JPS5910647B2 - Asymmetric synthesis method of optically active alcohols - Google Patents
Asymmetric synthesis method of optically active alcoholsInfo
- Publication number
- JPS5910647B2 JPS5910647B2 JP7263077A JP7263077A JPS5910647B2 JP S5910647 B2 JPS5910647 B2 JP S5910647B2 JP 7263077 A JP7263077 A JP 7263077A JP 7263077 A JP7263077 A JP 7263077A JP S5910647 B2 JPS5910647 B2 JP S5910647B2
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- Prior art keywords
- optically active
- group
- reaction
- formulas
- asymmetric synthesis
- Prior art date
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- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、医薬上および化学合成上有用な光学活性アル
コール類の不斉合成法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for asymmetrically synthesizing optically active alcohols useful in pharmaceutical and chemical synthesis.
さらに詳しくは、本発明は一般式 (”■□<:。More specifically, the present invention relates to the general formula (”■□<:.
、、0・・・〔式中、Rはアルキル基、シクロアルキル
基、アラルキル基またはアリール基を示す〕で表わされ
る光学活性環状アミン誘導体とLiAlH4を反応させ
て生成する複合体により、一般式
2>C=0(旧
〔式中、R1およびR2は互に異つて、アルキル基、シ
クロアルキル基、アラルキル基またはアリール基を示す
か、或いは、R”およびR”が結合した非対称的環状構
造を示す。,,0... [wherein R represents an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group] A complex produced by reacting LiAlH4 with an optically active cyclic amine derivative represented by the formula 2 >C=0 (formerly, R1 and R2 are different from each other and represent an alkyl group, a cycloalkyl group, an aralkyl group, or an aryl group, or an asymmetric cyclic structure in which R" and R" are bonded) show.
〕で表わされる化合物を還元することを特徴とする一般
式
2>c<(■)
〔式中、R1およびR2は前記と同意義〕で表わされる
光学活性アルコール類の不斉合成法である。] This is an asymmetric synthesis method for optically active alcohols represented by the general formula 2>c<(■) [wherein R1 and R2 have the same meanings as above].
上記一般式(1)において、Rで示されるアルキル基と
しては、直鎖状または分枝状の炭素数1〜6程度のアル
キル基(例:メチル、エチル、n−プロピル、i−プロ
ピル、n−ブチル、i−ブチル、t−ブチル、n−ペン
チル、n−ヘキシル基など)が好ましく、とりわけ分枝
状のアルキル基が好ましい。シクロアルキル基としては
、炭素数5〜7程度のシクロアルキル基(例:シクロペ
ンチル、シクロヘキシル、シクロヘプチル基)が好まし
い。アラルキル基として&ζたとえば、ベンジル基、フ
エネチル基、α−メチルベンジル基、ジフエニルメチル
基などがあげられる。アリール基としては、たとえばフ
エニル基、ナフチル基、トリール基、キシリル基などが
あげられる。これらのアルキル基、シクロアルキル基、
アラルキル基、アリール基は、反応に支障のない限り適
宜の置換基(例:アルコキシ、アリールオキシ、アルキ
ルチオ、アリールチオ、アミノ、置換アミノ、ハイドロ
キシ、メルカプト基など)を有していてもよい。上記一
般式()および()において、R1またはR2で示され
るアルキル基としては直鎖状または分枝状の炭素数1〜
22程度のアルキル基(例:メチル、エチル、n−プロ
ピル、i−プロピル、n−ブチル、i−ブチル、t−ブ
チル、2一エチルブチル、n−ヘキシル、オクチルドデ
シル、オクタデシル基など)が好ましい。In the above general formula (1), the alkyl group represented by R is a linear or branched alkyl group having about 1 to 6 carbon atoms (e.g. methyl, ethyl, n-propyl, i-propyl, n -butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, etc.) are preferred, and branched alkyl groups are particularly preferred. As the cycloalkyl group, a cycloalkyl group having about 5 to 7 carbon atoms (eg, cyclopentyl, cyclohexyl, cycloheptyl group) is preferable. Examples of the aralkyl group include a benzyl group, a phenethyl group, an α-methylbenzyl group, a diphenylmethyl group, and the like. Examples of the aryl group include phenyl group, naphthyl group, tolyl group, and xylyl group. These alkyl groups, cycloalkyl groups,
The aralkyl group and aryl group may have an appropriate substituent (eg, alkoxy, aryloxy, alkylthio, arylthio, amino, substituted amino, hydroxy, mercapto group, etc.) as long as it does not interfere with the reaction. In the above general formulas () and (), the alkyl group represented by R1 or R2 is linear or branched and has 1 to 1 carbon atoms.
