JPH0680617A - Production of optically active dihydrosphingosines - Google Patents
Production of optically active dihydrosphingosinesInfo
- Publication number
- JPH0680617A JPH0680617A JP4255443A JP25544392A JPH0680617A JP H0680617 A JPH0680617 A JP H0680617A JP 4255443 A JP4255443 A JP 4255443A JP 25544392 A JP25544392 A JP 25544392A JP H0680617 A JPH0680617 A JP H0680617A
- Authority
- JP
- Japan
- Prior art keywords
- group
- optically active
- binap
- formula
- alkyl group
- 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.)
- Granted
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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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、次の一般式（３）The present invention relates to the following general formula (3):
【０００２】[0002]
【化５】 [Chemical 5]
【０００３】（式中、Ｒ1 は炭素原子数が１１−２１個
の高級アルキル基を示し、＊印は光学活性であることを
示す）で表わされる光学活性ジヒドロスフィンゴシン類
の製造方法に関する。本発明の光学活性ジヒドロスフィ
ンゴシン類（３）は、セラミド類、セレブロシド及びガ
ングリオシドの重要な構成部分である。(In the formula, R 1 represents a higher alkyl group having 11 to 21 carbon atoms, and * indicates optically active), and relates to a process for producing an optically active dihydrosphingosine. The optically active dihydrosphingosines (3) of the present invention are important components of ceramides, cerebrosides and gangliosides.
【０００４】[0004]
【従来の技術】光学活性ジヒドロスフィンゴシン類は、
角質層保湿作用の鍵分子であるセラミド類の基本骨格で
あり、また、生理活性を示すセレブロシド及びガングリ
オシドの骨格部分でもある。例えば、Ｃａ2+−ＡＴＰア
ーゼ活性及び抗白血病活性を有するシンビオールアミド
（ｓｙｍｂｉｏｒａｍｉｄｅ）（Ｊ．Ｋｏｂａｙａｓｈ
ｉら、Ｅｘｐｅｒｉｅｎｔｉａ １９８８、４４、８０
０頁）、また、マウスの破傷風やうさぎの脳脊髄炎の予
防等に有効である生理活性セレブロシド及びガングリオ
シド（Ｊ．Ｍｅｌｌａｎｂｙら、Ｊ．Ｇｅｎ．Ｍｉｃｒ
ｏｂｉｏｌ．１９６９、５４、１６１頁、Ｂ．Ｎｉｅｄ
ｉｅｃｋら、Ｚ．Ｉｍｍｕｎｉｔａｅｔｓｆｏｒｓｈ．
Ａｌｌｅｒｇ．Ｋｌｉｎ．Ｉｍｍｕｎｏｌ．１９６７、
１３３、４３頁）が挙げられる。BACKGROUND OF THE INVENTION Optically active dihydrosphingosines are
It is the basic skeleton of ceramides, which are the key molecules for the stratum corneum moisturizing action, and is also the skeleton of cerebroside and ganglioside, which exhibit physiological activity. For example, symbiolamide (J. Kobayashi) having Ca 2+ -ATPase activity and anti-leukemic activity.
i et al., Experientia 1988, 44, 80.
0), and physiologically active cerebrosides and gangliosides (J. Mellanby et al., J. Gen. Micr), which are effective in preventing tetanus in mice and encephalomyelitis in rabbits.
obiol. 1969, 54, 161, B.I. Nied
ieck et al., Z. Immunitaetsforsh.
Allerg. Klin. Immunol. 1967,
133, p. 43).
【０００５】ところで、このような活性をもつセラミド
類、セレブロシド及びガングリオシドは、そのスフィン
ゴシン部分に通常２つの不斉炭素原子を有する。前述の
例中、前者のシンビオールアミドおよび後者の生理活性
セレブロシド及びガングリオシドは、いずれも（２Ｓ、
３Ｒ）の活性体である。したがって、かかるジヒドロス
フィンゴシンを製造するにあたっては、２つの不斉部分
が制御された光学活性体を得ることが要求される。By the way, ceramides, cerebrosides and gangliosides having such an activity usually have two asymmetric carbon atoms in their sphingosine moieties. In the above examples, the former symbiol amide and the latter bioactive cerebroside and ganglioside were both (2S,
3R) is the active form. Therefore, in producing such dihydrosphingosine, it is required to obtain an optically active substance in which two asymmetric moieties are controlled.
【０００６】従来の光学活性ジヒドロスフィンゴシン類
の製造方法は、次の（ａ）−（ｃ）に大別できる。 （ａ）ラセミ体のジヒドロスフィンゴシン類を光学分割
する方法。 （ｂ）光学活性天然物を原料として製造する方法。 （ｃ）不斉反応で生じた不斉点を利用して合成する方
法。Conventional methods for producing optically active dihydrosphingosines can be roughly classified into the following (a)-(c). (A) A method of optically resolving racemic dihydrosphingosines. (B) A method for producing an optically active natural product as a raw material. (C) A method of synthesizing by utilizing the asymmetric point generated in the asymmetric reaction.
【０００７】（ａ）の方法としては、例えば、ラセミ体
のジヒドロスフィンゴシンとＬ−グルタミン酸をエタノ
−ル中で攪拌して（＋）−Ｄ−ジヒドロスフィンゴシン
・Ｌ−グルタミン酸塩を析出させ、そしてこれを分離し
た後、塩基性条件下で脱塩することにより光学活性な
（＋）−Ｄ−ジヒドロスフィンゴシンを得ている例[C.
A.Grob ら、Helv. Chim. Acta, 35, 2106 (1952); D.Sh
apiroら、J. Am. Chem. Soc., 75, 5131 (1953)] が挙
げられる。しかし、この方法はラセミ体の製造自体は簡
便な方法であるが、目的物と同量の不要な鏡像体を分割
する操作が必要であるという欠点を持っていた。As the method (a), for example, racemic dihydrosphingosine and L-glutamic acid are stirred in ethanol to precipitate (+)-D-dihydrosphingosine L-glutamate, and Example of obtaining optically active (+)-D-dihydrosphingosine by demineralization under basic conditions after separating [C.
A. Grob et al., Helv. Chim. Acta, 35, 2106 (1952); D.Sh
apiro et al., J. Am. Chem. Soc., 75, 5131 (1953)]. However, although this method is a simple method for producing the racemate itself, it has a drawback in that it requires an operation of dividing an unnecessary enantiomer in the same amount as the target product.
【０００８】（ｂ）の方法としては、例えば、光学活性
な保護アミノ糖（ 3-amino-3-deoxy-1,2:5,6-di-O-isop
ropylidene- α-D-allofuranose ）を原料として、２回
にわたるメタ過ヨウ素酸ナトリウムを用いた開裂反応お
よび臭化テトラデシルトリフェニルホスホニウム塩との
ウィッティヒ反応等を経て、計６工程で光学活性な
（＋）−Ｄ−ジヒドロスフィンゴシンを得る方法[E.J.R
eistら、J. Org. Chem., 35, 3521 (1970)] が報告され
ている。しかし、この方法では多工程を要し、メタ過ヨ
ウ素酸ナトリウムを用いる工程が２回あって安全性上好
ましくなく、またウィッティヒ反応での収率が３０％と
満足できるものではなかった等の欠点を持っている。Examples of the method (b) include, for example, an optically active protected amino sugar (3-amino-3-deoxy-1,2: 5,6-di-O-isop
Ropylidene-α-D-allofuranose) is used as a starting material and undergoes twice the cleavage reaction with sodium metaperiodate and the Wittig reaction with tetradecyltriphenylphosphonium bromide, etc. Method for obtaining +)-D-dihydrosphingosine [EJR
eist et al., J. Org. Chem., 35, 3521 (1970)]. However, this method requires multiple steps, and there are two steps using sodium metaperiodate, which is not preferable in terms of safety, and the yield in the Wittig reaction is 30%, which is not satisfactory. have.
【０００９】また、Ｌ−セリンを原料としてその官能基
を保護し、メチルエステルとした後、カルボン酸エステ
ル部をアルデヒドに変換し、長鎖アルキンの付加、還元
等の工程を経て７工程で光学活性な（＋）−Ｄ−ジヒド
ロスフィンゴシンを得る方法[T.Hino ら、Chem. Lett.,
1407 (1990)] が報告されている。しかし、官能基保護
の際に使用するジ−ｔｅｒｔ−ブチル ジカーボネート
が高価であるうえ、長鎖アルキニル化におけるエリトロ
選択性が９０％であって、満足できるものではなかっ
た。Further, after L-serine is used as a raw material to protect its functional group to form a methyl ester, the carboxylic acid ester portion is converted to an aldehyde, and a long-chain alkyne is added, reduced, and the like to be optically processed in 7 steps. Method for Obtaining Active (+)-D-Dihydrosphingosine [T. Hino et al., Chem. Lett.,
1407 (1990)] has been reported. However, di-tert-butyl dicarbonate used for protecting the functional group is expensive, and the erythroselectivity in long-chain alkynylation is 90%, which is not satisfactory.
