JPH05239040A - Production of 5-hydroxymethyl-2-isoxyzoline compound and intermediate therefor - Google Patents
Production of 5-hydroxymethyl-2-isoxyzoline compound and intermediate thereforInfo
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- JPH05239040A JPH05239040A JP4117692A JP4117692A JPH05239040A JP H05239040 A JPH05239040 A JP H05239040A JP 4117692 A JP4117692 A JP 4117692A JP 4117692 A JP4117692 A JP 4117692A JP H05239040 A JPH05239040 A JP H05239040A
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- formula
- group
- represented
- hydroxymethyl
- isoxazoline
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は５−ヒドロキシメチル−
２−イソオキサゾリン類の製造方法及びその製造に用い
る中間体としての新規イソオキサゾリン誘導体、更には
該イソオキサゾリン誘導体の製造方法及びイソオキサゾ
リン誘導体の製造に用いる中間体としての新規アクリル
エステル誘導体に関する。The present invention relates to 5-hydroxymethyl-
The present invention relates to a method for producing 2-isoxazolines, a novel isoxazoline derivative as an intermediate used in the production, and a method for producing the isoxazoline derivative and a novel acrylic ester derivative as an intermediate used in the production of the isoxazoline derivative.
【０００２】[0002]
【発明の背景】ニトリルオキシドとアルケンの環状付加
反応によって得られるΔ2 −イソオキサゾリン類は、β
−ヒドロキしケトンや１，３−アミノアルコールなどの
種々の化合物の原料になり、これらの光学活性体は更な
る用途の拡大が期待されている。BACKGROUND OF THE INVENTION Δ 2 -Isoxazolines obtained by the cycloaddition reaction of nitrile oxides and alkenes are β
-It is a raw material for various compounds such as hydroxyketone and 1,3-aminoalcohol, and these optically active substances are expected to have further expanded applications.
【０００３】従来知られている（Ｓ）−５−ヒドロキシ
メチル−２−イソオキサゾリンの合成方法としては W.O
ppolzer らによる方法がある（Tetrahedron Letter, 32
No.37, pp 4893-4896(1991)参照) 。A conventionally known method for synthesizing (S) -5-hydroxymethyl-2-isoxazoline is WO
There is a method by ppolzer et al. (Tetrahedron Letter, 32
No. 37, pp 4893-4896 (1991)).
【０００４】この方法は（Ｓ）−５−ヒドロキシメチル
−２−イソオキサゾリンを合成するための不斉補助基を
得るために、まずラセミ体の化合物を合成し、これと
（１Ｓ）−１０−カンファースルホン酸との塩を作り、
光学分割することでＲ体の不斉補助基を得ることからな
る。しかし、より簡便に光学活性な５−ヒドロキシメチ
ル−２−イソオキサゾリン類を製造する方法の出現が望
まれている。According to this method, in order to obtain an asymmetric auxiliary group for synthesizing (S) -5-hydroxymethyl-2-isoxazoline, a racemic compound is first synthesized and then (1S) -10- Make a salt with camphorsulfonic acid,
It consists of obtaining an R-form asymmetric auxiliary group by optical resolution. However, the appearance of a method for more easily producing optically active 5-hydroxymethyl-2-isoxazolines is desired.
【０００５】[0005]
【発明の目的】本発明は光学活性を有するβ−ヒドロキ
シケトンや１，３−アミノアルコールなど抗生物質の原
料として用いられる（Ｓ）−５−ヒドロキシメチル−２
−イソオキサゾリン類及び（Ｒ）−５−ヒドロキシメチ
ル−２−イソオキサゾリン類の製造方法、これら光学活
性物質の製造に用いる中間体としての新規イソオキサゾ
リン誘導体、該イソオキサゾリン誘導体の製造方法及び
イソオキサゾリンの製造に用いる中間体としての新規ア
クリルエステル誘導体の提供を目的とする。The object of the present invention is to use (S) -5-hydroxymethyl-2 as a raw material for antibiotics such as optically active β-hydroxyketone and 1,3-aminoalcohol.
-Methods for producing isoxazolines and (R) -5-hydroxymethyl-2-isoxazolines, novel isoxazoline derivatives as intermediates used for producing these optically active substances, methods for producing the isoxazoline derivatives and isoxazolines An object of the present invention is to provide a novel acrylic ester derivative as an intermediate used in the production of
【０００６】[0006]
【発明の構成】本発明によれば、下記構造式（１）で示
されるイソオキサゾリン誘導体をAccording to the present invention, an isoxazoline derivative represented by the following structural formula (1)
【化９】 （但しここでＲ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ2 はアルキ
ル基又は芳香族基である。以下の構造式に於いても同意
である。）。 還元することを特徴とする下記構造式（２）で示される
（Ｓ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法[Chemical 9] (Here, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group. It is.). A method for producing (S) -5-hydroxymethyl-2-isoxazolines represented by the following structural formula (2), which comprises reducing
【化１０】 及び、下記構造式（３）で示されるイソオキサゾリン誘
導体を[Chemical 10] And an isoxazoline derivative represented by the following structural formula (3)
【化１１】 還元することを特徴とする構造式（４）で示される
（Ｒ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法が提供される。[Chemical 11] There is provided a method for producing (R) -5-hydroxymethyl-2-isoxazolines represented by structural formula (4), which comprises reducing.
【化１２】 [Chemical 12]
【０００７】更に、上記製造方法に於いて原料として用
いられる中間体としての上記式（１）又は（３）で示さ
れる新規イソオキサゾリン誘導体が提供される。Further, there is provided a novel isoxazoline derivative represented by the above formula (1) or (3) as an intermediate used as a raw material in the above production method.
【０００８】さらには該新規イソオキサゾリン誘導体の
製造方法として、下記構造式（５）で示されるアクリル
エステル誘導体にFurther, as a method for producing the novel isoxazoline derivative, an acrylic ester derivative represented by the following structural formula (5) is used.
【化１３】 Ｒ2 −Ｃ≡Ｎ+ −Ｏ- で示されるニトリルオキシドを反
応させることを特徴とする構造式（１）又は（３）で示
されるイソオキサゾリン誘導体の製造方法が提供され、
加えてこの製法の原料として用いる新規中間体物質（上
記式（５））が提供される。[Chemical 13] A method for producing an isoxazoline derivative represented by Structural Formula (1) or (3), which comprises reacting a nitrile oxide represented by R 2 -C≡N + —O − ,
In addition, a novel intermediate substance (the above formula (5)) used as a raw material of this production method is provided.
【０００９】以下、本発明の構成を詳述するが、本発明
のより好ましい態様及びそれに基づく利点がより明確に
なるであろう。Hereinafter, the constitution of the present invention will be described in detail, but more preferable embodiments of the present invention and advantages based on them will become clearer.
【００１０】イソオキサゾリン誘導体 前記構造式（１）及び（３）のイソオキサゾリン誘導体
に於いてＲ1 は−ＳｉＲ3 で示される有機シリル基であ
り、Ｒはアルキル基又は芳香族基で、炭素数１〜１０の
ものが好ましく、特には１〜６のものが好ましい。アル
キル基として具体的には、メチル基、エチル基、プロピ
ル基、イソプロピル基、ブチル基、ｓ−ブチル基、ｔ−
ブチル基、ペンチル基、ヘキシル基などを好ましく例示
できる。又、芳香族基としてはフェニル基、メチルフェ
ニル基などを好ましく例示することができる。 Isoxazoline Derivatives In the isoxazoline derivatives of the above structural formulas (1) and (3), R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and the number of carbon atoms is Those having 1 to 10 are preferable, and those having 1 to 6 are particularly preferable. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a s-butyl group and a t- group.
A butyl group, a pentyl group, a hexyl group and the like can be preferably exemplified. Further, as the aromatic group, a phenyl group, a methylphenyl group and the like can be preferably exemplified.
【００１１】有機シリル基である-SiR3 の好適な例とし
て、-Sit-BuMe2，-Sit-BuPh2などを挙げることができ
る。Preferred examples of -SiR 3 which is an organic silyl group include -Sit-BuMe 2 and -Sit-BuPh 2 .