Alkyl groups of about 22 (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2-ethylbutyl, n-hexyl, octyldodecyl, octadecyl groups, etc.) are preferred.
アラルキル基およびアリール基としてはそれぞれ前記R
と同様の基があげられる。またR1およびR2が結合し
た非対称環状構造としては、たとえば2−メチルシクロ
ペンタノン、3−メチルシクロヘキサノン、Trans
−β−デカロン、α−テトラロン、ケトステロイド(例
:プレグナンジオン、プレドニゾロンなど)があげられ
る。これらのアルキル基、アラルキル基、アリール基お
よび非対称環状構造は、前記Rにおける場合と同様の反
応に支障のない置換基を有してもよい。環状アミ7誘導
体(1)とLiAlH4との反応は、適当な溶媒(例:
エーテル、テトラヒドロフラン、ジオキサン、モノグラ
イム、メタノール、エタノールなど)中で氷冷下または
還流下に行なうのが好都合である。As the aralkyl group and the aryl group, each of the above R
A similar group can be mentioned. Examples of the asymmetric cyclic structure in which R1 and R2 are bonded include 2-methylcyclopentanone, 3-methylcyclohexanone, Trans
-β-decalone, α-tetralone, and ketosteroids (eg, pregnanedione, prednisolone, etc.). These alkyl groups, aralkyl groups, aryl groups, and asymmetric cyclic structures may have substituents that do not interfere with the same reaction as in R above. The reaction between the cyclic amide 7 derivative (1) and LiAlH4 is carried out using an appropriate solvent (e.g.
It is convenient to carry out the reaction in ether, tetrahydrofuran, dioxane, monoglyme, methanol, ethanol, etc.) under ice cooling or under reflux.
LiAlH4の使用量は化合物(1)1モル量に対して
約0.5〜2.5モル量程度が好ましい。上記の反応に
より下記一般式()の複合体が形成される。〔式中、R
は前記と同意義。The amount of LiAlH4 used is preferably about 0.5 to 2.5 moles per 1 mole of compound (1). The above reaction forms a complex represented by the following general formula (). [In the formula, R
has the same meaning as above.
Mはリチウム原子を、Aはアルミニウム原子を示す。〕
この様にして生成する複合体()は反応溶媒中から単離
することなく直接に、または単離後適宜の溶媒中で一般
式()の化合物を還元するために使用することが出来る
。M represents a lithium atom, and A represents an aluminum atom. ]
The complex () thus produced can be used directly without isolation from the reaction solvent, or after isolation in an appropriate solvent to reduce the compound of general formula ().
化合物()と複合物()との反応は、通常()1モル量
に対して()約0.5〜1.0モル量程度を反応温度約
−80〜100℃程度で、約10分間〜10時間程度反
応させることによつて行なわれる。本反応に依り化合物
()は不斉合成的に還元され、原料化合物(1)の光学
異性に応じた光学活性アルコール類()を極めて良好な
反応収率並びに光学収率で製造することができる。目的
とする光学活性アルコール類()は通常の分離精製手段
、たとえば再結晶、蒸留、溶媒抽出、カラムクロマトグ
ラフイ一などにより反応混合物から容易に単離精製する
ことができる。The reaction between the compound () and the composite () is usually carried out by adding about 0.5 to 1.0 mol of () to 1 mol of () at a reaction temperature of about -80 to 100°C for about 10 minutes. This is carried out by reacting for about 10 hours. Through this reaction, the compound () is reduced in an asymmetric manner, and an optically active alcohol () corresponding to the optical isomerism of the starting compound (1) can be produced with extremely good reaction yield and optical yield. . The desired optically active alcohol (2) can be easily isolated and purified from the reaction mixture by conventional separation and purification means, such as recrystallization, distillation, solvent extraction, column chromatography, etc.
本発明方法において用いられる環状アミン誘導体(1)
は新規化合物であり、たとえば下記の合成経路またはこ
れに準じた方法によつて製造することができる。〔各式
中、Rは前記と同意義。Cyclic amine derivative (1) used in the method of the present invention
is a new compound and can be produced, for example, by the following synthetic route or a method analogous thereto. [In each formula, R has the same meaning as above.
