) 1471, 1437, 1253, 1120, 1073, 835 cm
-1 ; MS (EI) m / z 525 (100), 582 (M + ); [α] D 22 -38.0 ° (c 1.02, CHCl 3 ); HRMS (EI) C 33 H 51 O 3 Si 2 P Calculated 582.3115; Found 58
2.3088; TLC (hexane: ethyl acetate = 1: 1, Rf0.5)
【００５２】実施例１４：オクタヒドロ−１−［１’−
（３”−メチル−３”−トリメチルシリルオキシ）エチ
ル］−７α−メチリデン−４−オン（ケトン化合物１
９）の製造Example 14: Octahydro-1- [1'-
(3 "-methyl-3" -trimethylsilyloxy) ethyl] -7α-methylidene-4-one (ketone compound 1
9) Manufacturing
【化２９】 ケトン化合物１９の製造のために、公知ビタミンＤ誘導
体である（５Ｚ，７Ｅ）−（１Ｓ，３Ｒ，２０Ｓ）−２
０−（３−ヒドロキシ−３−メチルブチルオキシ）−
９，１０−セコプレグナ−５，７，１０（１９）−トリ
エン−１，３−ジオール（本明細書中ではＯＣＴとも称
する）をトリメチルシリル化し、（５Ｚ，７Ｅ）−（１
Ｓ，３Ｒ，２０Ｓ）−１，３−ビス（トリメチルシリル
オキシ）−２０−（３−メチル−３−トリメチルシリル
オキシブチルオキシ）−９，１０−セコプレグナ−５，
７，１０（１９）−トリエン（本明細書中ではＯＣＴ−
トリ（トリメチルシリル）エーテルとも称する）を得、
次いでオゾンノリシス（オゾン分解）とＮａＢＨ4還元
によりオクタヒドロ−１−［１’−（３”−メチル−
３”−トリメチルシリルオキシ）エチル］−７α−メチ
リデン−４−オール（アルコール体）を得た。これをＴ
ＰＡＰ（ｎ−Ｐｒ4ＮＲｕＯ4）酸化して、ＯＣＴのＣＤ
環部であるオクタヒドロ−１−［１’−（３”−メチル
−３”−トリメチルシリルオキシ）エチル］−７α−メ
チリデン−４−オン（ケトン化合物１９）を合成した。Embedded image For the production of ketone compound 19, a known vitamin D derivative (5Z, 7E)-(1S, 3R, 20S) -2 is used.
0- (3-hydroxy-3-methylbutyloxy)-
9,10-Secopregna-5,7,10 (19) -triene-1,3-diol (also referred to herein as OCT) is trimethylsilylated to give (5Z, 7E)-(1
S, 3R, 20S) -1,3-bis (trimethylsilyloxy) -20- (3-methyl-3-trimethylsilyloxybutyloxy) -9,10-secopregna-5,
7,10 (19) -triene (herein, OCT-
Tri (trimethylsilyl) ether)
Next, octahydro-1- [1 ′-(3 ″ -methyl-) was obtained by ozone nolysis (ozonolysis) and NaBH 4 reduction.
3 "-Trimethylsilyloxy) ethyl] -7α-methylidene-4-ol (alcohol) was obtained.
PAP (n-Pr 4 NRuO 4 ) is oxidized to the CD of OCT.
Octahydro-1- [1 ′-(3 ″ -methyl-3 ″ -trimethylsilyloxy) ethyl] -7α-methylidene-4-one (ketone compound 19) as a ring portion was synthesized.
【００５３】（１）ＯＣＴ−トリ（トリメチルシリル）
エーテルの製造 ＯＣＴ（１３０．８ｍｇ、０．３１３ミリモル）とトリ
エチルアミン（０．３６ｍｌ、１．５８３ミリモル）の
ジクロロメタン（５ｍｌ）溶液に、アルゴン気流中氷冷
下でトリメチルシリルオキシＴｆ（０．２５ｍｌ、１．
２９３ミリモル）を加える。１時間攪拌後、反応液をジ
エチルエーテルで希釈し、水洗、乾燥（ＭｇＳＯ4）し
た後、溶媒を減圧下留去する。残渣をカラムクロマトグ
ラフィー（ＳｉＯ2＝１０ｇ、ヘキサン：酢酸エチル＝
１０：１）で精製し、ＯＣＴ−トリ（トリメチルシリ
ル）エーテル（１８６．３ｍｇ、９４％）を無色固形物
として得た。(1) OCT-tri (trimethylsilyl)
Preparation of Ether Trimethylsilyloxy Tf (0.25 ml, 10.8 mg, 0.313 ml) was added to a dichloromethane (5 ml) solution of OCT (130.8 mg, 0.313 mmol) and triethylamine (0.36 ml, 1.583 mmol) in an argon stream under ice cooling. .
293 mmol). After stirring for 1 hour, the reaction solution is diluted with diethyl ether, washed with water and dried (MgSO 4 ), and the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography (SiO 2 = 10 g, hexane: ethyl acetate =
10: 1) to give OCT-tri (trimethylsilyl) ether (186.3 mg, 94%) as a colorless solid.