【００１０】（ｃ）の方法としては、パルミチルアルデ
ヒドからホーナー−エモンス（Horner-Emmons ）反応に
より（２Ｅ）−オクタデカン−２−エン−１−オ−ルを
合成し、次いでｔｅｒｔ−ブチルヒドロペルオキシドを
用いたシャープレスの不斉エポキシ化反応により、光学
活性エポキシドを得、これと窒素求核種との反応により
エポキシ開環反応を行って光学活性な（＋）−Ｄ−ジヒ
ドロスフィンゴシンを得る方法（K.Moriら、Tetrahedro
n Lett., 22, 4433 (1981), W.R.Roush ら、J.Org. Che
m., 50, 3752 (1985)）が報告されている。しかし、上
述の方法では、光学純度の高いエポキシドを得るために
は高純度のオクタデカン−２−エン−１−オールのトラ
ンス体が必要であるうえ、酸化剤として安全性上好まし
くないｔｅｒｔ−ブチルヒドロペルオキシド等の過酸を
過剰量使用しなければならず、満足できるものではなか
った。以上のようにさまざまな方法で光学活性ジヒドロ
スフィンゴシンの合成が試みられているにもかかわら
ず、光学純度、大量合成に優れた工業的な方法としては
いずれも満足できるものではなかった。As the method (c), (2E) -octadecane-2-en-1-ol is synthesized from palmityl aldehyde by the Horner-Emmons reaction, and then tert-butyl hydroperoxide. A method for obtaining an optically active epoxide by asymmetric epoxidation reaction of Sharpless using, and carrying out an epoxy ring-opening reaction by reacting this with a nitrogen nucleophile to obtain an optically active (+)-D-dihydrosphingosine ( K. Mori et al., Tetrahedro
n Lett., 22, 4433 (1981), WR Roush et al., J. Org. Che
m., 50, 3752 (1985)). However, the above method requires a highly pure trans form of octadecane-2-en-1-ol in order to obtain an epoxide having a high optical purity, and tert-butylhydro, which is unfavorable in safety as an oxidizing agent. An excessive amount of peracid such as peroxide has to be used, which is not satisfactory. Although various attempts have been made to synthesize optically active dihydrosphingosine as described above, none of them was satisfactory as an industrial method excellent in optical purity and large-scale synthesis.
【００１１】一方、特開平１−１６５５６１号公報に
は、ルテニウム−光学活性ホスフィン錯体を触媒として
２−Ｎ−アシルアミノアセト酢酸エステル類に不斉水素
化を行い、光学活性スレオニンを製造する方法が報告さ
れている。On the other hand, Japanese Unexamined Patent Publication (Kokai) No. 1-165561 discloses a method for producing an optically active threonine by asymmetrically hydrogenating 2-N-acylaminoacetoacetic acid esters using a ruthenium-optically active phosphine complex as a catalyst. It has been reported.
【００１２】[0012]
【化６】 [Chemical 6]
【００１３】（式中、Ｒ2 は低級アルキル基、低級アル
キル基もしくは低級アルコキシ基で置換されていてもよ
いフェニル基、または低級アルキル基もしくは低級アル
コキシ基で置換されていてもよいベンジル基を示し、Ｒ
3 は水素原子、低級アルキル基、低級アルコキシ基、低
級アルキル基もしくは低級アルコキシ基で置換されてい
てもよいフェニル基、または低級アルキル基もしくは低
級アルコキシ基で置換されていてもよいベンジルオキシ
基を示す。）(In the formula, R 2 represents a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, or a benzyl group which may be substituted with a lower alkyl group or a lower alkoxy group. , R
3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, or a benzyloxy group which may be substituted with a lower alkyl group or a lower alkoxy group. . )
【００１４】[0014]
【発明が解決しようとする課題】よって、本発明の目的
は、現在及び将来的なスフィンゴシン類の需要に応え、
現実的に大量生産を可能にすべく、安全で簡便に目的の
光学活性ジヒドロスフィンゴシン類を高い光学純度で得
る方法を提供することにある。SUMMARY OF THE INVENTION Accordingly, the object of the present invention is to meet the present and future demand for sphingosines,
It is an object of the present invention to provide a method for safely and simply obtaining the desired optically active dihydrosphingosines with high optical purity so as to enable mass production practically.
【００１５】[0015]
【課題を解決するための手段】このような実情におい
て、本発明者らは鋭意研究を行った結果、次の一般式
（１）Under such circumstances, the inventors of the present invention have conducted diligent research, and as a result, the following general formula (1) is obtained.
【００１６】[0016]
【化７】 [Chemical 7]
【００１７】（式中、Ｒ1 は炭素原子数が１１個から２
１個までの高級アルキル基を示し、Ｒ2 は低級アルキル
基、低級アルキル基もしくは低級アルコキシ基で置換さ
れていてもよいフェニル基、または低級アルキル基もし
くは低級アルコキシ基で置換されていてもよいベンジル
基を示し、Ｒ3 は水素原子、低級アルキル基、低級アル
コキシ基、低級アルキル基もしくは低級アルコキシ基で
置換されていてもよいフェニル基、または低級アルキル
基もしくは低級アルコキシ基で置換されていてもよいベ
ンジルオキシ基を示す）で表わされる２−Ｎ−アシルア
ミノ−高級アシル酢酸エステル化合物を、ルテニウム−
光学活性ホスフィン錯体を触媒として不斉水素化を行
い、次の一般式（２）(In the formula, R 1 has 11 to 2 carbon atoms.
Up to one higher alkyl group is shown, and R 2 is a lower alkyl group, a phenyl group optionally substituted with a lower alkyl group or a lower alkoxy group, or benzyl optionally substituted with a lower alkyl group or a lower alkoxy group. represents a group, R 3 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, may be substituted with a lower alkyl group or a lower alkoxy phenyl group which may be substituted with a group or a lower alkyl group or lower alkoxy group, A 2-N-acylamino-higher acylacetic acid ester compound represented by
Asymmetric hydrogenation is carried out using an optically active phosphine complex as a catalyst, and the following general formula (2)
【００１８】[0018]
【化８】 [Chemical 8]
【００１９】（式中、Ｒ1 、Ｒ2 及びＲ3 は上記と同じ
意義を有し、＊印は光学活性であることを示す）で表わ
される光学活性２−Ｎ−アシルアミノ−３−ヒドロキシ
高級カルボン酸誘導体を得、ついでこれを必要に応じて
３位水酸基の立体配置を反転した後、加水分解及び還元
することにより、次の一般式（３）(Wherein R 1 , R 2 and R 3 have the same meanings as described above, and * indicates that they are optically active), and the optically active 2-N-acylamino-3-hydroxy higher-order compound A carboxylic acid derivative is obtained, which is then optionally reversed in the configuration of the 3-position hydroxyl group, followed by hydrolysis and reduction to give the following general formula (3):
【００２０】[0020]
【化９】 [Chemical 9]
【００２１】（式中、Ｒ1 及び＊印は上記と同じ意義を
有する）で表わされる光学活性ジヒドロスフィンゴシン
類を簡便に、高収率、高光学収率で得られることを見出
し、本発明を完成した。The present invention was found to find that optically active dihydrosphingosines represented by the formula (wherein R 1 and * have the same meaning as described above) can be easily obtained in high yield and high optical yield. completed.
【００２２】（原料）本発明方法の原料となる２−Ｎ−
アシルアミノ−高級アシル酢酸エステル化合物は、［Sh
apiro ら、J. Am. Chem. Soc., 75, 4705 (1953); J. A
m. Chem. Soc., 80, 2170 (1957)］に従って、例えば以
下のようにして得ることができる。(Raw material) 2-N- which is a raw material for the method of the present invention
Acylamino-higher acyl acetate compounds are
apiro et al., J. Am. Chem. Soc., 75, 4705 (1953); J. A.
m. Chem. Soc., 80, 2170 (1957)], for example, it can be obtained as follows.