【００１２】構造式（１）及び（２）に於いて、Ｒ2 は
アルキル基又は芳香族基であり、炭素数４〜６のものが
好ましい。好ましい具体例としてフェニル基、ｔ−ブチ
ル基、イソプロピル基、エチル基、メチル基などを例示
することができる。構造式（１）及び（３）に於いてＲ
1 とＲ2 の好適な組み合わせを表１として示す。In the structural formulas (1) and (2), R 2 is an alkyl group or an aromatic group and preferably has 4 to 6 carbon atoms. Preferred examples include phenyl group, t-butyl group, isopropyl group, ethyl group, methyl group and the like. R in structural formulas (1) and (3)
A suitable combination of 1 and R 2 is shown in Table 1.
【００１３】 [0013]
【００１４】構造式（１）及び（３）で示される化合物
はジアステレオマーの関係にあるので混合物であっても
例えばクロマトグラフィーを利用して容易に分離するこ
とができる。Since the compounds represented by the structural formulas (1) and (3) have a diastereomeric relationship, even a mixture can be easily separated by using, for example, chromatography.
【００１５】構造式（１）及び（３）のイゾオキサゾリ
ン誘導体は後に詳述する方法でアクリルエステル誘導体
（５）とニトリルオキシドとの反応によって得られる
が、その場合イソオキサゾリン誘導体（１）と（３）の
混合物として取得される。この混合物は前述のようにク
ロマトグラフィーの手法によって分離可能である。The isoxazoline derivatives of the structural formulas (1) and (3) can be obtained by reacting an acrylic ester derivative (5) with a nitrile oxide by a method described in detail later, in which case isoxazoline derivatives (1) and ( Obtained as a mixture of 3). This mixture can be separated by chromatographic techniques as described above.
【００１６】イソオキサゾリン誘導体の還元 イソオキサゾリン誘導体（１）又は（３）のエステル基
を還元することにより各々対応する光学活性な式（２）
又は式（４）で示される５−ヒドロキシメチル−２−イ
ソオキサゾリン類を生成する。 Reduction of isoxazoline derivative By reducing the ester group of the isoxazoline derivative (1) or (3), the corresponding optically active formula (2) is obtained.
Alternatively, 5-hydroxymethyl-2-isoxazolines represented by the formula (4) are produced.
【００１７】還元する方法としては、例えばエステル還
元試薬であるＬ−セレクトライド（L-selectride) をイ
ソオキサゾリン誘導体（１）に作用させる方法（ここで
Ｌ−セレクトライドとはリチウムトリ−ｓｅｃ−ブチル
ポロハイドライド LiB[CH(CH 3)C2H5]3H である）などの
方法が挙げられる。Examples of the reduction method include ester reduction.
The original reagent, L-selectride,
Method of acting on soxazoline derivative (1) (here
What is L-Selectride? Lithium tri-sec-butyl
Polo hydride LiB [CH (CH 3) C2HFive]3H) etc.
There is a method.
【００１８】Ｌ−セレクトライドを用いる場合、イソオ
キサゾリン誘導体（１）のテトラヒドロフラン溶液中に
４〜５モル倍のＬ−セレクトライドを添加し、半日程度
攪拌することにより（Ｓ）−５−ヒドロキシ−２−イソ
オキサゾリン類（式（２））が生成するので、反応混合
物をクロマトグラフィーにより分離して目的物を得るこ
とができる。When L-selectride is used, 4-5 mol times of L-selectride is added to a tetrahydrofuran solution of the isoxazoline derivative (1), and the mixture is stirred for about half a day to obtain (S) -5-hydroxy-. Since 2-isoxazolines (formula (2)) are produced, the reaction mixture can be separated by chromatography to obtain the desired product.
【００１９】このような方法で製造できる光学活性な５
−ヒドロキシメチル−２−オキサゾリン類の具体例とし
ては、以下のものが例示される。（Ｓ）−５−ヒドロキシメチル−２−オキサゾリン類
（式（２）） （Ｓ）−５−ヒドロキシメチル−３−フェニル−２−イ
ソオキサゾリン （Ｓ）−５−ヒドロキシメチル−３−ｔ−ブチル−２−
イソオキサゾリン（Ｒ）−５−ヒドロキシメチル−２−オキサゾリン類
（式（３）） （Ｒ）−５−ヒドロキシメチル−３−フェニル−２−イ
ソオキサゾリン （Ｒ）−５−ヒドロキシメチル−３−ｔ−ブチル−２−
イソオキサゾリンOptically active 5 which can be produced by such a method
Specific examples of -hydroxymethyl-2-oxazolines include the following. (S) -5-Hydroxymethyl-2-oxazolines
(Formula (2)) (S) -5-hydroxymethyl-3-phenyl-2-isoxazoline (S) -5-hydroxymethyl-3-t-butyl-2-
Isoxazoline (R) -5-hydroxymethyl-2-oxazolines
(Formula (3)) (R) -5-hydroxymethyl-3-phenyl-2-isoxazoline (R) -5-hydroxymethyl-3-t-butyl-2-
Isoxazoline
【００２０】しかしながら本発明に於いては式（２）の
（Ｓ）の立体配置を有する光学異性体を効率良く製造す
ることができる。However, in the present invention, the optical isomer having the configuration of (S) of formula (2) can be efficiently produced.
【００２１】オキサゾリン誘導体の製造 オキサゾリン誘導体（１）及び（３）は、前記構造式
（５）で示されるアクリルエステル誘導体とＲ2 −Ｃ≡
Ｎ+ −Ｏ- で示されるニトリルオキシドとを反応させる
ことにより製造することができる。式（５）に於けるＲ
1 及びニトリルオキシドのＲ2 の定義及び好ましい態様
はオキサゾリン誘導体（１）及び（３）について述べた
場合と同様である。ニトリルオキシドは対応する下式
（６）で示されるヒドロオキシム酸ハロゲン化合物を塩
基雰囲気下に置くと脱ハロゲン化水素することにより生
成する。 Production of Oxazoline Derivatives The oxazoline derivatives (1) and (3) are the same as the acrylic ester derivative represented by the structural formula (5) and R 2 -C≡.
It can be produced by reacting with a nitrile oxide represented by N + —O − . R in equation (5)
The definition and preferred embodiments of R 2 of 1 and nitrile oxide are the same as those described for the oxazoline derivatives (1) and (3). Nitrile oxide is produced by dehydrohalogenating a corresponding hydroxyoxime acid halogen compound represented by the following formula (6) under a basic atmosphere.
【００２２】[0022]
【化１４】 （Ｘ；ハロゲン）[Chemical 14] (X; halogen)
【００２３】従って、上記反応アクリルエステル誘導体
（５）１モルに対してヒドロオキシム酸ハロゲン化物を
５モル程度用いて適切な溶媒中と、トリエチルアミンな
どの塩基物質の存在下に行うことにより、反応系にニト
リルオキシドが生成し、反応が進行する。Therefore, the reaction system is prepared by using about 5 mol of the hydroxyoxime halide per 1 mol of the reaction acrylic ester derivative (5) in a suitable solvent and in the presence of a basic substance such as triethylamine. Nitrile oxide is generated in the reaction and the reaction proceeds.
【００２４】使用できる溶媒はベンゼン、トルエン、テ
トラヒドロフラン、アセトニトリルエーテル及びジクロ
ロメタンなどを好ましく挙げられる。塩基物質はハロゲ
ン化水素を補足できる程度の量、即ち化合物（６）と当
量あるいはそれよりも若干多い量用いればよい。この様
にしてイソオキサゾリン誘導体（１）及び（２）が生成
するが、その生成割合はＲ1 の種類によって異り、Ｒ1
がバルキーであるとイソオキサゾリン誘導体（１）の生
成割合が大となる、即ちジアステレオー選択性が大とな
る。本発明に於いては生成割合（（１）／（３））は９
５／５〜７０／３０の範囲であるが使用する溶媒、反応
温度によってもその割合は影響を受ける。The solvent which can be used is preferably benzene, toluene, tetrahydrofuran, acetonitrile ether, dichloromethane or the like. The basic substance may be used in an amount sufficient to capture hydrogen halide, that is, in an amount equivalent to or slightly higher than that of the compound (6). Although isoxazoline derivative (1) and (2) is formed in this manner, the generation ratio Ili depending on the type of R 1, R 1
Is bulky, the production rate of the isoxazoline derivative (1) is high, that is, diastereoselectivity is high. In the present invention, the production ratio ((1) / (3)) is 9
The ratio is in the range of 5/5 to 70/30, but the ratio is affected by the solvent used and the reaction temperature.