〕上記反応に用いられる光学活性アミノカルボン酸は合
成品のDL一体を公知の分割方法により分割して用いて
もよく、また容易に入手できる天然の光学活性環状アミ
ノ酸(例:L−プロリンなど)を用いてもよい。] The optically active aminocarboxylic acid used in the above reaction may be used by dividing the synthetic DL unit by a known splitting method, or it may be an easily available natural optically active cyclic amino acid (e.g. L-proline, etc.) may also be used.
以下に実施例により本発明をさらに具体的に説明するが
、これによつて本発明が何ら限定されるものではない。EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.
参考例
L−プロリンアニリド5.71f7を15m1のメチレ
ンクロリドに溶解し、この溶液を、LiAlH42.O
tを60dの乾燥エーテルに溶解した溶液に、攪拌下−
20℃で滴下する。Reference Example L-proline anilide 5.71f7 was dissolved in 15ml of methylene chloride, and this solution was dissolved in LiAlH42. O
t in 60 d of dry ether under stirring.
Add dropwise at 20°C.
全量滴下後、一20℃に30分間攪拌放置し、さらに徐
々に昇温し、室温に戻して一夜放置する。After dropping the entire amount, the mixture was stirred and left at -20°C for 30 minutes, and then the temperature was gradually raised, and the mixture was returned to room temperature and left overnight.
反応混合物を冷却し、飽和食塩水を攪拌下滴下し反応を
停止した後、有機層を分取する。残渣はメチレンクロリ
ドで抽出し、有機層とあわせて、ホウ硝で乾燥、濃縮し
減圧蒸留すると4.88fの目的物2−フエニルアミノ
メチルピロリジンが得られた。沸点(0.5511!H
g)111〜112℃0智+19.71(C−1.00
、EtOH)実施例 1LiA1H4のエーテル溶液(
1.02M/I!)2.26dにアルゴン雰囲気中、2
−フエニルアミノメチルビロリジンのエーテル溶液(4
68η/9mt)を加え、室温攪拌下、10分間放置す
る。The reaction mixture is cooled, saturated brine is added dropwise under stirring to stop the reaction, and the organic layer is separated. The residue was extracted with methylene chloride, combined with the organic layer, dried over boronic acid, concentrated, and distilled under reduced pressure to obtain 4.88f of the target product, 2-phenylaminomethylpyrrolidine. Boiling point (0.5511!H
g) 111-112℃0 +19.71 (C-1.00
, EtOH) Example 1 Ether solution of LiA1H4 (
1.02M/I! ) 2.26d in an argon atmosphere, 2
-Ether solution of phenylaminomethylpyrrolidine (4
68η/9mt) and left for 10 minutes under stirring at room temperature.
この反応混合物を−78℃に冷却し、アセトフエノンの
エーテル溶液(214.87!11!/8mt)を滴下
し、−78℃で2時間撹拌する。飽和硫酸ナトリウム水
を加えて反応を停止し有機層を分取し、残渣はさらに1
0m1のエーテルで抽出する。有機層と抽出液をあわせ
て、0.5Nの塩酸、水、飽和食塩水で洗浄し、ホウ硝
で乾燥する。溶媒を留去し、残渣をシリカゲル薄層クロ
マトグラフイ一(展開溶媒:メチレンクロリド)で分離
精製すると146.6ηの目的物、1−フエニルエタノ
ールが得られた。沸点(311Hg)120℃(0ve
ntemp.)0貨−32.6((Nml)実施例 2
LiA1H,のエーテル溶液(957!9/4.95d
)にアルゴン雰囲気中、2−フエニルアミノメチルピロ
リジンのエーテル溶液(528η/3d)を滴下し、0
℃で1時間攪拌放置する。The reaction mixture is cooled to -78°C, an ethereal solution of acetophenone (214.87!11!/8mt) is added dropwise, and the mixture is stirred at -78°C for 2 hours. The reaction was stopped by adding saturated sodium sulfate water, the organic layer was separated, and the residue was further divided into 1
Extract with 0 ml of ether. The organic layer and extract were combined, washed with 0.5N hydrochloric acid, water, and saturated saline, and dried over boronic acid. The solvent was distilled off, and the residue was separated and purified by silica gel thin layer chromatography (developing solvent: methylene chloride) to obtain the desired product, 1-phenylethanol, with a weight of 146.6η. Boiling point (311Hg) 120℃ (0ve
ntemp. ) 0 coins - 32.6 ((Nml) Example 2 Ether solution of LiA1H (957!9/4.95d
) in an argon atmosphere, an ether solution of 2-phenylaminomethylpyrrolidine (528η/3d) was added dropwise to
Leave stirring at ℃ for 1 hour.