【００２３】[0023]
【化１０】 [Chemical 10]
【００２４】（式中、Ｒ1 及びＲ2 は上記と同じ意義を
有し、Ｐｈはフェニル基を示す。）２−Ｎ−アシルアミ
ノ高級アシル酢酸エステル化合物（１）のＲ1 は炭素原
子数が１１−２１個の高級アルキル基を示すが、具体的
にはｎ−ウンデカニル基、ｎ−ドデカニル基、ｎ−トリ
デカニル基、ｎ−テトラデカニル基、ｎ−ペンタデカニ
ル基、ｎ−ヘキサデカニル基、ｎ−ヘプタデカニル基、
ｎ−オクタデカニル基、ｎ−ノナデカニル基、ｎ−イコ
サニル基、ｎ−ヘンイコサニル基等が挙げられ、特にｎ
−トリデカニル基、ｎ−ペンタデカニル基、ｎ−ヘプタ
デカニル基が好ましい。また、Ｒ2 の低級アルキル基と
してはメチル基、エチル基、ｎ−プロピル基、ｎ−ブチ
ル基等が挙げられ、低級アルキル基もしくは低級アルコ
キシ基で置換されたフェニル基としては、ｏ−トリル
基、ｍ−トリル基、ｐ−トリル基、ｏ−エチルフェニル
基、ｍ−エチルフェニル基、ｐ−エチルフェニル基、ｏ
−メトキシフェニル基、ｍ−メトキシフェニル基、ｐ−
メトキシフェニル基、ｍ−エトキシフェニル基、ｐ−エ
トキシフェニル基等が挙げられ、さらに低級アルキル基
もしくは低級アルコキシ基で置換されたベンジル基とし
ては、ｏ−メチルベンジル基、ｍ−メチルベンジル基、
ｐ−メチルベンジル基、ｏ−メトキシベンジル基、ｐ−
メトキシベンジル基等が挙げられるが、Ｒ2 としては特
に低級アルキル基が好ましい。Ｒ3 の低級アルコキシ基
としては、メトキシ基、エトキシ基、ｎ−プロピル基、
ｎ−ブトキシ基等が挙げられ、Ｒ3 の低級アルキル基及
び低級アルキル基もしくは低級アルコキシ基で置換され
たフェニル基としては、Ｒ2 として例示したものが挙げ
られる。また、低級アルキル基もしくは低級アルコキシ
基で置換されたベンジルオキシ基としては、そのフェニ
ル基の部分が前述したような置換フェニル基にあたるも
のが挙げられる。かかる２−Ｎ−アシルアミノ−高級ア
シル酢酸エステル化合物としては、例えば、２−Ｎ−ア
セトアミド−ヘキサデカノイル酢酸メチルエステル、２
−Ｎ−アセトアミド−ヘキサデカノイル酢酸エチルエス
テル、２−Ｎ−アセトアミド−ヘキサデカノイル酢酸ブ
チルエステル、２−Ｎ−アセトアミド−ヘキサデカノイ
ル酢酸フェニルエステル、２−Ｎ−アセトアミド−ヘキ
サデカノイル酢酸ｐ−メチルフェニルエステル、２−Ｎ
−アセトアミド−ヘキサデカノイル酢酸ｐ−メトキシフ
ェニルエステル、２−Ｎ−アセトアミド−ヘキサデカノ
イル酢酸ベンジルエステル、２−Ｎ−アセトアミド−ヘ
キサデカノイル酢酸ｐ−メチルベンジルエステル、２−
Ｎ−アセトアミド−ヘキサデカノイル酢酸ｐ−メトキシ
ベンジルエステル、２−Ｎ−ホルムアミド−ヘキサデカ
ノイル酢酸メチルエステル、２−Ｎ−ホルムアミド−ヘ
キサデカノイル酢酸エチルエステル、２−Ｎ−ホルムア
ミド−ヘキサデカノイル酢酸フェニルエステル、２−Ｎ
−ホルムアミド−ヘキサデカノイル酢酸ｏ−メチルフェ
ニルエステル、２−Ｎ−ホルムアミド−ヘキサデカノイ
ル酢酸ベンジルエステル、２−Ｎ−ホルムアミド−ヘキ
サデカノイル酢酸ｐ−メトキシベンジルエステル、２−
Ｎ−ベンズアミド−ヘキサデカノイル酢酸メチルエステ
ル、２−Ｎ−ベンズアミド−ヘキサデカノイル酢酸フェ
ニルエステル、２−Ｎ−ベンズアミド−ヘキサデカノイ
ル酢酸ｍ−メトキシフェニルエステル、２−Ｎ−ベンズ
アミド−ヘキサデカノイル酢酸ベンジルエステル、２−
Ｎ−ベンズアミド−ヘキサデカノイル酢酸ｐ−メチルベ
ンジルエステル、２−Ｎ−アセトアミド−テトラデカノ
イル酢酸メチルエステル、２−Ｎ−アセトアミド−テト
ラデカノイル酢酸ｎ−ブチルエステル、２−Ｎ−アセト
アミド−テトラデカノイル酢酸ｐ−メトキシフェニルエ
ステル、２−Ｎ−アセトアミド−テトラデカノイル酢酸
ベンジルエステル、２−Ｎ−アセトアミド−テトラデカ
ノイル酢酸ｐ−メトキシベンジルエステル、２−Ｎ−ア
セトアミド−オクタデカノイル酢酸エチルエステル、２
−Ｎ−アセトアミド−オクタデカノイル酢酸フェニルエ
ステル、２−Ｎ−アセトアミド−オクタデカノイル酢酸
ｐ−メトキシフェニルエステル、２−Ｎ−アセトアミド
−オクタデカノイル酢酸ｐ−メチルベンジルエステル、
２−Ｎ−ホルムアミド−ドデカノイル酢酸メチルエステ
ル、２−Ｎ−ホルムアミド−トリデカノイル酢酸エチル
エステル、２−Ｎ−ホルムアミド−ペンタデカノイル酢
酸フェニルエステル、２−Ｎ−ホルムアミド−ヘプタデ
カノイル酢酸ｏ−メチルフェニルエステル、２−Ｎ−ホ
ルムアミド−ノナデカノイル酢酸ｐ−メトキシフェニル
エステル、２−Ｎ−ホルムアミド−イコサノイル酢酸ベ
ンジルエステル、２−Ｎ−ホルムアミド−ヘンイコサノ
イル酢酸ｐ−メトキシベンジルエステル、２−Ｎ−ベン
ジルオキシカルボニルアミノ−ヘキサデカノイル酢酸エ
チルエステル、２−Ｎ−ベンジルオキシカルボニルアミ
ノ−ヘキサデカノイル酢酸フェニルエステル、２−Ｎ−
ベンジルオキシカルボニルアミノ−ヘキサデカノイル酢
酸ベンジルエステル、２−Ｎ−エトキシカルボニルアミ
ノ−ヘキサデカノイル酢酸メチルエステル、２−Ｎ−エ
トキシカルボニルアミノ−ヘキサデカノイル酢酸フェニ
ルエステル、２−Ｎ−エトキシカルボニルアミノ−ヘキ
サデカノイル酢酸ベンジルエステル、２−Ｎ−ｔｅｒｔ
−ブトキシカルボニルアミノ−ヘキサデカノイル酢酸メ
チルエステル、２−Ｎ−ｔｅｒｔ−ブトキシカルボニル
アミノ−ヘキサデカノイル酢酸ｐ−メチルフェニルエス
テル、２−Ｎ−ｔｅｒｔ−ブトキシカルボニルアミノ−
ヘキサデカノイル酢酸ベンジルエステル等が挙げられる
が、これらに限られるものではない。(In the formula, R 1 and R 2 have the same meanings as described above, and Ph represents a phenyl group.) In the 2-N-acylamino higher acyl acetic acid ester compound (1), R 1 has a carbon atom number. 11 to 21 higher alkyl groups, specifically, n-undecanyl group, n-dodecanyl group, n-tridecanyl group, n-tetradecanyl group, n-pentadecanyl group, n-hexadecanyl group, n-heptadecanyl group ,
Examples thereof include an n-octadecanyl group, an n-nonadecanyl group, an n-icosanyl group, and an n-henicosanyl group, and particularly n.