【００２５】従って、この反応はイソオキサゾリン誘導
体（１）を収率良く得る方法として有利である。Therefore, this reaction is advantageous as a method for obtaining the isoxazoline derivative (1) in good yield.
【００２６】アクリルエステル誘導体 アクリルエステル誘導体（５）は、下記構造式（７）で
示されるイノシトール誘導体 Acrylic ester derivative The acrylic ester derivative (5) is an inositol derivative represented by the following structural formula (7).
【化１５】 とアクリル酸とをエステル化反応することにより得られ
る。[Chemical 15] It is obtained by esterifying acrylic acid with acrylic acid.
【００２７】例えば、アクリル酸をアクリル酸クロリド
に一度変換後、塩基物質の存在下にイノシトール誘導体
（７）とを反応することにより極めて容易に取得するこ
とができる。For example, it can be obtained very easily by once converting acrylic acid into acrylic acid chloride and then reacting it with the inositol derivative (7) in the presence of a basic substance.
【００２８】イノシトール誘導体（７）はそれ自体公知
の物質であり、下式（８）で示される化合物とR1ClでThe inositol derivative (7) is a substance known per se, and is composed of a compound represented by the following formula (8) and R 1 Cl.
【化１６】 示される化合物とを反応させることにより容易に得るこ
とができる。[Chemical 16] It can be easily obtained by reacting with the compound shown.
【００２９】アクリルエステル誘導体（５）、イノシト
ール誘導体（７）に於けるＲ1 は、イソオキサゾリン誘
導体（１）及び（３）について記載したことが、好まし
い態様を含めてすべてあてはまる。As for R 1 in the acrylic ester derivative (5) and the inositol derivative (7), the descriptions in the isoxazoline derivatives (1) and (3) are all applicable including the preferable embodiment.
【００３０】[0030]
【実施例】以下実施例を以って本発明を具体的に説明す
る。EXAMPLES The present invention will be specifically described below with reference to examples.
【００３１】（合成例１）１Ｌ−１，２：５，６−ジ−
Ｏ−シクロヘキシリデン−３−Ｏ−ｔｅｒｔ−ブチルジ
フェニルシリル−キロ−イノシトール（1L-1,2:5,6-Di-
O-cyclohexylidene-3-O-tert-butyldiphenylsilyl-chir
o-inositol：一般式（７）のイノシトール誘導体）の合
成 １Ｌ−１，２：５，６−ジ−Ｏ−シクロヘキシリデン−
キロ−イノシトール（1L-1,2:5,6-Di-O-cyclohexyliden
e-chiro-inositol)(500mg, 1.47mmol)および、イミダゾ
ール（200mg, 2.9mmol) 、ｔｅｒｔ−ブチルジフェニル
シリル クロリド（458 μl, 1.76mmol)のＤＭＦ懸濁液
（4.0 ml）を６０℃で攪拌する。１０％ＫＨＳＯ4 水溶
液を加え、反応を停止した。水層を酢酸エチルで抽出
し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリ
ウムで乾燥した。乾燥剤を濾別した後、溶媒を留去し、
得られた油状物をシリカゲルカラムクロマトグラフィー
（酢酸エチル：ヘキサン＝１：２０）により生成し、標
記化合物（650mg,収率：76％）を得た。(Synthesis Example 1) 1L-1,2: 5,6-di-
O-cyclohexylidene-3-O-tert-butyldi
Phenylsilyl-kilo-inositol (1L-1,2: 5,6-Di-
O-cyclohexylidene-3-O-tert-butyldiphenylsilyl-chir
o-inositol: an inositol derivative of the general formula (7))
Compound 1L-1,2: 5,6-di-O-cyclohexylidene-
Chiro-inositol (1L-1,2: 5,6-Di-O-cyclohexyliden
A mixture of e-chiro-inositol) (500 mg, 1.47 mmol), imidazole (200 mg, 2.9 mmol) and tert-butyldiphenylsilyl chloride (458 μl, 1.76 mmol) in DMF (4.0 ml) is stirred at 60 ° C. .. The reaction was stopped by adding 10% KHSO 4 aqueous solution. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off,
The obtained oil was produced by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give the title compound (650 mg, yield: 76%).
【００３２】1H NMR (CDCl3) δ: 1.10(9H, s, (C
H3)3), 1.09-1.72(20H, m, (CH2)10), 3.56(1H, dd, J
3,4=11.0 Hz, J2,3=5.8 Hz, H-3), 3.64(1H, dd, J3,4=
11.0 Hz,J4,5=7.0 Hz, H-4), 3.97(1H, dd, J5,4=7.0 H
z, J5,6=7.3 Hz, H-5), 4.10(1H,dd, J2,1=7.3 Hz, J
2,3=5.8 Hz, H-2), 4.21-4.30(2H, m, H-1,6), 7.32-7.
43(6H, m, aromatic), 7.65-7.75(4H, m, aromatic). [ α ]D 18 ＋17°（c 1.14, CHCl3)． 1 H NMR (CDCl 3 ) δ: 1.10 (9H, s, (C
H 3) 3), 1.09-1.72 ( 20H, m, (CH 2) 10), 3.56 (1H, dd, J
3,4 = 11.0 Hz, J 2,3 = 5.8 Hz, H-3), 3.64 (1H, dd, J 3,4 =
11.0 Hz, J 4,5 = 7.0 Hz, H-4), 3.97 (1H, dd, J 5,4 = 7.0 H
z, J 5,6 = 7.3 Hz, H-5), 4.10 (1H, dd, J 2,1 = 7.3 Hz, J
2,3 = 5.8 Hz, H-2), 4.21-4.30 (2H, m, H-1,6), 7.32-7.
43 (6H, m, aromatic), 7.65-7.75 (4H, m, aromatic). [Α] D 18 + 17 ° (c 1.14, CHCl 3 ).
【００３３】（合成例２）１Ｌ−４−Ｏ−アクリロイル−１，２：５，６−ジ−Ｏ
−シクロヘキシリデン−３−Ｏ−ｔｅｒｔ−ブチルジメ
チルシリル−キロ−イノシトール（1L-4-O-Acryloyl-1,
2:5,6-di-O-cyclohexylidene-3-O-tert-butyldimethyls
ilyl-chiro-inositol ：一般式（５）のアクリルエステ
ル誘導体）の合成 一般式（７）のＲ1 がｔｅｒｔ−ブチルジメチルシリル
基であるイノシトール誘導体(3.82g, 7.9mmol)とトリエ
チルアミン(3.3mL, 23.7mmol) のＣＨ2 Ｃｌ2溶液(20m
l)に０℃でアクリル酸塩化物(1.28ml, 15.8mmol)を加え
た。０℃で１時間攪拌した後、１０％ＫＨＳＯ4 水溶液
を加え、反応を停止する。水層を酢酸エチルで抽出し、
有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウム
で乾燥する。乾燥剤を炉別した後、溶媒を留去し、得ら
れた油状物をシリカゲルカラムクロマトグラフィー（酢
酸エチル：ヘキサン＝1:20) により精製し、標記化合物
(1.78g, 収率44％）を得た。(Synthesis example 2) 1L-4-O-acryloyl-1,2: 5,6-di-O
-Cyclohexylidene-3-O-tert-butyl dime
Cylsilyl-kilo-inositol (1L-4-O-Acryloyl-1,
2: 5,6-di-O-cyclohexylidene-3-O-tert-butyldimethyls
ilyl-chiro-inositol: Acrylic ester of general formula (5)
Of the inositol derivative (3.82 g, 7.9 mmol) in which R 1 of the general formula (7) is a tert-butyldimethylsilyl group and a solution of triethylamine (3.3 mL, 23.7 mmol) in CH 2 Cl 2 (20 m
Acrylic acid chloride (1.28 ml, 15.8 mmol) was added to (l) at 0 ° C. After stirring at 0 ° C. for 1 hour, 10% KHSO 4 aqueous solution is added to stop the reaction. The aqueous layer was extracted with ethyl acetate,
The organic layer is washed with saturated saline and then dried over anhydrous sodium sulfate. After separating the desiccant by furnace, the solvent was distilled off, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give the title compound.