【００５４】[α]D 26 +14.9 (c 0.37, CHCl3); IR (neat) 1251, 1075, 839 cm-1;1 H NMR (300 MHz, CDCl3) d 6.27 (d, 1H, J=11.1 H
z), 6.05 (d, 1H, J=11.1 Hz), 5.20 (d, 1H, J=1.2 H
z), 4.90 (d, 1H, J=2.4 Hz), 4.37 (dd, 1H, J=6.6,
3.9 Hz), 4.18 (m, 1H), 3.65 (dt, 1H, J=8.7, 6.6 H
z), 3.32 (dt, 1H, J=8.7, 6.2 Hz), 3.20 (br quint,
1H, J=6.0 Hz), 2.84 (br d, 1H, J=12.3 Hz), 2.46 (d
d, 1H, J=13.8, 3.8 Hz), 2.23 (dd, 1H, J=13.8, 7.8
Hz), 2.10-1.20 (m, 15H), 1.23 (s, 6H), 1.15 (d, 3
H, J=6.0 Hz), 0.53 (s, 3H), 0.12, 0.10 (s x 2, 27
H);13 C NMR (75 MHz, CDCl3) d 148.0, 141.0, 135.0, 12
3.4, 118.1, 111.6, 78.1, 73.1, 71.7, 67.3, 65.0, 5
7.5, 56.3, 45.9, 44.9, 44.7, 44.6, 39.8, 30.5, 30.
0, 25.8, 23.4, 22.2, 19.4, 12.6, 2.66, 0.31, 0.25[Α] D 26 +14.9 (c 0.37, CHCl 3 ); IR (neat) 1251, 1075, 839 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) d 6.27 (d, 1H, J = 11.1 H
z), 6.05 (d, 1H, J = 11.1 Hz), 5.20 (d, 1H, J = 1.2 H
z), 4.90 (d, 1H, J = 2.4 Hz), 4.37 (dd, 1H, J = 6.6,
3.9 Hz), 4.18 (m, 1H), 3.65 (dt, 1H, J = 8.7, 6.6 H
z), 3.32 (dt, 1H, J = 8.7, 6.2 Hz), 3.20 (br quint,
1H, J = 6.0 Hz), 2.84 (br d, 1H, J = 12.3 Hz), 2.46 (d
d, 1H, J = 13.8, 3.8 Hz), 2.23 (dd, 1H, J = 13.8, 7.8
Hz), 2.10-1.20 (m, 15H), 1.23 (s, 6H), 1.15 (d, 3
H, J = 6.0 Hz), 0.53 (s, 3H), 0.12, 0.10 (sx 2, 27
H); 13 C NMR (75 MHz, CDCl 3 ) d 148.0, 141.0, 135.0, 12
3.4, 118.1, 111.6, 78.1, 73.1, 71.7, 67.3, 65.0, 5
7.5, 56.3, 45.9, 44.9, 44.7, 44.6, 39.8, 30.5, 30.
0, 25.8, 23.4, 22.2, 19.4, 12.6, 2.66, 0.31, 0.25
【００５５】（２）アルコール体の製造 上記で得たＯＣＴ−トリ（トリメチルシリル）エーテル
（１８５ｍｇ、０．２９２ミリモル）とＮａＨＣＯ
3（１００ｍｇ、１．１９０ミリモル）のジクロロメタ
ン（４ｍｌ）およびメタノール（１ｍｌ）混合溶液に、
−７８℃で３０分間Ｏ3を通す。Ｏ3を除くためＯ2を−
７８℃で１０分間通し、次いで、メタノール（５ｍｌ）
とＮａＢＨ4（２００ｍｇ、５．２６３ミリモル）を加
える。冷却浴を外し、反応液の温度が０℃に上がるまで
攪拌する。溶媒をほとんど減圧下留去し、残渣に水を加
えジクロロメタンで抽出する。抽出液を乾燥（ＭｇＳＯ
4）後、減圧下で濃縮し、残渣をカラムクロマトグラフ
ィー（ＳｉＯ2＝１０ｇ、ヘキサン：酢酸エチル＝８：
１）で精製し、アルコール体（７４．３ｍｇ、７２％）
を無色油状物として得る。(2) Production of alcoholic product OCT-tri (trimethylsilyl) ether (185 mg, 0.292 mmol) obtained above and NaHCO
3 (100 mg, 1.190 mmol) in a mixed solution of dichloromethane (4 ml) and methanol (1 ml)
Pass O 3 at −78 ° C. for 30 minutes. The O 2 to remove O 3 -
Pass at 78 ° C. for 10 minutes, then methanol (5 ml)
And NaBH 4 is added (200 mg, 5.263 mmol). Remove the cooling bath and stir until the temperature of the reaction solution rises to 0 ° C. The solvent is almost distilled off under reduced pressure, water is added to the residue, and the mixture is extracted with dichloromethane. Dry the extract (MgSO 4
4 ) After that, the mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO 2 = 10 g, hexane: ethyl acetate = 8:
Purified in 1), alcohol form (74.3 mg, 72%)
As a colorless oil.