A -tridecanyl group, an n-pentadecanyl group and an n-heptadecanyl group are preferred. Examples of the lower alkyl group for R 2 include a methyl group, an ethyl group, an n-propyl group, and an n-butyl group, and a phenyl group substituted with a lower alkyl group or a lower alkoxy group includes an o-tolyl group. , M-tolyl group, p-tolyl group, o-ethylphenyl group, m-ethylphenyl group, p-ethylphenyl group, o
-Methoxyphenyl group, m-methoxyphenyl group, p-
A methoxyphenyl group, an m-ethoxyphenyl group, a p-ethoxyphenyl group and the like can be mentioned. Examples of the benzyl group further substituted with a lower alkyl group or a lower alkoxy group include an o-methylbenzyl group, an m-methylbenzyl group,
p-methylbenzyl group, o-methoxybenzyl group, p-
A methoxybenzyl group and the like can be mentioned, and a lower alkyl group is particularly preferable as R 2 . Examples of the lower alkoxy group for R 3 include methoxy group, ethoxy group, n-propyl group,
n- butoxy group, a phenyl group substituted with a lower alkyl group and a lower alkyl group or lower alkoxy group R 3, those exemplified as R 2. As the benzyloxy group substituted with a lower alkyl group or a lower alkoxy group, those in which the phenyl group portion corresponds to the above-mentioned substituted phenyl group can be mentioned. Examples of the 2-N-acylamino-higher acyl acetic acid ester compound include 2-N-acetamide-hexadecanoyl acetic acid methyl ester, 2
-N-acetamide-hexadecanoyl acetic acid ethyl ester, 2-N-acetamide-hexadecanoyl acetic acid butyl ester, 2-N-acetamide-hexadecanoyl acetic acid phenyl ester, 2-N-acetamide-hexadecanoyl acetic acid p- Methyl phenyl ester, 2-N
-Acetamide-hexadecanoyl acetic acid p-methoxyphenyl ester, 2-N-acetamide-hexadecanoyl acetic acid benzyl ester, 2-N-acetamide-hexadecanoyl acetic acid p-methylbenzyl ester, 2-
N-acetamide-hexadecanoyl acetic acid p-methoxybenzyl ester, 2-N-formamide-hexadecanoyl acetic acid methyl ester, 2-N-formamide-hexadecanoyl acetic acid ethyl ester, 2-N-formamide-hexadecanoyl acetic acid Phenyl ester, 2-N
-Formamide-hexadecanoyl acetic acid o-methylphenyl ester, 2-N-formamide-hexadecanoyl acetic acid benzyl ester, 2-N-formamide-hexadecanoyl acetic acid p-methoxybenzyl ester, 2-
N-benzamide-hexadecanoyl acetic acid methyl ester, 2-N-benzamide-hexadecanoyl acetic acid phenyl ester, 2-N-benzamide-hexadecanoyl acetic acid m-methoxyphenyl ester, 2-N-benzamide-hexadecanoyl acetic acid Benzyl ester, 2-
N-benzamide-hexadecanoyl acetic acid p-methylbenzyl ester, 2-N-acetamide-tetradecanoyl acetic acid methyl ester, 2-N-acetamide-tetradecanoyl acetic acid n-butyl ester, 2-N-acetamide-tetradeca Noyl acetic acid p-methoxyphenyl ester, 2-N-acetamide-tetradecanoyl acetic acid benzyl ester, 2-N-acetamide-tetradecanoyl acetic acid p-methoxybenzyl ester, 2-N-acetamide-octadecanoyl acetic acid ethyl ester, Two
-N-acetamide-octadecanoyl acetic acid phenyl ester, 2-N-acetamide-octadecanoyl acetic acid p-methoxyphenyl ester, 2-N-acetamide-octadecanoyl acetic acid p-methylbenzyl ester,
2-N-formamide-dodecanoyl acetic acid methyl ester, 2-N-formamide-tridecanoyl acetic acid ethyl ester, 2-N-formamide-pentadecanoyl acetic acid phenyl ester, 2-N-formamide-heptadecanoyl acetic acid o-methylphenyl ester, 2 -N-formamide-nonadecanoyl acetic acid p-methoxyphenyl ester, 2-N-formamide-icosanoyl acetic acid benzyl ester, 2-N-formamide-henicosanoyl acetic acid p-methoxybenzyl ester, 2-N-benzyloxycarbonylamino-hexadecanoyl Acetic acid ethyl ester, 2-N-benzyloxycarbonylamino-hexadecanoyl acetic acid phenyl ester, 2-N-
Benzyloxycarbonylamino-hexadecanoyl acetic acid benzyl ester, 2-N-ethoxycarbonylamino-hexadecanoyl acetic acid methyl ester, 2-N-ethoxycarbonylamino-hexadecanoyl acetic acid phenyl ester, 2-N-ethoxycarbonylamino- Hexadecanoyl acetic acid benzyl ester, 2-N-tert
-Butoxycarbonylamino-hexadecanoyl acetic acid methyl ester, 2-N-tert-butoxycarbonylamino-hexadecanoyl acetic acid p-methylphenyl ester, 2-N-tert-butoxycarbonylamino-
Hexadecanoyl acetic acid benzyl ester and the like can be mentioned, but not limited thereto.
【００２５】（触媒）本発明で使用するルテニウム−光
学活性ホスフィン錯体としては、例えば特開昭６１−６
３６９０号公報に記載の次の一般式（４） Ｒｕx Ｈy Ｃｌz （Ｒ4 −ＢＩＮＡＰ）2 （Ｓ）p （４） （式中、Ｒ4 −ＢＩＮＡＰは次の一般式（５）(Catalyst) The ruthenium-optically active phosphine complex used in the present invention is, for example, JP-A-61-6.
Following general formula described in 3690 JP (4) Ru x H y Cl z (R 4 -BINAP) 2 (S) p (4) ( wherein, R 4 -BINAP the following general formula (5)
【００２６】[0026]
【化１１】 [Chemical 11]
【００２７】で表わされる光学活性三級ホスフィンを示
し、Ｒ4 は水素原子、メチル基又はｔｅｒｔ−ブチル基
を示し、Ｓは三級アミンを示し、ｙが０のときｘは２、
ｚは４、ｐは１を示し、ｙが１のときｘは１、ｚは１、
ｐは０を示す）で表わされるものが挙げられる。その
他、特開昭６３−４１４８７号公報、特開平１−６８３
８７号公報、特開平１−１６５５６１号公報等に報告さ
れている類似のルテニウム−光学活性ホスフィン錯体が
挙げられるが、これらに限定されるものではない。次に
その具体例を示す。 Ｒｕ2 Ｃｌ4 （ＢＩＮＡＰ）2 （ＮＥｔ3 ） ［ＢＩＮＡＰは、２、２’−ビス（ジフェニルホスフィ
ノ）−１、１’−ビナフチルを意味し、Ｅｔはエチル基
を意味する。］ Ｒｕ2 Ｃｌ4 （Ｔ−ＢＩＮＡＰ）2 （ＮＥｔ3 ） ［Ｔ−ＢＩＮＡＰは、２、２’−ビス（ジ−ｐ−トリル
ホスフィノ）−１、１’−ビナフチルを意味する。］ Ｒｕ2 Ｃｌ4 （ｔ−Ｂｕ−ＢＩＮＡＰ）2 （ＮＥｔ3 ） ［ｔ−Ｂｕ−ＢＩＮＡＰは、２、２’−ビス（ジ−ｐ−
ｔｅｒｔ−ブチルフェニルホスフィノ）−１、１’−ビ
ナフチルを意味する。］ ＲｕＨＣｌ（ＢＩＮＡＰ）2 ＲｕＨＣｌ（Ｔ−ＢＩＮＡＰ）2 ＲｕＨＣｌ（ｔ−Ｂｕ−ＢＩＮＡＰ）2 ［Ｒｕ（ＢＩＮＡＰ）］（ＣｌＯ4 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）］（ＣｌＯ4 ）2 ［Ｒｕ（ｔ−Ｂｕ−ＢＩＮＡＰ）］（ＣｌＯ4 ）2 ［Ｒｕ（ＢＩＮＡＰ）］（ＢＦ4 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）］（ＢＦ4 ）2 ［Ｒｕ（ｔ−Ｂｕ−ＢＩＮＡＰ）］（ＢＦ4 ）2 ［Ｒｕ（ＢＩＮＡＰ）］（ＰＦ6 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）］（ＰＦ6 ）2 ［ＲｕＨ（ＢＩＮＡＰ）2 ］ＣｌＯ4 ［ＲｕＨ（Ｔ−ＢＩＮＡＰ）2 ］ＣｌＯ4 ［ＲｕＨ（ＢＩＮＡＰ）2 ］ＢＦ4 ［ＲｕＨ（Ｔ−ＢＩＮＡＰ）2 ］ＢＦ4 ［ＲｕＨ（ＢＩＮＡＰ）2 ］ＰＦ6 ［ＲｕＨ（Ｔ−ＢＩＮＡＰ）2 ］ＰＦ6 Ｒｕ（ＢＩＮＡＰ）（ＯＣＯＣＨ3 ）2 Ｒｕ（ＢＩＮＡＰ）（ＯＣＯＣＦ3 ）2 Ｒｕ（Ｔ−ＢＩＮＡＰ）（ＯＣＯＣＨ3 ）2 Ｒｕ（ＢＩＮＡＰ）（ＯＣＯ−ｔ−Ｂｕ）2 （ｔ−Ｂｕはｔｅｒｔ−ブチル基を意味する。） Ｒｕ（Ｔ−ＢＩＮＡＰ）（ＯＣＯＣＦ3 ）2 Ｒｕ（ｔ−Ｂｕ−ＢＩＮＡＰ）（ＯＣＯＣＨ3 ）2 ［Ｒｕ（ＢＩＮＡＰ）ＺｎＣｌ4 ］2 （ＮＥｔ3 ） ［Ｒｕ（ＢＩＮＡＰ）ＡｌＣｌ5 ］2 （ＮＥｔ3 ） ［Ｒｕ（ＢＩＮＡＰ）ＳｎＣｌ6 ］2 （ＮＥｔ3 ） ［Ｒｕ（ＢＩＮＡＰ）ＴｉＣｌ6 ］2 （ＮＥｔ3 ） ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＺｎＣｌ4 ］2 （ＮＥｔ3 ） ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＡｌＣｌ5 ］2 （ＮＥｔ3 ） ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＳｎＣｌ6 ］2 （ＮＥｔ3 ） ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＴｉＣｌ6 ］2 （ＮＥｔ3 ） ［Ｒｕ（ＢＩＮＡＰ）ＺｎＣｌ2 ］（ＯＣＯＣＨ3 ）2 ［Ｒｕ（ＢＩＮＡＰ）ＡｌＣｌ3 ］（ＯＣＯＣＨ3 ）2 ［Ｒｕ（ＢＩＮＡＰ）ＳｎＣｌ4 ］（ＯＣＯＣＨ3 ）2 ［Ｒｕ（ＢＩＮＡＰ）ＴｉＣｌ4 ］（ＯＣＯＣＨ3 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＺｎＣｌ2 ］（ＯＣＯＣＨ
3 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＡｌＣｌ3 ］（ＯＣＯＣＨ
3 ）2 ［Ｒｕ（Ｔ−ＢＩＮＡＰ）ＳｎＣｌ4 ］（ＯＣＯＣＨ
3 ）2 ［Ｒｕ（ＢＩＮＡＰ）ＴｉＣｌ4 ］（ＯＣＯＣＨ3 ）2 Represents an optically active tertiary phosphine, R 4 represents a hydrogen atom, a methyl group or a tert-butyl group, S represents a tertiary amine, and when y is 0, x is 2,
z is 4, p is 1, and when y is 1, x is 1, z is 1,
p represents 0). In addition, JP-A-63-41487 and JP-A-1-683.