(1.78 g, yield 44%) was obtained.
【００３４】1H NMR (CDCl3) δ: 0.00(3H, s, CH3),
0.15(3H, s, CH3), 0.80(9H, s, (CH3)3), 1.22-1.80(2
0H, m, (CH2)10), 3.62(1H, dd, J3,4=11.3 Hz, J2,3=
7.0 Hz, H-3), 4.18(1H, dd, J2,1=6.7 Hz, J2,3=7.0 H
z, H-2), 4.22(1H, dd, J5,4=8.5 Hz, J5,6=6.1 Hz, H-
5), 4.37(1H, dd, J6,1=4.0 Hz, J6,5=6.1 Hz, H-6),4.
42(1H, dd, J6,1=4.0 Hz, J2,1=6.7 Hz, H-1), 5.08(1
H, dd, J3,4=11.3 Hz,J4,5=8.5 Hz, H-4), 5.85(1H, d
d, J=1.5 Hz, 10.4 Hz), 6.16(1H, dd, J=10.4Hz, 17.4
Hz), 6.44(1H, dd, J=1.5 Hz, 17.4 Hz). IR (neat) 2930, 2870, 1720, 1630, 1420, 1400, 135
0, 1240, 1160, 1080,1020, cm-1. [ α ]D 18 −41°（c 1.05, CHCl3)． 1 H NMR (CDCl 3 ) δ: 0.00 (3H, s, CH 3 ),
0.15 (3H, s, CH 3 ), 0.80 (9H, s, (CH 3 ) 3 ), 1.22-1.80 (2
0H, m, (CH 2 ) 10 ), 3.62 (1H, dd, J 3,4 = 11.3 Hz, J 2,3 =
7.0 Hz, H-3), 4.18 (1H, dd, J 2,1 = 6.7 Hz, J 2,3 = 7.0 H
z, H-2), 4.22 (1H, dd, J 5,4 = 8.5 Hz, J 5,6 = 6.1 Hz, H-
5), 4.37 (1H, dd, J 6,1 = 4.0 Hz, J 6,5 = 6.1 Hz, H-6), 4.
42 (1H, dd, J 6,1 = 4.0 Hz, J 2,1 = 6.7 Hz, H-1), 5.08 (1
H, dd, J 3,4 = 11.3 Hz, J 4,5 = 8.5 Hz, H-4), 5.85 (1H, d
d, J = 1.5 Hz, 10.4 Hz), 6.16 (1H, dd, J = 10.4Hz, 17.4
Hz), 6.44 (1H, dd, J = 1.5 Hz, 17.4 Hz). IR (neat) 2930, 2870, 1720, 1630, 1420, 1400, 135
0, 1240, 1160, 1080,1020, cm -1 . [Α] D 18 −41 ° (c 1.05, CHCl 3 ).
【００３５】（合成例３）１Ｌ−４−Ｏ−アクリロイル−１，２：５，６−ジ−Ｏ
−シクロヘキシリデン−３−Ｏ−ｔｅｒｔ−ブチルジフ
ェニルシリル−キロ−イノシトール（1L-4-O-Acryloyl-
1,2:5,6-di-O-cyclohexylidene-3-O-tert-butyldipheny
lsilyl-chiro-inositol ：一般式（５）のアクリルエス
テル誘導体）の合成 合成例（１）で合成したイノシトール誘導体(0.92g, 1.
6mmol)とトリエチルアミン(3.3mL, 23.7mmol) のＣＨ2
Ｃｌ2 溶液(20ml)に０℃で塩化アクリロイル(1.28ml, 1
5.8mmol)を加えた。０℃で１時間攪拌した後、１０％Ｋ
ＨＳＯ4 水溶液を加え、反応を停止した。水層を酢酸エ
チルで抽出し、有機層を飽和食塩水で洗浄した後、無水
硫酸ナトリウムで乾燥した。乾燥剤を濾別した後、溶媒
を留去し、得られた油状物をシリカゲルカラムクロマト
グラフィー（酢酸エチル：ヘキサン＝1:20) により精製
し、標記化合物(0.42g, 41％）を得た。(Synthesis Example 3) 1L-4-O-acryloyl-1,2: 5,6-di-O
-Cyclohexylidene-3-O-tert-butyldiph
Phenylsilyl-kilo-inositol (1L-4-O-Acryloyl-
1,2: 5,6-di-O-cyclohexylidene-3-O-tert-butyldipheny
lsilyl-chiro-inositol: Acrylic ester of general formula (5)
Synthesis of tellur derivative) Inositol derivative synthesized in Synthesis Example (1) (0.92g, 1.
6 mmol) and triethylamine (3.3 mL, 23.7 mmol) CH 2
Acryloyl chloride (1.28 ml, 1 ml in Cl 2 solution (20 ml) at 0 ° C.
5.8 mmol) was added. After stirring for 1 hour at 0 ° C, 10% K
Aqueous HSO 4 solution was added to stop the reaction. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off, and the obtained oil was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to obtain the title compound (0.42g, 41%). ..
【００３６】1H NMR (CDCl3) δ: 1.00(9H, s, (C
H3)3), 1.10-1.80(20H, m, (CH2)10), 3.64(1H, dd, J
3,4=11.3 Hz, J2,3=7.3 Hz, H-3), 3.97(1H, dd, J5,4=
8.6 Hz, J 5,6=6.1 Hz, H-5), 4.26(1H, dd, J6,1=3.1 H
z, J6,5=6.1 Hz, H-6), 4.34(1H,dd, J2,1=6.4 Hz, J
2,3=7.3 Hz, H-2), 4.43(1H, dd, J6,1=3.1 Hz, J2,1=
6.4 Hz, H-1), 5.17(1H, dd, J3,4=11.3 Hz, J4,5=8.6
Hz, H-4), 5.59(1H, dd, J=1.5 Hz, 10.4 Hz), 5.77(1
H, dd, J=10.4 Hz, 17.1 Hz), 6.18(1H, dd, J=1.5 Hz,
17.1 Hz), 7.25-7.43(6H, m, aromatic), 7.51-7.60(2
H, m, aromatic), 7.70-7.78(2H, m, aromatic). IR (nujol) 3050, 1740, 1580, 1240, 1180, and 1100,
cm-1. [ α ]D 18 −44°（c 1.10, CHCl3)．[0036]1H NMR (CDCl3) δ: 1.00 (9H, s, (C
H3)3), 1.10-1.80 (20H, m, (CH2)Ten), 3.64 (1H, dd, J
3,4= 11.3 Hz, J2,3= 7.3 Hz, H-3), 3.97 (1H, dd, J5,4=
8.6 Hz, J 5,6= 6.1 Hz, H-5), 4.26 (1H, dd, J6,1= 3.1 H
z, J6,5= 6.1 Hz, H-6), 4.34 (1H, dd, J2,1= 6.4 Hz, J
2,3= 7.3 Hz, H-2), 4.43 (1H, dd, J6,1= 3.1 Hz, J2,1=
6.4 Hz, H-1), 5.17 (1H, dd, J3,4= 11.3 Hz, J4,5= 8.6
Hz, H-4), 5.59 (1H, dd, J = 1.5 Hz, 10.4 Hz), 5.77 (1
H, dd, J = 10.4 Hz, 17.1 Hz), 6.18 (1H, dd, J = 1.5 Hz,
17.1 Hz), 7.25-7.43 (6H, m, aromatic), 7.51-7.60 (2
H, m, aromatic), 7.70-7.78 (2H, m, aromatic). IR (nujol) 3050, 1740, 1580, 1240, 1180, and 1100,
cm-1. [α]D 18 −44 ° (c 1.10, CHCl3).