【００５６】[α]D 25 +38.4 (c 0.37, CHCl3); IR (neat) 3455, 1250, 1169, 1036, 842 cm-1;1 H NMR (300 MHz, CDCl3) d 4.08 (br q, 1H, J=2.4 H
z), 3.64 (ddd, 1H, J=9.0, 8.1, 6.3 Hz), 3.32 (ddd,
1H, J=9.0, 8.1, 6.6 Hz), 3.18 (dq, 1H, J=8.7, 6.3
Hz), 2.14-1.25 (m, 13H), 1.22 (s, 6H), 1.13 (d, 3
H, J=6.3 Hz),0.91 (s, 3H), 0.09 (s, 9H),13 C NMR (75 MHz, CDCl3) d 77.9, 73.2, 69.3, 64.9,
57.6, 52.6, 44.6, 41.0, 39.7, 33.6, 30.5, 25.7, 2
2.5, 19.2, 17.4, 14.2, 2.66[Α] D 25 +38.4 (c 0.37, CHCl 3 ); IR (neat) 3455, 1250, 1169, 1036, 842 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) d 4.08 (br q , 1H, J = 2.4 H
z), 3.64 (ddd, 1H, J = 9.0, 8.1, 6.3 Hz), 3.32 (ddd,
1H, J = 9.0, 8.1, 6.6 Hz), 3.18 (dq, 1H, J = 8.7, 6.3
Hz), 2.14-1.25 (m, 13H), 1.22 (s, 6H), 1.13 (d, 3
H, J = 6.3 Hz), 0.91 (s, 3H), 0.09 (s, 9H), 13 C NMR (75 MHz, CDCl 3 ) d 77.9, 73.2, 69.3, 64.9,
57.6, 52.6, 44.6, 41.0, 39.7, 33.6, 30.5, 25.7, 2
2.5, 19.2, 17.4, 14.2, 2.66
【００５７】（３）ケトン体の製造 上記で得たアルコール体（２２．２ｍｇ、０．０６２ミ
リモル）のジクロロメタン（４ｍｌ）溶液にＮ−メチル
モルホリンＮ−オキシド（ＮＭＯ）（１１．４ｍｇ、
０．０９７ミリモル）と４Ａモレキュラーシーブス（２
１．８ｍｇ）を加え、アルゴン気流中室温下で１時間攪
拌し、さらにｎ−Ｐｒ4ＮＲｕＯ4（１．０ｍｇ、０．０
０２８ミリモル）を加える。５時間後、反応液をセライ
ト濾過し、濾液を減圧下で濃縮する。残渣をカラムクロ
マトグラフィー（ＳｉＯ2＝１ｇ、ヘキサン：酢酸エチ
ル＝５：１）で精製し、オクタヒドロ−１−［１’−
（３”−メチル−３”−トリメチルシリルオキシ）エチ
ル］−７α−メチリデン−４−オン（ケトン化合物１
９）（２０．２ｍｇ、９３％）を無色油状物として得
る。(3) Production of Ketone Compound N-methylmorpholine N-oxide (NMO) (11.4 mg, N-methyl morpholine N-oxide) was added to a solution of the alcohol compound (22.2 mg, 0.062 mmol) obtained above in dichloromethane (4 ml).
0.097 mmol) and 4A molecular sieves (2
1.8 mg), and the mixture was stirred at room temperature in an argon stream for 1 hour, and further n-Pr 4 NRuO 4 (1.0 mg, 0.0 mg) was added.
028 mmol). After 5 hours, the reaction solution is filtered through celite, and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 = 1 g, hexane: ethyl acetate = 5: 1) to give octahydro-1- [1′-
(3 "-methyl-3" -trimethylsilyloxy) ethyl] -7α-methylidene-4-one (ketone compound 1
9) (20.2 mg, 93%) is obtained as a colorless oil.