The similar ruthenium-optically active phosphine complex reported in Japanese Patent Application Laid-Open No. 87, Japanese Patent Application Laid-Open No. 1-165561 and the like can be mentioned, but the invention is not limited thereto. Next, a specific example is shown. Ru 2 Cl 4 (BINAP) 2 (NEt 3) [BINAP means 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, Et means ethyl group. ] Ru 2 Cl 4 (T- BINAP) 2 (NEt 3) [T-BINAP means 2,2'-bis (di -p- tolylphosphino) -1,1'-binaphthyl. ] Ru 2 Cl 4 (t- Bu-BINAP) 2 (NEt 3) [t-Bu-BINAP is 2,2'-bis (di -p-
tert-butylphenylphosphino) -1,1′-binaphthyl. ] RuHCl (BINAP) 2 RuHCl (T-BINAP) 2 RuHCl (t-Bu-BINAP) 2 [Ru (BINAP)] (ClO 4 ) 2 [Ru (T-BINAP)] (ClO 4 ) 2 [Ru (t -Bu-BINAP)] (ClO 4 ) 2 [Ru (BINAP)] (BF 4) 2 [Ru (T-BINAP)] (BF 4) 2 [Ru (t-Bu-BINAP)] (BF 4) 2 [Ru (BINAP)] (PF 6 ) 2 [Ru (T-BINAP)] (PF 6 ) 2 [RuH (BINAP) 2 ] ClO 4 [RuH (T-BINAP) 2 ] ClO 4 [RuH (BINAP) 2 ] BF 4 [RuH (T-BINAP) 2 ] BF 4 [RuH (BINAP) 2 ] PF 6 [RuH (T-BINAP) 2 ] PF 6 Ru (BINAP) (OCOCH 3 ) 2 Ru (BINAP) (OCOCF 3 ) 2 Ru (T-BINAP) (OCOCH 3 ) 2 Ru (BINAP) (OCO-t-Bu) 2 (t-Bu means a tert-butyl group) Ru (T-BINAP) (OCOCF) 3) 2 Ru (t-Bu -BINAP) (OCOCH 3) 2 [Ru (BINAP) ZnCl 4] 2 (NEt 3) [Ru (BINAP) AlCl 5] 2 (NEt 3) [Ru (BINAP) SnCl 6] 2 (NEt 3) [Ru ( BINAP) TiCl 6] 2 (NEt 3) [Ru (T-BINAP) ZnCl 4] 2 (NEt 3) [Ru (T-BINAP) AlCl 5] 2 (NEt 3) [Ru (T-BINAP) SnCl 6] 2 (NEt 3) [Ru (T-BINAP) TiCl 6] 2 (NEt 3) [Ru (BINAP) ZnCl 2] (OCOCH 3) 2 [Ru (BINAP) AlCl 3 ] (OCOCH 3) 2 [Ru (BINAP) SnCl 4] (OCOCH 3) 2 [Ru (BINAP) TiCl 4] (OCOCH 3) 2 [Ru (T-BINAP) ZnCl 2] (OCOCH
3 ) 2 [Ru (T-BINAP) AlCl 3 ] (OCOCH
3 ) 2 [Ru (T-BINAP) SnCl 4 ] (OCOCH
3 ) 2 [Ru (BINAP) TiCl 4 ] (OCOCH 3 ) 2
【００２８】（操作手順）本発明を実施するには、まず
窒素気流下にあるオートクレーブに、２−Ｎ−アシルア
ミノ−高級アシル酢酸エステル化合物（１）をこれと等
量〜１００倍量の塩化メチレン、メタノール、エタノー
ル、イソプロパノール等の溶媒に溶解したものを入れ、
続いて基質（１）に対して５０分の１〜１０００分の１
モルのルテニウム−光学活性ホスフィン錯体を加える。
これを水素圧１０〜１００ａｔｍ、温度２５〜５０℃で
１２〜４８時間反応させることにより、光学活性２−Ｎ
−アシルアミノ−３−ヒドロキシ−高級カルボン酸誘導
体（２）を得ることができる。このものを必要に応じて
常法により塩化チオニルを用いて３位水酸基を分子内反
転させる。次いで、塩酸等でアミド基を加水分解した
後、水素化ホウ素リチウムや水素化リチウムアルミニウ
ム等の還元剤によりエステルを還元して、目的とする光
学活性ジヒドロスフィンゴシン類（３）を得ることがで
きる。(Operating Procedure) To carry out the present invention, first, the 2-N-acylamino-higher acylacetic acid ester compound (1) is placed in an autoclave under a nitrogen stream in an amount equivalent to 100 times that of methylene chloride. , Dissolved in a solvent such as methanol, ethanol or isopropanol,
Subsequent to the substrate (1) 1/50 to 1/1000
Molar ruthenium-optically active phosphine complex is added.
By reacting this at a hydrogen pressure of 10 to 100 atm and a temperature of 25 to 50 ° C. for 12 to 48 hours, optically active 2-N
-Acylamino-3-hydroxy-higher carboxylic acid derivative (2) can be obtained. If necessary, the 3-position hydroxyl group is inverted in the molecule using thionyl chloride by a conventional method. Then, after hydrolyzing the amide group with hydrochloric acid or the like, the ester is reduced with a reducing agent such as lithium borohydride or lithium aluminum hydride to obtain the desired optically active dihydrosphingosines (3).
【００２９】ここで、使用するルテニウム−光学活性ホ
スフィン錯体の配位子の絶対配置を選択し、及び必要に
応じて３位水酸基を反転させることで、所望の絶対配置
の天然型又は非天然型ジヒドロスフィンゴシン類を作り
分けることができる。すなわち、例えば、使用するルテ
ニウム−光学活性ホスフィン錯体（４）の光学活性三級
ホスフィンとして（−）−体を用いて水素化した場合、
（２Ｒ，３Ｓ）のシン体（６）が得られ、最終的に、反
転操作をすれば（２Ｓ，３Ｒ）のアンチ体（７）、反転
操作をしなければ（２Ｓ，３Ｓ）のシン体（８）が得ら
れる。一方、（＋）−体を用いて水素化した場合には、
（２Ｓ，３Ｒ）のシン体（９）が得られる。Here, by selecting the absolute configuration of the ligand of the ruthenium-optically active phosphine complex to be used and, if necessary, inverting the hydroxyl group at the 3-position, a natural type or non-natural type having a desired absolute configuration is selected. Different types of dihydrosphingosine can be produced. That is, for example, when the ruthenium-optically active phosphine complex (4) used is hydrogenated using the (-)-form as the optically active tertiary phosphine,
A (2R, 3S) syn body (6) is obtained, and finally, an inversion operation (2S, 3R) anti body (7), and no reversal operation (2S, 3S) syn body (8) is obtained. On the other hand, when hydrogenated using the (+)-form,
A syn body (9) of (2S, 3R) is obtained.