【００３７】（合成例４）イソオキサゾリン誘導体（１）及び（３）の合成（但
し、Ｒ1 ；Sit-BuMe2 ，Ｒ2 ；Ｐｈ） （合成例２）で合成したアクリルエステル誘導体(51mg,
0.10mmol)およびフェニルヒトロキシム酸クロリド(78m
g, 0.50mmol)ベンゼン溶液(4ml) に室温でトリエチルア
ミン(70 μl, 0.50mmol)のベンゼン溶液(3ml) を加え、
室温で１．５時間攪拌する。１０％ＫＨＳＯ4 水溶液を
加え、反応を停止した。水層を酢酸エチルで抽出し、有
機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで
乾燥した。乾燥剤を濾別した後、溶媒を留去し、得られ
た油状物をシリカゲル薄層クロマトグラフィー（酢酸エ
チル：ヘキサン＝1:10, ２回展開) により精製し、１ａ
(46mg)および３ａ(9mg) を得た。但し１ａは誘導体
（１）、３ａは誘導体（３）である。Synthesis Example 4 Synthesis of isoxazoline derivatives (1) and (3) (however,
R 1 ; Sit-BuMe 2 , R 2 ; Ph) (Acrylic ester derivative (51 mg,
0.10 mmol) and phenyl human troxime acid chloride (78 m
g, 0.50 mmol) benzene solution (4 ml) at room temperature with triethylamine (70 μl, 0.50 mmol) benzene solution (3 ml),
Stir at room temperature for 1.5 hours. The reaction was stopped by adding 10% KHSO 4 aqueous solution. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off, and the obtained oily substance was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 10, developed twice) to give 1a.
(46 mg) and 3a (9 mg) were obtained. However, 1a is a derivative (1) and 3a is a derivative (3).
【００３８】1a: 1H NMR (CDCl3) δ: 0.10(3H, s, CH
3), 0.18(3H, s, CH3), 0.90(9H, s, (CH3)3), 1.12-1.
73(20H, m, (CH2)10), 3.61(1H, dd, J=11.3 Hz, 16.8
Hz),3.68(1H, dd, J3,4=11.3 Hz, J2,3=6.7 Hz, H-3),
3.72(1H, dd, J=7.3 Hz, 16.8 Hz), 4.16(1H, dd, J5,4
=8.4 Hz, J5,6=6.1 Hz, H-5), 4.20(1H, dd, J2,1=6.4
Hz, J2,3=6.7 Hz, H-2), 4.35(1H, dd, J6,1=3.7 Hz, J
6,5=6.1 Hz, H-6), 4.41(1H, dd, J6,1=3.7 Hz, J2,1=
6.4 Hz, H-1), 5.04(1H, dd, J3,4=11.3 Hz, J 4,5=8.6
Hz, H-4), 5.18(1H, dd, J=7.3 Hz, 11.3 Hz), 7.32-7.
50 (3H, m, aromatic), 7.62-7.70(2H, m, aromatic). IR (neat) 2900, 2850, 1730, 1580, 1430, 1340, 124
0, 1100, 1030, 930, 880, 750, 680, cm -1.[0038]1a:1H NMR (CDCl3) δ: 0.10 (3H, s, CH
3), 0.18 (3H, s, CH3), 0.90 (9H, s, (CH3)3), 1.12-1.
73 (20H, m, (CH2)Ten), 3.61 (1H, dd, J = 11.3 Hz, 16.8
Hz), 3.68 (1H, dd, J3,4= 11.3 Hz, J2,3= 6.7 Hz, H-3),
3.72 (1H, dd, J = 7.3 Hz, 16.8 Hz), 4.16 (1H, dd, J5,4
= 8.4 Hz, J5,6= 6.1 Hz, H-5), 4.20 (1H, dd, J2,1= 6.4
Hz, J2,3= 6.7 Hz, H-2), 4.35 (1H, dd, J6,1= 3.7 Hz, J
6,5= 6.1 Hz, H-6), 4.41 (1H, dd, J6,1= 3.7 Hz, J2,1=
6.4 Hz, H-1), 5.04 (1H, dd, J3,4= 11.3 Hz, J 4,5= 8.6
Hz, H-4), 5.18 (1H, dd, J = 7.3 Hz, 11.3 Hz), 7.32-7.
50 (3H, m, aromatic), 7.62-7.70 (2H, m, aromatic). IR (neat) 2900, 2850, 1730, 1580, 1430, 1340, 124
0, 1100, 1030, 930, 880, 750, 680, cm-1.
【００３９】3a: 1H NMR (CDCl3) δ: 0.07(3H, s, CH
3), 0.12(3H, s, CH3), 0.82(9H, s, (CH3)3), 1.30-1.
72(20H, m, (CH2)10), 3.64(1H, dd, J3,4=11.0 Hz, J
2,3=7.0 Hz, H-3), 3.65(1H, s), 3.69(1H, s), 4.17(1
H, dd, J2,1=6.4 Hz, J2,3=7.0 Hz, H-2), 4.20(1H, d
d, J5,4=8.6 Hz, J5,6=5.8 Hz, H-5), 4.40(1H, dd, J6
,1=3.1 Hz, J6,5=5.8 Hz, H-6), 4.45(1H, dd, J6,1=3.
1 Hz, J2,1=6.4 Hz, H-1), 5.03(1H, dd, J3,4=11.0 H
z, J4,5=8.6 Hz, H-4), 5.21(1H, t, J=9.5 Hz),7.33-
7.45 (3H, m, aromatic), 7.61-7.70(2H, m, aromati
c). IR (neat) 2900, 2850, 1740, 1580, 1430, 1320, 120
0, 1100, 1030, 900, 880, 750, 680, cm-1. 3a : 1 H NMR (CDCl 3 ) δ: 0.07 (3H, s, CH
3 ), 0.12 (3H, s, CH 3 ), 0.82 (9H, s, (CH 3 ) 3 ), 1.30-1.
72 (20H, m, (CH 2 ) 10 ), 3.64 (1H, dd, J 3,4 = 11.0 Hz, J
2,3 = 7.0 Hz, H-3), 3.65 (1H, s), 3.69 (1H, s), 4.17 (1
H, dd, J 2,1 = 6.4 Hz, J 2,3 = 7.0 Hz, H-2), 4.20 (1H, d
d, J 5,4 = 8.6 Hz, J 5,6 = 5.8 Hz, H-5), 4.40 (1H, dd, J 6
, 1 = 3.1 Hz, J 6,5 = 5.8 Hz, H-6), 4.45 (1H, dd, J 6,1 = 3.
1 Hz, J 2,1 = 6.4 Hz, H-1), 5.03 (1H, dd, J 3,4 = 11.0 H
z, J 4,5 = 8.6 Hz, H-4), 5.21 (1H, t, J = 9.5 Hz), 7.33-
7.45 (3H, m, aromatic), 7.61-7.70 (2H, m, aromati
c). IR (neat) 2900, 2850, 1740, 1580, 1430, 1320, 120
0, 1100, 1030, 900, 880, 750, 680, cm -1 .
【００４０】（合成例５）イソオキサゾリン誘導体（１）及び（３）の合成（但
し、Ｒ1 ；Sit-BuPh2 ，Ｒ2 ；Ｐｈ） （合成例４）で合成したアクリルエステル誘導体(54mg,
0.085mmol) およびフェニルヒドロキシム酸クロリド(6
6mg, 0.43mmol)ベンゼン溶液(4ml) に室温でトリエチル
アミン(60 μl, 0.43mmol)のベンゼン溶液(3ml) を加
え、室温で１．５時間攪拌した。１０％ＫＨＳＯ4 水溶
液を加え、反応を停止した。水層を酢酸エチルで抽出
し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリ
ウムで乾燥した。乾燥剤を濾別した後、溶媒を留去し、
得られた油状物をシリカゲル薄層クロマトグラフィー
（酢酸エチル：ヘキサン＝1:10, ２回展開) により精製
し、１ｂ(49mg)および３ｂ(2.8mg) を得た。但し、１ｂ
はイソオキサゾリン誘導体（１）、３ｂはイソオキサゾ
リン誘導体（３）である。Synthesis Example 5 Synthesis of isoxazoline derivatives (1) and (3) (however,
R 1 ; Sit-BuPh 2 , R 2 ; Ph) (Acrylic ester derivative synthesized in Synthesis Example 4) (54 mg,
0.085 mmol) and phenylhydroxymedium chloride (6
6 mg, 0.43 mmol) benzene solution (4 ml) was added with triethylamine (60 μl, 0.43 mmol) benzene solution (3 ml) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The reaction was stopped by adding 10% KHSO 4 aqueous solution. The aqueous layer was extracted with ethyl acetate, the organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the solvent was distilled off,
The obtained oily substance was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 10, developed twice) to obtain 1b (49 mg) and 3b (2.8 mg). However, 1b
Is an isoxazoline derivative (1) and 3b is an isoxazoline derivative (3).