【００５８】IR (neat) 1716, 1251, 1036, 839 cm-1;1 H NMR (300 MHz, CDCl3) d 3.65 (ddd, 1H, J=9.3,
8.1, 6.6 Hz), 3.31 (ddd, 1H, J=9.3, 8.7, 6.6 Hz),
3.22 (dq, 1H, J=7.5, 6.4 Hz), 2.44 (dd, 1H,J=11.4,
7.5 Hz), 2.25 (m, 2H), 2.10-1.48 (m, 11H), 1.22
(s, 6H), 1.17 (d, 3H, J=6.0 Hz), 0.62 (s, 3H), 0.0
9 (s, 9H),13 C NMR (75 MHz, CDCl3) d 211.9, 65.2, 61.9, 57.5,
48.9, 44.5, 41.0, 38.2, 30.5, 30.4, 25.2, 23.9, 1
9.3, 19.1, 13.3, 2.68IR (neat) 1716, 1251, 1036, 839 cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) d 3.65 (ddd, 1H, J = 9.3,
8.1, 6.6 Hz), 3.31 (ddd, 1H, J = 9.3, 8.7, 6.6 Hz),
3.22 (dq, 1H, J = 7.5, 6.4 Hz), 2.44 (dd, 1H, J = 11.4,
7.5 Hz), 2.25 (m, 2H), 2.10-1.48 (m, 11H), 1.22
(s, 6H), 1.17 (d, 3H, J = 6.0 Hz), 0.62 (s, 3H), 0.0
9 (s, 9H), 13 C NMR (75 MHz, CDCl 3 ) d 211.9, 65.2, 61.9, 57.5,
48.9, 44.5, 41.0, 38.2, 30.5, 30.4, 25.2, 23.9, 1
9.3, 19.1, 13.3, 2.68
【００５９】実施例１５：（５Ｚ，７Ｅ）−（１Ｓ，３
Ｓ，２０Ｓ）−１，３−ビス（tert−ブチルジメチルシ
リルオキシ）−２０−（３−メチル−３−トリメチルシ
リルオキシブチルオキシ）−９，１０−セコプレグナ−
５，７，１０（１９）−トリエン（化合物２０）の製造Embodiment 15: (5Z, 7E)-(1S, 3
(S, 20S) -1,3-bis (tert-butyldimethylsilyloxy) -20- (3-methyl-3-trimethylsilyloxybutyloxy) -9,10-secopregna
Production of 5,7,10 (19) -triene (compound 20)
【化３０】 アルゴン雰囲気下−７８℃で、実施例１３で得た（Ｚ，
３Ｓ，５Ｓ）−２−［［３，５−ビス（tert−ブチルジ
メチルシリル）オキシ−２−メチレンシクロヘキシリデ
ン］エチル］ジフェニルホスフィンオキシド（化合物１
６）（４３．３ｍｇ、０．０７４５ミリモル）のＴＨＦ
（０．７ｍｌ）溶液にｎ−ＢｕＬｉ（１．５８Ｍのヘキ
サン溶液；４７μｌ、０．０７４５ミリモル）を加え８
分間攪拌した後、実施例１４で得たオクタヒドロ−１−
［１’−（３”−メチル−３”−トリメチルシリルオキ
シ）エチル］−７α−メチリデン−４−オン（ケトン化
合物１９）（１３．１ｍｇ、０．０３７０ミリモル）の
ＴＨＦ（２ｍｌ）溶液をゆっくりと滴下し、さらに６時
間攪拌した。反応混合物にＮＨ4Ｃｌ水（５ｍｌ）を加
え室温にした後、ＣＨ2Ｃｌ2（１０ｍｌ）と水（１ｍ
ｌ）を加え分液した後、さらに水層をＣＨ2Ｃｌ2（１０
ｍｌ×２）で抽出した。有機層を合わせてＮａ2ＳＯ4乾
燥、濾過、濃縮後、分取用薄層クロマトグラフィー
（０．５ｍｍ×１、ヘキサン：酢酸エチル＝４：１）で
精製して無色油状の表題化合物２０（１２．６ｍｇ、
０．０１６５ミリモル、４５％）を得た。Embedded image In an argon atmosphere at −78 ° C., obtained in Example 13 (Z,
3S, 5S) -2-[[3,5-bis (tert-butyldimethylsilyl) oxy-2-methylenecyclohexylidene] ethyl] diphenylphosphine oxide (Compound 1
6) (43.3 mg, 0.0745 mmol) in THF
N-BuLi (1.58 M hexane solution; 47 μl, 0.0745 mmol) was added to the solution (0.7 ml), and 8
After stirring for minutes, the octahydro-1-
A solution of [1 ′-(3 ″ -methyl-3 ″ -trimethylsilyloxy) ethyl] -7α-methylidene-4-one (ketone compound 19) (13.1 mg, 0.0370 mmol) in THF (2 ml) was slowly added. The mixture was added dropwise and further stirred for 6 hours. NH 4 Cl aqueous solution (5 ml) was added to the reaction mixture, and the mixture was brought to room temperature. CH 2 Cl 2 (10 ml) and water (1 m
1) and liquid separation was performed, and the aqueous layer was further separated with CH 2 Cl 2 (10
ml × 2). The organic layers were combined, dried over Na 2 SO 4 , filtered, concentrated, and then purified by preparative thin-layer chromatography (0.5 mm × 1, hexane: ethyl acetate = 4: 1) to give the title compound 20 (colorless oil). 12.6 mg,
0.0165 mmol, 45%).
【００６０】1H NMR (300 MHz, CDCl3) 0.07 (s, 6H),
0.08 (s, 3H), 0.10 (s, 12H), 0.54 (s, 3H), 0.89
(s, 9H), 0.94 (s, 9H), 1.15 (d, J=6.3 Hz, 3H), 1.2
3 (s,6H), 1.42-1.76 (m, 12H), 1.84-2.04 (m, 3H),
2.16-2.26 (2H), 2.43 (br dd, J=2.7, 12.3 Hz, 1H),
2.83 (br d, J=11.1 Hz, 1H), 3.21 (quint., J=6.6 H
z, 1H), 3.12 (q, J=6.6 Hz, 1H), 3.65 (q, J=6.6 Hz,
1H), 3.65-3.76 (m, 1H), 3.95 (br d, J=11.1 Hz, 1
H), 4.93 (t, J=2.4 Hz, 1H), 5.38 (t, J=2.4 Hz, 1
H), 6.01 (d, J=11.4 Hz, 1H), 6.27 (d, J=11.4 Hz, 1
H);13 C NMR (75 MHz, CDCl3) -5.0, -4.9, -4.6, 2.7, 12.