【００３０】[0030]
【化１２】 [Chemical 12]
【００３１】[0031]
【実施例】以下、実施例および参考例により本発明をさ
らに詳細に説明するが、本発明はこれらの実施例に限定
されるものではない。The present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples.
【００３２】参考例１ Ru2Cl4[(-)-T-BINAP]2(NEt3)の合成 [RuCl2(COD)]n１ｇ（３．５６ｍｍｏｌ）（式中、ＣＯ
Ｄは１，５−シクロオクタジエンを示す）、（−）−Ｔ
−ＢＩＮＡＰ ２．９ｇ（４．２７ｍｍｏｌ）（式中、
Ｔ−ＢＩＮＡＰは２，２’−ビス［ジ−（ｐ−トリル）
ホスフィノ］−１，１’−ビナフチルを示す）及びトリ
エチルアミン１．５ｇを５０ｍｌのトルエン中に窒素雰
囲気下に加えた。加熱攪拌をトルエン還流下に行ない、
６時間反応せしめた後、冷却し、析出した結晶をろ別し
た。この結晶をトルエンに溶解し、この中にジエチルエ
ーテルを徐々に加えて再結晶化を行ない、Ru2Cl4[(-)-T
-BINAP]2(NEt3）の結晶２．２４ｇを得た。 参考例２ Ru2Cl4[(＋）-T-BINAP]2(NEt3)の合成 （−）−Ｔ−ＢＩＮＡＰの代わりに（＋）−Ｔ−ＢＩＮ
ＡＰを用いた外は参考例１と同様に操作を行ない、Ru2C
l4[(＋）-T-BINAP]2(NEt3)を得た。 実施例１ （２Ｓ，３Ｒ）−ジヒドロスフィンゴシンの合成 あらかじめ窒素置換を行った３００ｍｌのステンレスオ
ートクレーブに、２−Ｎ−アセトアミド−ヘキサデカノ
イル酢酸メチルエステル８．４ｇ（２２．７ｍｍｏｌ）
及び参考例１に準じて合成したルテニウム−光学活性ホ
スフィン錯体Ru2Cl4［(-)-T-BINAP ］2(NEt3) （T-BINA
P は２，２’−ビス［ジ（ｐ−トリル）ホスフィノ］−
１，１’−ビナフチルを示す。）１０２ｍｇ（０．０５
７ｍｍｏｌ）を二塩化メチレン４０ｍｌに溶かしたもの
を加え、５０℃、水素圧５０ａｔｍで４５時間攪拌して
反応させた。水添反応物の溶媒を留去し、残留物をｎ−
ヘキサンと酢酸エチル８０：１の混合溶媒から結晶化し
て８．４ｇの結晶を得た。この結晶をシリカゲルカラム
クロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝５／
１〜１／４（容量比））にて精製し８．０ｇの（２Ｒ，
３Ｓ）−２−Ｎ−アセトアミド−３−ヒドロキシオクタ
デカン酸メチルエステルを得た。収率９５％、融点９５
〜９６℃、 [α]D 28＝−１１．１°（Ｃ＝１．０５，CH
Cl3)、光学純度９８％ｅ．ｅ．。Reference Example 1 Synthesis of Ru 2 Cl 4 [(-)-T-BINAP] 2 (NEt 3 ) [RuCl 2 (COD)] n 1 g (3.56 mmol) (in the formula, CO
D represents 1,5-cyclooctadiene), (-)-T
-BINAP 2.9 g (4.27 mmol) (wherein
T-BINAP is 2,2'-bis [di- (p-tolyl)
Phosphino] -1,1′-binaphthyl) and 1.5 g of triethylamine were added to 50 ml of toluene under a nitrogen atmosphere. Heat stirring under reflux of toluene,
After reacting for 6 hours, the mixture was cooled and the precipitated crystals were separated by filtration. The crystals were dissolved in toluene, and diethyl ether was gradually added to the crystals for recrystallization, and Ru 2 Cl 4 [(-)-T
2.24 g of crystals of -BINAP] 2 (NEt 3 ) were obtained. Reference Example 2 Synthesis of Ru 2 Cl 4 [(+)-T-BINAP] 2 (NEt 3 ) (+)-T-BIN Instead of (-)-T-BINAP
The same operation as in Reference Example 1 was performed except that AP was used, and Ru 2 C was used.
l 4 [(+)-T-BINAP] 2 (NEt 3 ) was obtained. Example 1 Synthesis of (2S, 3R) -dihydrosphingosine In a 300 ml stainless steel autoclave previously subjected to nitrogen substitution, 8.4 g (22.7 mmol) of 2-N-acetamide-hexadecanoyl acetic acid methyl ester was added.
And a ruthenium-optically active phosphine complex synthesized according to Reference Example 1 and Ru 2 Cl 4 [(-)-T-BINAP] 2 (NEt 3 ) (T-BINA
P is 2,2'-bis [di (p-tolyl) phosphino]-
1,1'-binaphthyl is shown. ) 102 mg (0.05
(7 mmol) dissolved in 40 ml of methylene dichloride was added, and the mixture was reacted by stirring at 50 ° C. and hydrogen pressure of 50 atm for 45 hours. The solvent of the hydrogenation reaction product was distilled off, and the residue was n-
Crystallization from a mixed solvent of hexane and ethyl acetate 80: 1 gave 8.4 g of crystals. This crystal was subjected to silica gel column chromatography (n-hexane / ethyl acetate = 5 /
1 to 1/4 (volume ratio) and purified to 8.0 g (2R,
3S) -2-N-acetamido-3-hydroxyoctadecanoic acid methyl ester was obtained. Yield 95%, melting point 95
~ 96 ° C, [α] D 28 = -11.1 ° (C = 1.05, CH
Cl 3 ), optical purity 98% e. e. .
【００３３】光学純度は、得られた（２Ｒ，３Ｓ）−２
−Ｎ−アセトアミド−３−ヒドロキシオクタデカン酸メ
チルエステルをピリジン溶媒中（＋）及び（−）−メト
キシ−トリフルオロメチル−フェニル酢酸クロライド
（ＭＴＰＡクロライド）を用いて、３位の水酸基のエス
テル化を行ない、４００ＭＨｚ ＮＭＲによりメチルエ
ステル基、アセトアミド基のシングレットピークあるい
はアミド基のダブレットピークのジアステレオマー比か
ら決定した。以下の実施例においても同様に光学純度を
決定した。The optical purity was obtained as (2R, 3S) -2.
-N-acetamido-3-hydroxyoctadecanoic acid methyl ester was esterified at the 3-hydroxy group using (+) and (-)-methoxy-trifluoromethyl-phenylacetic acid chloride (MTPA chloride) in a pyridine solvent. , 400 MHz NMR to determine from the diastereomeric ratio of the singlet peak of the methyl ester group or acetamide group or the doublet peak of the amide group. The optical purity was similarly determined in the following examples.
【００３４】1H-NMR(400 MHz, CDCl3,δ) ; 0.88 (t, 3
H, J=6.9 Hz, CH3), 1.26 (br.s, 24H), 1.32-1.52 (m,
4H), 1.95 (br.s, 1H, OH), 2.08 (s, 3H, AcN), 3.77
(s,3H, CO2Me), 4.12 (dt, 1H, J=6.6 Hz, J=2.1 Hz,C
H-O), 4.66 (dd, 1H, J=9.0Hz, J=2.1 Hz, CH-N), 6.24
(d, 1H, J=9.0 Hz, NH). IR(KBr，νcm-1）； 3400 (s,OH), 3310 (s, NH), 173
5 (s, CO2Me), 1710 (s, CO2Me), 1655 (s, CON), 1545
(s, NH), 1285 (s, C-O). Mass(m/z) ；373 (15), 371 (1), 354 (7), 311 (20),
295 (90), 271 (15),252 (10), 222 (10), 196 (10), 1
60 (10), 131 (100), 99 (80), 82 (92), 57(50), 43
(57), 28 (80). 1 H-NMR (400 MHz, CDCl 3 , δ); 0.88 (t, 3
H, J = 6.9 Hz, CH 3 ), 1.26 (br.s, 24H), 1.32-1.52 (m,
4H), 1.95 (br.s, 1H, OH), 2.08 (s, 3H, AcN), 3.77
(s, 3H, CO 2 Me), 4.12 (dt, 1H, J = 6.6 Hz, J = 2.1 Hz, C
HO), 4.66 (dd, 1H, J = 9.0Hz, J = 2.1 Hz, CH-N), 6.24
(d, 1H, J = 9.0 Hz, NH). IR (KBr, νcm- 1 ); 3400 (s, OH), 3310 (s, NH), 173
5 (s, CO 2 Me), 1710 (s, CO 2 Me), 1655 (s, CON), 1545
(s, NH), 1285 (s, CO). Mass (m / z) 373 (15), 371 (1), 354 (7), 311 (20),
295 (90), 271 (15), 252 (10), 222 (10), 196 (10), 1
60 (10), 131 (100), 99 (80), 82 (92), 57 (50), 43
(57), 28 (80).