【００４１】1b: 1H NMR (CDCl3) δ: 1.10(9H, s, (C
H3)3), 1.20-1.72(20H, m, (CH2)10), 3.11(1H, dd, J=
11.6 Hz, 16.8 Hz), 3.41(1H, dd, J=6.7 Hz, 16.8 H
z), 3.63(1H, dd, J3,4=11.0 Hz, J2,3=7.3 Hz, H-3),
3.94(1H, dd, J5,4=8.5 Hz, J5 ,6=5.8 Hz, H-5), 4.09
(1H, dd, J=6.7 Hz, 11.6 Hz), 4.26(1H, dd, J6,1=2.4
Hz, J6,5=5.8 Hz, H-6), 4.32(1H, dd, J2,1=6.1 Hz, J
2,3=7.3 Hz, H-2), 4.43(1H, dd, J6,1=2.4 Hz, J2,1=
6.1 Hz, H-1), 5.10(1H, dd, J3,4=11.0 Hz, J4,5=8.5
Hz, H-4), 7.29-7.45 (9H, m, aromatic), 7.50-7.62(4
H, m, aromatic),7.80-7.90(2H, m, aromatic). IR (nujol) 2900, 1850, 1740, 1580, 1440, 1360, 126
0, 1200, 1160, 1100,1040, 930, 750, 730, 690 cm-1. [ α ]D 18 ＋14°（c 1.07, CHCl3)． 1b : 1 H NMR (CDCl 3 ) δ: 1.10 (9H, s, (C
H 3) 3), 1.20-1.72 ( 20H, m, (CH 2) 10), 3.11 (1H, dd, J =
11.6 Hz, 16.8 Hz), 3.41 (1H, dd, J = 6.7 Hz, 16.8 H
z), 3.63 (1H, dd, J 3,4 = 11.0 Hz, J 2,3 = 7.3 Hz, H-3),
3.94 (1H, dd, J 5,4 = 8.5 Hz, J 5 , 6 = 5.8 Hz, H-5), 4.09
(1H, dd, J = 6.7 Hz, 11.6 Hz), 4.26 (1H, dd, J 6,1 = 2.4
Hz, J 6,5 = 5.8 Hz, H-6), 4.32 (1H, dd, J 2,1 = 6.1 Hz, J
2,3 = 7.3 Hz, H-2), 4.43 (1H, dd, J 6,1 = 2.4 Hz, J 2,1 =
6.1 Hz, H-1), 5.10 (1H, dd, J 3,4 = 11.0 Hz, J 4,5 = 8.5
Hz, H-4), 7.29-7.45 (9H, m, aromatic), 7.50-7.62 (4
H, m, aromatic), 7.80-7.90 (2H, m, aromatic). IR (nujol) 2900, 1850, 1740, 1580, 1440, 1360, 126
0, 1200, 1160, 1100, 1040, 930, 750, 730, 690 cm -1 . [Α] D 18 + 14 ° (c 1.07, CHCl 3 ).
【００４２】3b: 1H NMR (CDCl3) δ: 1.10(9H, s, (C
H3)3), 1.12-1.68(20H, m, (CH2)10), 3.25(1H, dd, J=
6.7 Hz, 16.8 Hz), 3.37(1H, dd, J=11.6 Hz, 16.8 H
z), 3.58(1H, dd, J2,3=7.6 Hz, J3,4=11.3 Hz, H-3),
3.89(1H, dd, J4,5=9.0 Hz, J5 ,6=5.8 Hz, H-5), 4.25-
4.38(3H, m, H-2.6, ring), 4.46(1H, dd, J6,1=1.8 H
z, J2,1=6.4 Hz, H-1), 5.11(1H, dd, J3,4=11.3 Hz, J
4,5=9.0 Hz, H-4), 7.26-7.42 (9H, m, aromatic), 7.4
5-7.60(4H, m, aromatic), 7.70-7.75(2H, m, aromati
c). IR (neat) 3000, 2900, 2850, 2255, 1740, 1550, 144
0, 1410, 1360, 1270,1110, 1040, 920, 740, 700 c
m-1. [ α ]D 18 −73°（c 1.04, CHCl3)． 3b : 1 H NMR (CDCl 3 ) δ: 1.10 (9H, s, (C
H 3) 3), 1.12-1.68 ( 20H, m, (CH 2) 10), 3.25 (1H, dd, J =
6.7 Hz, 16.8 Hz), 3.37 (1H, dd, J = 11.6 Hz, 16.8 H
z), 3.58 (1H, dd, J 2,3 = 7.6 Hz, J 3,4 = 11.3 Hz, H-3),
3.89 (1H, dd, J 4,5 = 9.0 Hz, J 5 , 6 = 5.8 Hz, H-5), 4.25-
4.38 (3H, m, H-2.6, ring), 4.46 (1H, dd, J 6,1 = 1.8 H
z, J 2,1 = 6.4 Hz, H-1), 5.11 (1H, dd, J 3,4 = 11.3 Hz, J
4,5 = 9.0 Hz, H-4), 7.26-7.42 (9H, m, aromatic), 7.4
5-7.60 (4H, m, aromatic), 7.70-7.75 (2H, m, aromati
c). IR (neat) 3000, 2900, 2850, 2255, 1740, 1550, 144
0, 1410, 1360, 1270, 1110, 1040, 920, 740, 700 c
m −1 . [α] D 18 −73 ° (c 1.04, CHCl 3 ).
【００４３】（合成例６）イソオキサゾリン誘導体（１）及び（３）の合成（但
し、Ｒ1 ；Sit-BuMe2 ，Ｒ2 ；t-Bu） （合成例４）で合成したアクリルエステル誘導体(48mg,
0.076mmol) およびｔ−ブチルヒドロキシム酸クロリド
(51.4mg, 0.38mmol)ベンゼン溶液(5ml) に室温でトリエ
チルアミン(53 μl, 0.38mmol)のベンゼン溶液(5ml) を
加え、室温で２．０時間攪拌する。１０％ＫＨＳＯ4 水
溶液を加え、反応を停止した。水層を酢酸エチルで抽出
し、有機層を飽和食塩水で洗浄した後、無水硫酸ナトリ
ウムで乾燥する。乾燥剤を炉別した後、溶媒を留去し、
得られた油状物をシリカゲル薄層クロマトグラフィー
（酢酸エチル：ヘキサン＝1:6,２回展開) により精製
し、１ｃ(46.6mg)および３ｃ(4.4mg) を得た。但し、１
ｃはイソオキサゾリン誘導体（１）、３ｃはイソオキサ
ゾリン誘導体（３）である。Synthesis Example 6 Synthesis of isoxazoline derivatives (1) and (3) (however,
R 1 ; Sit-BuMe 2 , R 2 ; t-Bu) (Acrylic ester derivative (48 mg,
0.076 mmol) and t-butylhydroxychromic acid chloride
(51.4 mg, 0.38 mmol) Benzene solution (5 ml) was added with benzene solution (5 ml) of triethylamine (53 μl, 0.38 mmol) at room temperature and stirred at room temperature for 2.0 hours. The reaction was stopped by adding 10% KHSO 4 aqueous solution. The aqueous layer is extracted with ethyl acetate, the organic layer is washed with saturated brine and then dried over anhydrous sodium sulfate. After separating the desiccant from the oven, the solvent is distilled off,
The obtained oil was purified by silica gel thin layer chromatography (ethyl acetate: hexane = 1: 6, developed twice) to give 1c (46.6 mg) and 3c (4.4 mg). However, 1
c is an isoxazoline derivative (1) and 3c is an isoxazoline derivative (3).