5, 18.3, 18.6, 19.4,22.2, 23.5, 25.7, 26.0, 29.1,
29.8, 30.5, 39.7, 44.6, 44.8, 46.6, 47.0,56.3, 57.
5, 65.0, 68.8, 70.3, 78.0, 110.0, 117.9, 123.0, 13
4.9, 142.0,148.1; FT-IR (neat) 1644, 1471, 1370, 1250, 1075, 909, 87
5, 835 cm-1; MS(EI) m/z 75 (100), 703, 718 (M+); HRMS (EI) C41H78O4Si3の計算値 718.5208; 実測値718.
5201; TLC (ヘキサン：酢酸エチル＝２０：１、Rf0.3) 1 H NMR (300 MHz, CDCl 3 ) 0.07 (s, 6H),
0.08 (s, 3H), 0.10 (s, 12H), 0.54 (s, 3H), 0.89
(s, 9H), 0.94 (s, 9H), 1.15 (d, J = 6.3 Hz, 3H), 1.2
3 (s, 6H), 1.42-1.76 (m, 12H), 1.84-2.04 (m, 3H),
2.16-2.26 (2H), 2.43 (br dd, J = 2.7, 12.3 Hz, 1H),
2.83 (br d, J = 11.1 Hz, 1H), 3.21 (quint., J = 6.6 H
z, 1H), 3.12 (q, J = 6.6 Hz, 1H), 3.65 (q, J = 6.6 Hz,
1H), 3.65-3.76 (m, 1H), 3.95 (br d, J = 11.1 Hz, 1
H), 4.93 (t, J = 2.4 Hz, 1H), 5.38 (t, J = 2.4 Hz, 1
H), 6.01 (d, J = 11.4 Hz, 1H), 6.27 (d, J = 11.4 Hz, 1
H); 13 C NMR (75 MHz, CDCl 3 ) -5.0, -4.9, -4.6, 2.7, 12.
5, 18.3, 18.6, 19.4, 22.2, 23.5, 25.7, 26.0, 29.1,
29.8, 30.5, 39.7, 44.6, 44.8, 46.6, 47.0, 56.3, 57.
5, 65.0, 68.8, 70.3, 78.0, 110.0, 117.9, 123.0, 13
4.9, 142.0, 148.1; FT-IR (neat) 1644, 1471, 1370, 1250, 1075, 909, 87
5, 835 cm -1; MS ( EI) m / z 75 (100), 703, 718 (M +); HRMS (EI) C 41 H 78 O 4 Calculated Si 3 718.5208; Found 718.
5201; TLC (hexane: ethyl acetate = 20: 1, Rf0.3)
【００６１】実施例１６：（５Ｚ，７Ｅ）−（１Ｓ，３
Ｓ，２０Ｓ）−２０−（３−ヒドロキシ−３−メチルブ
チルオキシ）−９，１０−セコプレグナ−５，７，１０
（１９）−トリエン−１，３−ジオール（化合物２１）
の製造Embodiment 16: (5Z, 7E)-(1S, 3
S, 20S) -20- (3-Hydroxy-3-methylbutyloxy) -9,10-secopregna-5,7,10
(19) -Triene-1,3-diol (compound 21)
Manufacturing of
【化３１】 アルゴン雰囲気下、実施例１５で得た（５Ｚ，７Ｅ）−
（１Ｓ，３Ｓ，２０Ｓ）−１，３−ビス（tert−ブチル
ジメチルシリルオキシ）−２０−（３−メチル−３−ト
リメチルシリルオキシブチルオキシ）−９，１０−セコ
プレグナ−５，７，１０（１９）−トリエン（化合物２
０）（１２．６ｍｇ、０．０１６５ミリモル）のＴＨＦ
（０．３ｍｌ）溶液にフッ化ｎ−テトラブチルアンモニ
ウム（１．０ＭのＴＨＦ溶液；７０μｌ、０．０７０ミ
リモル）を加え１８時間攪拌した。反応混合物に水（３
ｍｌ）を加え酢酸エチル（５ｍｌ×３）で抽出した後、
抽出液をＮａ2ＳＯ4乾燥、濾過、濃縮後、分取用薄層ク
ロマトグラフィー（０．５ｍｍ×１、ヘキサン：酢酸エ
チル＝１：１５）で精製して無色油状の表題化合物（化
合物２１）（７．７ｍｇ、０．０１８４ミリモル、quan
t.）を得た。Embedded image (5Z, 7E) obtained in Example 15 under an argon atmosphere
(1S, 3S, 20S) -1,3-bis (tert-butyldimethylsilyloxy) -20- (3-methyl-3-trimethylsilyloxybutyloxy) -9,10-secopregna-5,7,10 (19 ) -Triene (compound 2
0) (12.6 mg, 0.0165 mmol) in THF
(0.3 ml) n-tetrabutylammonium fluoride (1.0 M THF solution; 70 μl, 0.070 mmol) was added to the solution and stirred for 18 hours. Add water (3
ml) and extracted with ethyl acetate (5 ml × 3).