【００３５】次に（２Ｒ，３Ｓ）−２−Ｎ−アセトアミ
ド−３−ヒドロキシオクタデカン酸メチルエステル７．
５９ｇ（２２．１ｍｍｏｌ）の乾燥ベンゼン（２００ｍ
ｌ）溶液に、氷冷下塩化チオニル１６．５ｍｌ（０．２
２６ｍｏｌ）を３０分間で滴下し、室温下４時間攪拌
後、氷冷下で水（２００ｍｌ）を加え室温下１４時間攪
拌した。有機層を分離後、水層をジエチルエーテル（２
００ｍｌ）で抽出し、合わせた有機層を減圧下溶媒を留
去し粗反転生成物（２Ｒ，３Ｒ）−体８．８９ｇを得
た。結晶をシリカゲルカラムクロマトグラフィ−（ｎ−
ヘキサン／酢酸エチル＝５／１〜１／４（容量比））に
て精製し７．０ｇの（２Ｒ，３Ｒ）−２−Ｎ−アセトア
ミド−３−ヒドロキシオクタデカン酸メチルエステルを
得た。収率９２％、融点８２〜８４℃、[α]D 25＝−２
４．２°(c=0.53, CHCl3)。Then, (2R, 3S) -2-N-acetamido-3-hydroxyoctadecanoic acid methyl ester 7.
59 g (22.1 mmol) of dry benzene (200 m
1) The solution was thionyl chloride 16.5 ml (0.2
(26 mol) was added dropwise over 30 minutes, the mixture was stirred at room temperature for 4 hours, water (200 ml) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. After separating the organic layer, the aqueous layer was washed with diethyl ether (2
(00 ml), and the combined organic layers were evaporated under reduced pressure to remove the solvent to obtain 8.89 g of a crude inversion product (2R, 3R) -form. The crystals are purified by silica gel column chromatography- (n-
It was purified by hexane / ethyl acetate = 5/1 to 1/4 (volume ratio) to obtain 7.0 g of (2R, 3R) -2-N-acetamido-3-hydroxyoctadecanoic acid methyl ester. Yield 92%, melting point 82-84 ° C, [α] D 25 = -2
4.2 ° (c = 0.53, CHCl 3 ).
【００３６】1H-NMR(400 MHz, CDCl3 ，δ）； 0.88
(t, 3H, J=6.9 Hz, CH3), 1.26 (br.s, 24H）, 1.32-1.
52 (m, 4H), 2.07 (s, 3H, AcN), 3.79 (s, 3H, CO2M
e), 3.90-3.94 (m, 1H, CH-O), 4.68 (dd, 1H, J=7.2 H
z, J=3.2 Hz, CH-N), 6.45 (d, 1H, J=7.2 Hz, NH). IR(KBr，ν cm-1） 3300(s, OH, NH), 1735 (s, CO2M
e), 1655 (s, CON), 1550 (s, NH), 1255 (s, C-O). Mass(m/z) ； 373 (40), 371 (2), 354 (15), 312 (5
0), 295 (98), 270 (25), 253 (100), 160 (10), 131
(98), 99 (50), 89 (98), 57 (25), 43 (70), 28(20). 1 H-NMR (400 MHz, CDCl 3 , δ); 0.88
(t, 3H, J = 6.9 Hz, CH 3 ), 1.26 (br.s, 24H), 1.32-1.
52 (m, 4H), 2.07 (s, 3H, AcN), 3.79 (s, 3H, CO 2 M
e), 3.90-3.94 (m, 1H, CH-O), 4.68 (dd, 1H, J = 7.2 H
z, J = 3.2 Hz, CH-N), 6.45 (d, 1H, J = 7.2 Hz, NH). IR (KBr, ν cm- 1 ) 3300 (s, OH, NH), 1735 (s, CO 2 M
e), 1655 (s, CON), 1550 (s, NH), 1255 (s, CO). Mass (m / z); 373 (40), 371 (2), 354 (15), 312 (5
0), 295 (98), 270 (25), 253 (100), 160 (10), 131
(98), 99 (50), 89 (98), 57 (25), 43 (70), 28 (20).
【００３７】粗（２Ｒ，３Ｒ）−体８．８９ｇを５％塩
酸水（１００ｍｌ）と１，４−ジオキサン（１００ｍ
ｌ）の混合溶媒に加え、４時間加熱還流下攪拌した。氷
冷下６Ｎ塩酸（１００ｍｌ）を加え、冷所にて16時間放
置してアミンの塩酸塩を析出させ、結晶を濾過後乾燥し
て塩酸塩９．８２ｇを得た。融点１３３〜１３６℃。塩
酸塩９．８２ｇを乾燥テトラヒドロフラン（ＴＨＦ）
（３００ｍｌ）に加え、氷冷攪拌下で水素化リチウムア
ルミニウム（５．０４ｇ，０．１３３ｍｏｌ）を加えた
後、３０分間加熱還流下攪拌した。反応溶液を氷冷下１
０％水酸化ナトリウム水（２０００ｍｌ）で処理した
後、ジエチルエーテル（２０００ｍｌ×２回) で抽出
し、合わせた有機層を飽和食塩水で洗浄し、無水硫酸ナ
トリウムで乾燥後、減圧下溶媒を留去し粗ジヒドロスフ
ィンゴシン６．４５ｇを得た。これをｎ−ヘキサン（３
００ｍｌ）から再結晶化し、濾過後結晶をｎ−ペンタン
で洗浄して４．９５ｇの光学活性（２Ｓ，３Ｒ）−ジヒ
ドロスフィンゴシンを得た。収率７４％（水添化合物か
ら）、融点８４〜８６℃、 [α]D 24＝＋２．９°（c=0.
28, CHCl3).8.89 g of the crude (2R, 3R) -form was added to 5% aqueous hydrochloric acid (100 ml) and 1,4-dioxane (100 m).
It was added to the mixed solvent of l) and stirred under heating under reflux for 4 hours. Under ice-cooling, 6N hydrochloric acid (100 ml) was added, and the mixture was allowed to stand in a cold place for 16 hours to precipitate an amine hydrochloride, and the crystal was filtered and dried to obtain 9.82 g of hydrochloride. Melting point 133-136 [deg.] C. 9.82 g of hydrochloride salt is dried on tetrahydrofuran (THF)
In addition to (300 ml), lithium aluminum hydride (5.04 g, 0.133 mol) was added with stirring under ice-cooling, and the mixture was stirred with heating under reflux for 30 minutes. Reaction solution under ice cooling 1
After treating with 0% aqueous sodium hydroxide (2000 ml), the mixture was extracted with diethyl ether (2000 ml x 2 times), the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was removed to obtain 6.45 g of crude dihydrosphingosine. Add this to n-hexane (3
The crystals were washed with n-pentane to obtain 4.95 g of optically active (2S, 3R) -dihydrosphingosine. Yield 74% (from hydrogenated compound), melting point 84-86 ° C, [α] D 24 = + 2.9 ° (c = 0.
28, CHCl 3 ).
【００３８】1H-NMR[400 MHz, CDCl3/CD3OD(容量比5/
1)，δ] ； 0.88 (t, 3H, J=6.9Hz, CH3), 1.27 (br.s,
26H), 1.42-1.55 (m, 2H), 2.78 (ddd, 1H, J=6.7Hz,
J=4.4Hz, J=3.9Hz, CH-N), 3.56-3.62 (m, 1H, CH-O),
3.62 (dd, 1H, J=11.2Hz, J=6.7Hz, CH-O), 3.70 (dd,
1H, J=11.2Hz, J=3.9Hz, CH-O). IR(KBr，νcm-1）； 3600-3100 (s, OH,NH), 1600 (w,
NH), 1100-1000 (m,C-O,C-N). Mass(m/z): 303 (15), 301 (2), 271 (100), 252 (6),
176 (6), 90 (20), 60(98), 43 (95), 28 (48). 1 H-NMR [400 MHz, CDCl 3 / CD 3 OD (volume ratio 5 /
1), δ] ； 0.88 (t, 3H, J = 6.9Hz, CH 3 ), 1.27 (br.s,
26H), 1.42-1.55 (m, 2H), 2.78 (ddd, 1H, J = 6.7Hz,
J = 4.4Hz, J = 3.9Hz, CH-N), 3.56-3.62 (m, 1H, CH-O),
3.62 (dd, 1H, J = 11.2Hz, J = 6.7Hz, CH-O), 3.70 (dd,
1H, J = 11.2Hz, J = 3.9Hz, CH-O). IR (KBr, νcm- 1 ); 3600-3100 (s, OH, NH), 1600 (w,
NH), 1100-1000 (m, CO, CN). Mass (m / z): 303 (15), 301 (2), 271 (100), 252 (6),
176 (6), 90 (20), 60 (98), 43 (95), 28 (48).