【００４４】1c: 1H NMR (CDCl3) δ: 1.09(9H, s, (C
H3)3), 1.20(9H, s, (CH3)3), 1.22-1.80(20H, m, (C
H2)10), 2.86(1H, dd, J=17.1 Hz, 11.3 Hz), 3.12(1H,
dd, J=17.1 Hz, 5.5 Hz), 3.61(1H, dd, J2,3=7.6 Hz,
J3,4=11.3 Hz, H-3), 3.94(1H, dd, J=5.5 Hz, 11.3 H
z), 3.95(1H, dd, J4,5=8.6 Hz, J5,6=5.8 Hz, H-5),
4.30(1H, dd, J6,1=2.4 Hz, J5,6=5.8 Hz, H-6), 4.33
(1H, dd, J2,1=6.1 Hz, J2 ,3=7.6 Hz, H-2), 4.46(1H,
dd, J6,1=2.4 Hz, J2,1=6.1 Hz, H-1), 5.10(1H, dd, J
3,4=11.3 Hz, J4,5=9.0 Hz, H-4), 7.31-7.49 (6H, m,
aromatic), 7.55-7.63(2H, m, aromatic), 7.84-7.93(2
H, m, aromatic). IR (neat) 2970, 2950, 2900, 2260, 1740, 1580, 155
0, 1440, 1420, 1360,1260, 1100, 1040, 930, 700 cm
-1. 1c : 1 H NMR (CDCl 3 ) δ: 1.09 (9H, s, (C
H 3) 3), 1.20 ( 9H, s, (CH 3) 3), 1.22-1.80 (20H, m, (C
H 2 ) 10 ), 2.86 (1H, dd, J = 17.1 Hz, 11.3 Hz), 3.12 (1H,
dd, J = 17.1 Hz, 5.5 Hz), 3.61 (1H, dd, J 2,3 = 7.6 Hz,
J 3,4 = 11.3 Hz, H-3), 3.94 (1H, dd, J = 5.5 Hz, 11.3 H
z), 3.95 (1H, dd, J 4,5 = 8.6 Hz, J 5,6 = 5.8 Hz, H-5),
4.30 (1H, dd, J 6,1 = 2.4 Hz, J 5,6 = 5.8 Hz, H-6), 4.33
(1H, dd, J 2,1 = 6.1 Hz, J 2 , 3 = 7.6 Hz, H-2), 4.46 (1H,
dd, J 6,1 = 2.4 Hz, J 2,1 = 6.1 Hz, H-1), 5.10 (1H, dd, J
3,4 = 11.3 Hz, J 4,5 = 9.0 Hz, H-4), 7.31-7.49 (6H, m,
aromatic), 7.55-7.63 (2H, m, aromatic), 7.84-7.93 (2
H, m, aromatic). IR (neat) 2970, 2950, 2900, 2260, 1740, 1580, 155
0, 1440, 1420, 1360, 1260, 1100, 1040, 930, 700 cm
-1 .
【００４５】3c: 1H NMR (CDCl3) δ: 1.06(9H, s, (C
H3)3), 1.14(9H, s, (CH3)3), 1.20-1.80(20H, m, (C
H2)10), 2.95(1H, dd, J=6.4 Hz, 17.1 Hz), 3.05(1H,
dd, J=11.3 Hz, 17.1 Hz), 3.55(1H, dd, J3,4=11.0 H
z, J2,3=7.6 Hz, H-3), 3.84(1H, dd, J5,4=8.9 Hz, J
5,6=5.8 Hz, H-5), 3.95(1H, dd, J=6.4 Hz, 11.3 Hz),
4.29(1H, dd, J6,1=2.1 Hz, J6,5=5.8 Hz, H-6), 4.32
(1H, dd, J2,1=6.1 Hz, J2 ,3=7.6 Hz, H-2), 4.46(1H,
dd, J6,1=2.1 Hz, J2,1=6.1 Hz, H-1), 5.09(1H, dd, J
3,4=11.0 Hz, J4,5=8.9 Hz, H-4), 7.31-7.45 (6H, m,
aromatic), 7.49-7.56(2H, m, aromatic), 7.69-7.75(2
H, m, aromatic). IR (nujol) 2950, 2900, 1730, 1580, 1440, 1370, 126
0, 1200, 1150, 1090,1040, 900, 760, 720, 690 cm-1. 3c : 1 H NMR (CDCl 3 ) δ: 1.06 (9H, s, (C
H 3) 3), 1.14 ( 9H, s, (CH 3) 3), 1.20-1.80 (20H, m, (C
H 2 ) 10 ), 2.95 (1H, dd, J = 6.4 Hz, 17.1 Hz), 3.05 (1H,
dd, J = 11.3 Hz, 17.1 Hz), 3.55 (1H, dd, J 3,4 = 11.0 H
z, J 2,3 = 7.6 Hz, H-3), 3.84 (1H, dd, J 5,4 = 8.9 Hz, J
5,6 = 5.8 Hz, H-5), 3.95 (1H, dd, J = 6.4 Hz, 11.3 Hz),
4.29 (1H, dd, J 6,1 = 2.1 Hz, J 6,5 = 5.8 Hz, H-6), 4.32
(1H, dd, J 2,1 = 6.1 Hz, J 2 , 3 = 7.6 Hz, H-2), 4.46 (1H,
dd, J 6,1 = 2.1 Hz, J 2,1 = 6.1 Hz, H-1), 5.09 (1H, dd, J
3,4 = 11.0 Hz, J 4,5 = 8.9 Hz, H-4), 7.31-7.45 (6H, m,
aromatic), 7.49-7.56 (2H, m, aromatic), 7.69-7.75 (2
H, m, aromatic). IR (nujol) 2950, 2900, 1730, 1580, 1440, 1370, 126
0, 1200, 1150, 1090, 1040, 900, 760, 720, 690 cm -1 .
【００４６】（合成例７）（Ｓ）−５−ヒドロキシメチル−３−フェニル−２−イ
ソオキサゾリンの合成 （合成例４）で合成したオキサゾリン誘導体１ａ(80mg,
0.127mmol) のＴＨＦ溶液(2.0ml) にL-Selectride(1.0
M THF solution 0.57ml)を加え、室温で終夜攪拌する。
1N-HCl(2.0ml) を加え、反応を停止した。水層をエーテ
ルで抽出し、有機層を飽和ＮａＨＣＯ3 水溶液、飽和食
塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した後、
溶媒を留去しえられた油状物をシリカゲルカラムクロマ
トグラフィー（酢酸エチル：ヘキサン＝1:2)により精
製、標記化合物(20mg, 収率89％)を得た。(Synthesis example 7) (S) -5-hydroxymethyl-3-phenyl-2-i
Oxazoline derivative 1a (80 mg, synthesized in Synthesis of Soxazoline (Synthesis Example 4))
0.127 mmol) in THF (2.0 ml) with L-Selectride (1.0
M THF solution (0.57 ml) is added, and the mixture is stirred at room temperature overnight.
The reaction was stopped by adding 1N-HCl (2.0 ml). The aqueous layer was extracted with ether, the organic layer was washed successively with saturated aqueous NaHCO 3 solution and saturated brine, dried over anhydrous sodium sulfate,
The oily substance obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to obtain the title compound (20 mg, yield 89%).
【００４７】1H NMR (CDCl3) δ: 3.28(1H, dd, J=7.9
Hz, 16.5 Hz, H=4), 3.39(1H, dd,J=10.4 Hz, 16.5 H
z, H-4), 3.68(1H, dd, J=4.6 Hz, J=12.2 Hz, H-6),
3.88(1H, dd, J=3.1 Hz, 12.2 Hz, H-6'), 4.87(1H, dd
dd, J=3.1 Hz, 4.6 Hz, 7.9 Hz, 10.4 Hz, H-5). [ α ]D 20 ＋ 145°（c 2.0, CHCl3) (lit.R-isomer:
[ α ]D 25 − 161°（c 1.0, CHCl3) D.P.Curran Tet
rahedran Lett., 29 No.29 pp 3555〜2558, 1988) 1 H NMR (CDCl 3 ) δ: 3.28 (1H, dd, J = 7.9
Hz, 16.5 Hz, H = 4), 3.39 (1H, dd, J = 10.4 Hz, 16.5 H
z, H-4), 3.68 (1H, dd, J = 4.6 Hz, J = 12.2 Hz, H-6),
3.88 (1H, dd, J = 3.1 Hz, 12.2 Hz, H-6 '), 4.87 (1H, dd
dd, J = 3.1 Hz, 4.6 Hz, 7.9 Hz, 10.4 Hz, H-5). [α] D 20 + 145 ° (c 2.0, CHCl 3 ) (lit.R-isomer:
[α] D 25 − 161 ° (c 1.0, CHCl 3 ) DP Curran Tet
(rahedran Lett., 29 No. 29 pp 3555-2558, 1988)
【００４８】同様な方法で、（合成例４）で合成した３
ａ、（合成例５）で合成した３ｂより（Ｒ）−５−ヒド
ロキシメチル−３−フェニル−２−イソオキサゾリンを
合成した。又（合成例５）で合成した１ｂより標記化合
物を合成した。3 synthesized in (Synthesis example 4) by the same method
(R) -5-hydroxymethyl-3-phenyl-2-isoxazoline was synthesized from a and 3b synthesized in (Synthesis example 5). Also, the title compound was synthesized from 1b synthesized in (Synthesis Example 5).