The extract was dried over Na 2 SO 4 , filtered, concentrated and purified by preparative thin-layer chromatography (0.5 mm × 1, hexane: ethyl acetate = 1: 15) to give the title compound as a colorless oil (Compound 21) (7.7 mg, 0.0184 mmol, quan
t.).
【００６２】1H NMR (300 MHz, CDCl3) 0.53 (s, 3H),
1.19 (d, J=6.0 Hz, 3H), 1.24 (s, 6H), [1.44-1.74
(m), 1.75 (t, J=5.7 Hz), 12H], 1.84-2.06 (m, 2H),
2.25(br s, 1H), 2.44 (dd, J=5.1, 13.2 Hz, 1H), 2.5
6 (br dd, J=2.7, 13.2 Hz,1H), 3.25 (quint., J=6.3
Hz, 1H), 3.48 (dt, J=6.0, 9.3 Hz, 1H), 3.82 (br s,
1H), 3.85 (dt, J=5.7, 9.3 Hz, 1H), 4.06 (br q, J=
5.1 Hz, 1H), 4.32(br q, J=3.9 Hz, 1H), 5.25 (d, J=
1.8 Hz, 1H), 5.55 (br s, 1H), 6.28 (d,J=11.1 Hz, 1
H), 6.68 (d, J=11.1 Hz, 1H);13 C NMR (75 MHz, CDCl3) 12.8, 18.9, 22.3, 23.3, 2
5.7, 29.0, 29.2, 29.4, 39.7, 40.7, 41.6, 44.9, 45.
6, 56.2, 57.2, 65.6, 68.3, 70.6, 73.3, 78.9, 113.
1, 117.5, 125.5, 132.1, 142.4, 147.2; FT-IR (neat) 3319, 1453, 1371, 1077, 898 cm-1; MS(EI) m/z 44 (100), 400, 418 (M+); [α]D 17 -33.0°(c 0.39, EtOH); HRMS (EI) C26H42O4の計算値 418.3083; 実測値418.307
0; TLC (ヘキサン：酢酸エチル＝１：１０、Rf0.4) 1 H NMR (300 MHz, CDCl 3 ) 0.53 (s, 3H),
1.19 (d, J = 6.0 Hz, 3H), 1.24 (s, 6H), (1.44-1.74
(m), 1.75 (t, J = 5.7 Hz), 12H], 1.84-2.06 (m, 2H),
2.25 (br s, 1H), 2.44 (dd, J = 5.1, 13.2 Hz, 1H), 2.5
6 (br dd, J = 2.7, 13.2 Hz, 1H), 3.25 (quint., J = 6.3
Hz, 1H), 3.48 (dt, J = 6.0, 9.3 Hz, 1H), 3.82 (br s,
1H), 3.85 (dt, J = 5.7, 9.3 Hz, 1H), 4.06 (br q, J =
5.1 Hz, 1H), 4.32 (br q, J = 3.9 Hz, 1H), 5.25 (d, J =
1.8 Hz, 1H), 5.55 (br s, 1H), 6.28 (d, J = 11.1 Hz, 1
H), 6.68 (d, J = 11.1 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) 12.8, 18.9, 22.3, 23.3, 2
5.7, 29.0, 29.2, 29.4, 39.7, 40.7, 41.6, 44.9, 45.
6, 56.2, 57.2, 65.6, 68.3, 70.6, 73.3, 78.9, 113.
1, 117.5, 125.5, 132.1, 142.4, 147.2; FT-IR (neat) 3319, 1453, 1371, 1077, 898 cm -1 ; MS (EI) m / z 44 (100), 400, 418 (M + ) ; [α] D 17 -33.0 ° (c 0.39, EtOH); HRMS (EI) calcd for C 26 H 42 O 4 418.3083; found 418.307
0; TLC (hexane: ethyl acetate = 1: 10, Rf0.4)
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 ＦＩ // Ａ６１Ｋ 31/00 ６０５ Ａ６１Ｋ 31/00 ６０５Ｋ ６１７ ６１７Ｅ ６２６ ６２６Ａ ６３５ ６３５ 31/59 31/59 ──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. 6 Identification symbol FI // A61K 31/00 605 A61K 31/00 605K 617 617E 626 626A 635 635 31/59 31/59
Claims (8)
の直鎖または分枝鎖のアルキル基を示し、Ｒ2およびＲ3
は、互いに独立して水素原子または保護基を示す）で示
される２２−オキサビタミンＤ誘導体。1. A compound of the general formula (I): Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Represents a linear or branched alkyl group of R 2 and R 3
Represents a hydrogen atom or a protecting group independently of each other).