この反応混合物を−100℃に冷却し、1−アセチルシ
クロヘキセンのエーテル溶液(126η/3d)を滴下
し、−100℃で3時間攪拌する。水を加えて反応を停
止し、有機層を分取し、残渣はさらにエーテルで抽出し
、有機層と抽出液を併せて、希塩酸、重曹水、飽和食塩
水で洗浄し、ホウ硝で乾燥体(Phはフエニ′基を、E
tは
※する。The reaction mixture was cooled to -100°C, an ether solution of 1-acetylcyclohexene (126η/3d) was added dropwise, and the mixture was stirred at -100°C for 3 hours. The reaction was stopped by adding water, the organic layer was separated, the residue was further extracted with ether, the organic layer and the extract were combined, washed with dilute hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, and dried with boronic acid. (Ph represents the pheni' group, E
t does *.
溶媒を留去し、残渣をシリカゲルカラムクロ、トグラフ
ィ一でエーテル/n−ヘキサン−1:1を流出溶媒とし
て分離精製すると90〜の目的物、1−(1−シクロヘ
キセニル)エタノールが得られた。02h5−5.5(
C5.86、ClI,Cl,)実施例 3実施例2と同
様にして、2−フエニルアミノメチルピロリジン2mM
,.LiA1H41.75T!LM,lを用いて各種ケ
トン式()1mMを還元し、対応する光学活性アルコー
ル〔式()を下表の通り得た。The solvent was distilled off, and the residue was separated and purified using silica gel column chromatography and chromatography using ether/n-hexane (1:1) as the eluent solvent to obtain the target product 90, 1-(1-cyclohexenyl)ethanol. . 02h5-5.5(
C5.86, ClI, Cl,) Example 3 In the same manner as in Example 2, 2-phenylaminomethylpyrrolidine 2mM
、. LiA1H41.75T! 1 mM of various ketone formulas () was reduced using LM,l to obtain the corresponding optically active alcohols [formula ()] as shown in the table below.
実施例 4
参考例と同様にして製造した光学活性2−モノ置換アミ
ノメチルピロリジン、式(1)を用いて、*(アセトフ
エノンを還元し、光学活性1−フエニルェタノールを下
表の通り得た。Example 4 Using optically active 2-monosubstituted aminomethylpyrrolidine produced in the same manner as in Reference Example, formula (1), *(acetophenone) was reduced to obtain optically active 1-phenylethanol as shown in the table below. Ta.
Claims (1)
ル基またはアリール基を示す〕で表わされる光学活性環
状アミン誘導体とLiAlH_4を反応させて生成する
複合体により、一般式▲数式、化学式、表等があります
▼ 〔式中、R^1およびR^2は互に異つて、アルキル基
、シクロアルキル基、アラルキル基またはアリール基を
示すか、或いは、R^1およびR^2が結合した非対称
的環状構造を示す〕で表わされる化合物を還元すること
を特徴とする一般式▲数式、化学式、表等があります▼ 〔式中、R^1およびR^2は前記と同意義〕で表わさ
れる光学活性アルコール類の不斉合成法。[Claims] 1. An optically active cyclic amine derivative represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. Depending on the complex formed by reacting, there are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula A method for asymmetric synthesis of optically active alcohols, wherein R^1 and R^2 have the same meanings as above.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7263077A JPS5910647B2 (en) | 1977-06-17 | 1977-06-17 | Asymmetric synthesis method of optically active alcohols |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP7263077A JPS5910647B2 (en) | 1977-06-17 | 1977-06-17 | Asymmetric synthesis method of optically active alcohols |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP19932282A Division JPS601304B2 (en) | 1982-11-12 | 1982-11-12 | New optically active amine derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS545963A JPS545963A (en) | 1979-01-17 |
JPS5910647B2 true JPS5910647B2 (en) | 1984-03-10 |
Family
ID=13494887
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP7263077A Expired JPS5910647B2 (en) | 1977-06-17 | 1977-06-17 | Asymmetric synthesis method of optically active alcohols |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5910647B2 (en) |
-
1977
- 1977-06-17 JP JP7263077A patent/JPS5910647B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS545963A (en) | 1979-01-17 |
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