【００４９】以上の合成例から、光学活性な５−ヒドロ
キシメチル−２−イソオキサゾリン類の製造法、各中間
体の物性等が明確にされたが、更にアクリルエステル誘
導体にニトリルオキシドを付加せしめてイソオキサゾリ
ン誘導体を生成させる際のジアステレオマー選択性を明
確にする目的で、表２に反応条件とジアステレオマー選
択性の関係を示す。From the above synthesis examples, the method for producing optically active 5-hydroxymethyl-2-isoxazolines, the physical properties of each intermediate, and the like were clarified. Further, nitrile oxide was added to the acrylic ester derivative. For the purpose of clarifying the diastereomer selectivity when producing an isoxazoline derivative, Table 2 shows the relationship between the reaction conditions and the diastereomer selectivity.
【００５０】[0050]
【表１】 [Table 1]
【００５１】[0051]
【発明の効果】本発明によれば光学活性の５−ヒドロキ
シメチル−２−オキザリン類、特に（Ｓ）−５−ヒドロ
キシメチル−２−イソオキサゾリン類を効率良く簡便に
製造することができる。INDUSTRIAL APPLICABILITY According to the present invention, optically active 5-hydroxymethyl-2-oxarines, particularly (S) -5-hydroxymethyl-2-isoxazolines, can be efficiently and simply produced.
【手続補正書】[Procedure amendment]
【提出日】平成４年４月６日[Submission date] April 6, 1992
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項１[Name of item to be corrected] Claim 1
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【化１】 （但しここでＲ１は−ＳｉＲ３で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ２はアルキ
ル基又は芳香族基である） 還元することを特徴とする下記構造式（２）で示される
（Ｓ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法。[Chemical 1] (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.) The following structure characterized by reduction: A method for producing (S) -5-hydroxymethyl-2-isoxazolines represented by formula (2).
【化２】 [Chemical 2]
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項２[Name of item to be corrected] Claim 2
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【化３】 （但しここでＲ１は−ＳｉＲ３で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ２はアルキ
ル基又は芳香族基である） 還元することを特徴とする構造式（４）で示される
（Ｒ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法。[Chemical 3] (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.) Structural formula characterized by reduction A method for producing (R) -5-hydroxymethyl-2-isoxazolines represented by (4).
【化４】 [Chemical 4]
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項３[Name of item to be corrected] Claim 3
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【化５】 [Chemical 5]
【化６】 （但しここでＲ１は−ＳｉＲ３で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ２はアルキ
ル基又は芳香族基である）[Chemical 6] (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.)
【手続補正４】[Procedure amendment 4]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００６[Correction target item name] 0006
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００６】[0006]
【発明の構成】本発明によれば、下記構造式（１）で示
されるイソオキサゾリン誘導体をAccording to the present invention, an isoxazoline derivative represented by the following structural formula (1)
【化９】 （但しここでＲ１は−ＳｉＲ３で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ２はアルキ
ル基又は芳香族基である。以下の構造式に於いても同意
である。）。 還元することを特徴とする下記構造式（２）で示される
（Ｓ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法[Chemical 9] (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group. The same applies to the following structural formulas. It is.). A method for producing (S) -5-hydroxymethyl-2-isoxazolines represented by the following structural formula (2), which comprises reducing
【化１０】 及び、下記構造式（３）で示されるイソオキサゾリン誘
導体を[Chemical 10] And an isoxazoline derivative represented by the following structural formula (3)
【化１１】 還元することを特徴とする構造式（４）で示される
（Ｒ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法が提供される。[Chemical 11] There is provided a method for producing (R) -5-hydroxymethyl-2-isoxazolines represented by structural formula (4), which comprises reducing.
【化１２】 [Chemical 12]
Claims (5)
リン誘導体を 【化１】 （但しここでＲ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ2 はアルキ
ル基又は芳香族基である） 還元することを特徴とする下記構造式（２）で示される
（Ｓ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法。 【化２】 1. An isoxazoline derivative represented by the following structural formula (1): (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.) The following structure characterized by reduction: A method for producing (S) -5-hydroxymethyl-2-isoxazolines represented by formula (2). [Chemical 2]
リン誘導体を 【化３】 （但しここでＲ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ2 はアルキ
ル基又は芳香族基である） 還元することを特徴とする構造式（４）で示される
（Ｒ）−５−ヒドロキシメチル−２−イソオキサゾリン
類の製造方法。 【化４】 2. An isoxazoline derivative represented by the following structural formula (3): (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.) Structural formula characterized by reduction A method for producing (R) -5-hydroxymethyl-2-isoxazolines represented by (4). [Chemical 4]
ソオキサゾリン誘導体。 【化５】 【化６】 （但しここでＲ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基であり、Ｒ2 はアルキ
ル基又は芳香族基である）3. An isoxazoline derivative represented by the following structural formula (1) or (3). [Chemical 5] [Chemical 6] (However, R 1 is an organic silyl group represented by —SiR 3 , R is an alkyl group or an aromatic group, and R 2 is an alkyl group or an aromatic group.)
テル誘導体に 【化７】 （ここで、Ｒ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基である） Ｒ2 −Ｃ≡Ｎ+ −Ｏ- で示されるニトリルオキシド（こ
こでＲ2 はアルキル基又は芳香族基である）を反応させ
ることを特徴とする請求項（３）に記載の構造式（１）
又は（３）で示されるイソオキサゾリン誘導体の製造方
法。4. An acrylic ester derivative represented by the following structural formula (5): (Here, R 1 is an organic silyl group represented by —SiR 3 , and R is an alkyl group or an aromatic group.) R 2 —C≡N + —O − A nitrile oxide represented by (where R 2 is The structural formula (1) according to claim (3), wherein an alkyl group or an aromatic group is reacted.
Alternatively, a method for producing the isoxazoline derivative represented by (3).
テル誘導体。 【化８】 （ここで、Ｒ1 は−ＳｉＲ3 で示される有機シリル基
で、Ｒはアルキル基又は芳香族基である）5. An acrylic ester derivative represented by the following structural formula (5). [Chemical 8] (Here, R 1 is an organic silyl group represented by —SiR 3 , and R is an alkyl group or an aromatic group.)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4117692A JPH05239040A (en) | 1992-02-27 | 1992-02-27 | Production of 5-hydroxymethyl-2-isoxyzoline compound and intermediate therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4117692A JPH05239040A (en) | 1992-02-27 | 1992-02-27 | Production of 5-hydroxymethyl-2-isoxyzoline compound and intermediate therefor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05239040A true JPH05239040A (en) | 1993-09-17 |
Family
ID=12601125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4117692A Withdrawn JPH05239040A (en) | 1992-02-27 | 1992-02-27 | Production of 5-hydroxymethyl-2-isoxyzoline compound and intermediate therefor |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05239040A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001131160A (en) * | 1999-10-29 | 2001-05-15 | Tosoh Corp | New oxazolidinone derivative and its use |
-
1992
- 1992-02-27 JP JP4117692A patent/JPH05239040A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001131160A (en) * | 1999-10-29 | 2001-05-15 | Tosoh Corp | New oxazolidinone derivative and its use |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Withdrawal of application because of no request for examination |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 19990518 |