独立して０〜２の整数を示す）の基である、請求項１に
記載の２２−オキサビタミンＤ誘導体。2. R 1 is represented by the general formula (II): The 22-oxavitamin D derivative according to claim 1, wherein n is an integer of 1 to 3, and k and l independently represent an integer of 0 to 2.
チル基、２−ヒドロキシ−３−メチルブチル基、４−ヒ
ドロキシ−３−メチルブチル基、２，３−ジヒドロキシ
−３−メチルブチル基、２，４−ジヒドロキシ−３−メ
チルブチル基、３，４−ジヒドロキシ−３−メチルブチ
ル基、３−ヒドロキシ−３−エチルペンチル基、２−ヒ
ドロキシ−３−エチルペンチル基、４−ヒドロキシ−３
−エチルペンチル基、２，３−ジヒドロキシ−３−エチ
ルペンチル基、２，４−ジヒドロキシ−３−エチルペン
チル基、３，４−ジヒドロキシ−３−エチルペンチル
基、４−ヒドロキシ−４−メチルペンチル基、３−ヒド
ロキシ−４−メチルペンチル基、５−ヒドロキシ−４−
メチルペンチル基、３，４−ジヒドロキシ−４−メチル
ペンチル基、３，５−ジヒドロキシ−４−メチルペンチ
ル基、４，５−ジヒドロキシ−４−メチルペンチル基、
３−ヒドロキシ−３−（ｎ−プロピル）ヘキシル基、４
−ヒドロキシ−３−（ｎ−プロピル）ヘキシル基、２−
ヒドロキシ−３−（ｎ−プロピル）ヘキシル基、２，３
−ジヒドロキシ−３−（ｎ−プロピル）ヘキシル基、
３，４−ジヒドロキシ−３−（ｎ−プロピル）ヘキシル
基、２，４−ジヒドロキシ−３−（ｎ−プロピル）ヘキ
シル基、３−ヒドロキシ−４−エチルヘキシル基、４−
ヒドロキシ−４−エチルヘキシル基、５−ヒドロキシ−
４−エチルヘキシル基、３，４−ジヒドロキシ−４−エ
チルヘキシル基、３，５−ジヒドロキシ−４−エチルヘ
キシル基、４，５−ジヒドロキシ−４−エチルヘキシル
基、４−ヒドロキシ−５−メチルヘキシル基、５−ヒド
ロキシ−５−メチルヘキシル基、６−ヒドロキシ−５−
メチルヘキシル基、４，５−ジヒドロキシ−５−メチル
ヘキシル基、４，６−ジヒドロキシ−５−メチルヘキシ
ル基、５，６−ジヒドロキシ−５−メチルヘキシル基、
５−ヒドロキシ−６−メチルヘプチル基、６−ヒドロキ
シ−６−メチルヘプチル基、７−ヒドロキシ−６−メチ
ルヘプチル基、５，６−ジヒドロキシ−６−メチルヘプ
チル基、５，７−ジヒドロキシ−６−メチルヘプチル
基、６，７−ジヒドロキシ−６−メチルヘプチル基、４
−ヒドロキシ−５−エチルヘプチル基、５−ヒドロキシ
−５−エチルヘプチル基、６−ヒドロキシ−５−エチル
ヘプチル基、４，５−ジヒドロキシ−５−エチルヘプチ
ル基、４，６−ジヒドロキシ−５−エチルヘプチル基、
５，６−ジヒドロキシ−５−エチルヘプチル基、３−ヒ
ドロキシ−４−（ｎ−プロピル）ヘプチル基、４−ヒド
ロキシ−４−（ｎ−プロピル）ヘプチル基、５−ヒドロ
キシ−４−（ｎ−プロピル）ヘプチル基、３，４−ジヒ
ドロキシ−４−（ｎ−プロピル）ヘプチル基、３，５−
ジヒドロキシ−４−（ｎ−プロピル）ヘプチル基または
４，５−ジヒドロキシ−４−（ｎ−プロピル）ヘプチル
基である、請求項１または２に記載の２２−オキサビタ
ミンＤ誘導体。3. R 1 is a 3-hydroxy-3-methylbutyl group, a 2-hydroxy-3-methylbutyl group, a 4-hydroxy-3-methylbutyl group, a 2,3-dihydroxy-3-methylbutyl group, a 2,4 -Dihydroxy-3-methylbutyl group, 3,4-dihydroxy-3-methylbutyl group, 3-hydroxy-3-ethylpentyl group, 2-hydroxy-3-ethylpentyl group, 4-hydroxy-3
-Ethylpentyl group, 2,3-dihydroxy-3-ethylpentyl group, 2,4-dihydroxy-3-ethylpentyl group, 3,4-dihydroxy-3-ethylpentyl group, 4-hydroxy-4-methylpentyl group , 3-hydroxy-4-methylpentyl group, 5-hydroxy-4-
Methylpentyl group, 3,4-dihydroxy-4-methylpentyl group, 3,5-dihydroxy-4-methylpentyl group, 4,5-dihydroxy-4-methylpentyl group,
3-hydroxy-3- (n-propyl) hexyl group, 4
-Hydroxy-3- (n-propyl) hexyl group, 2-
Hydroxy-3- (n-propyl) hexyl group, 2,3
A dihydroxy-3- (n-propyl) hexyl group,
3,4-dihydroxy-3- (n-propyl) hexyl group, 2,4-dihydroxy-3- (n-propyl) hexyl group, 3-hydroxy-4-ethylhexyl group, 4-
Hydroxy-4-ethylhexyl group, 5-hydroxy-
4-ethylhexyl group, 3,4-dihydroxy-4-ethylhexyl group, 3,5-dihydroxy-4-ethylhexyl group, 4,5-dihydroxy-4-ethylhexyl group, 4-hydroxy-5-methylhexyl group, 5- Hydroxy-5-methylhexyl group, 6-hydroxy-5-
Methylhexyl group, 4,5-dihydroxy-5-methylhexyl group, 4,6-dihydroxy-5-methylhexyl group, 5,6-dihydroxy-5-methylhexyl group,
5-hydroxy-6-methylheptyl group, 6-hydroxy-6-methylheptyl group, 7-hydroxy-6-methylheptyl group, 5,6-dihydroxy-6-methylheptyl group, 5,7-dihydroxy-6 Methylheptyl group, 6,7-dihydroxy-6-methylheptyl group, 4
-Hydroxy-5-ethylheptyl group, 5-hydroxy-5-ethylheptyl group, 6-hydroxy-5-ethylheptyl group, 4,5-dihydroxy-5-ethylheptyl group, 4,6-dihydroxy-5-ethyl Heptyl group,
5,6-dihydroxy-5-ethylheptyl group, 3-hydroxy-4- (n-propyl) heptyl group, 4-hydroxy-4- (n-propyl) heptyl group, 5-hydroxy-4- (n-propyl ) Heptyl group, 3,4-dihydroxy-4- (n-propyl) heptyl group, 3,5-
The 22-oxavitamin D derivative according to claim 1 or 2, which is a dihydroxy-4- (n-propyl) heptyl group or a 4,5-dihydroxy-4- (n-propyl) heptyl group.
ル基である、請求項１から３のいずれか１項に記載の２
２−オキサビタミンＤ誘導体。4. The compound according to claim 1, wherein R 1 is a 3-hydroxy-3-methylbutyl group.
2-oxavitamin D derivatives.
ることを特徴とする、請求項１から４のいずれか１項に
記載の２２−オキサビタミンＤ誘導体。5. The 22-oxavitamin D derivative according to claim 1, wherein the 20-position of the vitamin D derivative has an S configuration.
ィンオキシド基を示し、Ｒ2およびＲ3は、互いに独立し
て水素原子または保護基を示す）で示される化合物。6. A compound of the general formula (III): (Wherein X represents a hydroxyl group, a chlorine atom or a diphenylphosphine oxide group, and R 2 and R 3 independently represent a hydrogen atom or a protecting group).
の直鎖または分枝鎖のアルキル基を示す）で示される化
合物。7. A compound of the general formula (IV): Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Which represents a linear or branched alkyl group).
は保護基を示す）で示される化合物を一般式（ＩＶ）： 【化６】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示す）で示される化
合物と、溶媒中で塩基の存在下において反応させること
を含む、一般式（Ｉ）： 【化７】 （式中、Ｒ1は、１から３個の水酸基を有するＣ4〜Ｃ10
の直鎖または分枝鎖のアルキル基を示し、Ｒ2およびＲ3
は、互いに独立して水素原子または保護基を示す）で示
される２２−オキサビタミンＤ誘導体の製造方法。8. A compound of the general formula (IIIa): (Wherein R 2 and R 3 independently represent a hydrogen atom or a protecting group) by a compound represented by the general formula (IV): Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
With a compound of the general formula (I): in a solvent in the presence of a base. Wherein R 1 is a C 4 -C 10 having 1 to 3 hydroxyl groups.
Represents a linear or branched alkyl group of R 2 and R 3
Represents a hydrogen atom or a protecting group independently of each other).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10264190A JPH11171859A (en) | 1997-09-19 | 1998-09-18 | Vitamin d derivative and its production |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25547097 | 1997-09-19 | ||
| JP9-255470 | 1997-09-19 | ||
| JP10264190A JPH11171859A (en) | 1997-09-19 | 1998-09-18 | Vitamin d derivative and its production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH11171859A true JPH11171859A (en) | 1999-06-29 |
Family
ID=26542225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10264190A Pending JPH11171859A (en) | 1997-09-19 | 1998-09-18 | Vitamin d derivative and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH11171859A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014532622A (en) * | 2011-10-21 | 2014-12-08 | ウイスコンシン アラムニ リサーチ ファンデーション | 2-Methylene-vitamin D analogs and their use |
-
1998
- 1998-09-18 JP JP10264190A patent/JPH11171859A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014532622A (en) * | 2011-10-21 | 2014-12-08 | ウイスコンシン アラムニ リサーチ ファンデーション | 2-Methylene-vitamin D analogs and their use |
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