【００３９】実施例２ （２Ｒ，３Ｒ）−２−アミノヘキサデカン−１，３−ジ
オールの合成 あらかじめ窒素置換を行った１００ｍｌのステンレスオ
ートクレーブに、２−Ｎ−アセトアミド−テトラデカノ
イル酢酸メチルエステル ０．８０ｇ（２．３４ｍｍｏ
ｌ）及び参考例２に準じて合成したルテニウム−光学活
性ホスフィン錯体Ru2Cl4［(+)-T-BINAP ］2(NEt3) ２
９．５ｍｇ（０．０１６ｍｍｏｌ）を二塩化メチレン８
ｍｌに溶かしたものを加え、５０℃、水素圧５０ａｔｍ
で２０時間攪拌して反応させた。水添反応物の溶媒を留
去し、残留物をｎ− ヘキサンと酢酸エチル２０：１の
混合溶媒から結晶化して０．７５ｇの結晶を得た。この
結晶をシリカゲルカラムクロマトグラフィー（ｎ−ヘキ
サン／ 酢酸エチル＝５／１〜１／４（容量比））にて
精製し ０．７３ｇの（２Ｓ，３Ｒ）−２−Ｎ−アセト
アミド−３−ヒドロキシヘキサデカン酸メチルエステル
を得た。収率９０％、融点９２〜９４℃、[α]D 25＝＋
１３．１°(c=0.29,CHCl3)、光学純度９８％ｅ．ｅ．。Example 2 Synthesis of (2R, 3R) -2-aminohexadecane-1,3-diol In a 100 ml stainless steel autoclave previously substituted with nitrogen, 2-N-acetamide-tetradecanoyl acetic acid methyl ester was added. 80 g (2.34 mmo
1) and a ruthenium-optically active phosphine complex Ru 2 Cl 4 [(+)-T-BINAP] 2 (NEt 3 ) 2 synthesized according to Reference Example 2
9.5 mg (0.016 mmol) of methylene dichloride 8
Add the one dissolved in ml, 50 ℃, hydrogen pressure 50atm
The mixture was stirred for 20 hours and reacted. The solvent of the hydrogenation reaction product was distilled off, and the residue was crystallized from a mixed solvent of n-hexane and ethyl acetate 20: 1 to obtain 0.75 g of crystals. The crystals were purified by silica gel column chromatography (n-hexane / ethyl acetate = 5/1 to 1/4 (volume ratio)) and 0.73 g of (2S, 3R) -2-N-acetamide-3-hydroxy was obtained. Hexadecanoic acid methyl ester was obtained. Yield 90%, melting point 92-94 ° C, [α] D 25 = +
13.1 ° (c = 0.29, CHCl 3 ), optical purity 98% e. e. .
【００４０】1H-NMR(400 MHz, CDCl3 ，δ）； 0.88
(t, 3H, J=6.9 Hz, CH3), 1.26 (br.s, 20H), 1.32-1.5
2 (m, 4H), 1.95 (br.s, 1H, OH), 2.08 (s, 3H, AcN),
3.77(s, 3H, CO2Me), 4.12 (dt, 1H, J=6.6 Hz, J=2.1
Hz,CH-O), 4.66 (dd, 1H, J=9.0 Hz, J=2.1 Hz, CH-
N), 6.24 (d, 1H, J=9.0 Hz, NH). IR(KBr，ν cm-1)；3400(s,OH), 3310 (s, NH), 1735
(s, CO2Me), 1710 (s,CO2Me), 1655 (s, CON), 1545
(s, NH), 1285 (s, C-O). Mass(m/z): 344 (30), 325 (5), 312 (5), 293 (8), 28
4 (30), 266 (25), 242 (40), 224 (10), 160 (25), 13
1 (100), 99 (100), 89 (100), 82 (35), 72 (30), 57
(40), 43 (35), 28 (46). 1 H-NMR (400 MHz, CDCl 3 , δ); 0.88
(t, 3H, J = 6.9 Hz, CH 3 ), 1.26 (br.s, 20H), 1.32-1.5
2 (m, 4H), 1.95 (br.s, 1H, OH), 2.08 (s, 3H, AcN),
3.77 (s, 3H, CO 2 Me), 4.12 (dt, 1H, J = 6.6 Hz, J = 2.1
Hz, CH-O), 4.66 (dd, 1H, J = 9.0 Hz, J = 2.1 Hz, CH-
N), 6.24 (d, 1H, J = 9.0 Hz, NH). IR (KBr, ν cm- 1 ); 3400 (s, OH), 3310 (s, NH), 1735
(s, CO 2 Me), 1710 (s, CO 2 Me), 1655 (s, CON), 1545
(s, NH), 1285 (s, CO). Mass (m / z): 344 (30), 325 (5), 312 (5), 293 (8), 28
4 (30), 266 (25), 242 (40), 224 (10), 160 (25), 13
1 (100), 99 (100), 89 (100), 82 (35), 72 (30), 57
(40), 43 (35), 28 (46).
【００４１】（２Ｓ，３Ｒ）−体０．７３ｇを５％塩酸
水（８ｍｌ）と１，４−ジオキサン（８ｍｌ）の混合溶
媒に加え、２．５時間加熱還流下攪拌した。氷冷下6N塩
酸（８ｍｌ）を加え、冷所にて１６時間放置してアミン
の塩酸塩を析出させ、結晶を濾過後、乾燥して塩酸塩
０．４９ｇを得た。融点１８８〜１９０℃。0.73 g of (2S, 3R) -form was added to a mixed solvent of 5% hydrochloric acid water (8 ml) and 1,4-dioxane (8 ml), and the mixture was stirred under heating under reflux for 2.5 hours. Under ice-cooling, 6N hydrochloric acid (8 ml) was added, and the mixture was allowed to stand in a cold place for 16 hours to precipitate an amine hydrochloride, and the crystals were filtered and dried to obtain 0.49 g of hydrochloride. Melting point 188-190 [deg.] C.
【００４２】塩酸塩０．４９ｇを乾燥ＴＨＦ（５０ｍ
ｌ）に加え、氷冷攪拌下に水素化リチウムアルミニウム
（１．４ｇ、０．０３６ｍｏｌ）を加えた後、３時間加
熱還流下に攪拌した。反応溶液を氷冷下に１０％水酸化
ナトリウム水（２００ｍｌ）で処理した後、ジエチルエ
ーテル（２００ｍｌ×２回)で抽出し、あわせた有機層
を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、
減圧下に溶媒を留去して粗生成物０．３２ｇを得た。こ
れを酢酸エチルから再結晶化し、濾過後、結晶をｎ−ペ
ンタンで洗浄して０．２８ｇの光学活性（２Ｒ，３Ｒ）
−２−アミノヘキサデカン−１，３−ジオールを得た。
収率６８％（水添化合物から）、融点１０４〜１０６
℃、[α]D 24＝＋８．０°(c=0.075, CHCl3)。0.49 g of the hydrochloride salt was added to dry THF (50 m
In addition to 1), lithium aluminum hydride (1.4 g, 0.036 mol) was added with stirring under ice-cooling, and then the mixture was stirred with heating under reflux for 3 hours. The reaction solution was treated with 10% aqueous sodium hydroxide (200 ml) under ice cooling, extracted with diethyl ether (200 ml x 2 times), the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. rear,
The solvent was distilled off under reduced pressure to obtain 0.32 g of a crude product. This was recrystallized from ethyl acetate, filtered, and the crystals were washed with n-pentane to give 0.28 g of optically active (2R, 3R)
2-Aminohexadecane-1,3-diol was obtained.
Yield 68% (from hydrogenated compound), melting point 104-106
C, [α] D 24 = + 8.0 ° (c = 0.075, CHCl 3 ).
【００４３】1H-NMR[400 MHz, CDCl3/CD3OD(容量比5/
1)，δ]； 0.88 (t, 3H, J=6.9Hz, CH3), 1.27 (br.s,
22H), 1.43-1.53 (m, 2H), 2.73-2.79 (m, 1H, CH-N),
3.55 (dd, 1H, J=11.1Hz, J=5.5Hz, CH-O), 3.54-3.60
(m, 1H, CH-O), 3.67 (dd, 1H,J=11.1Hz, J=4.4Hz, -CH
-O). IR(KBr，ν cm-1 ）； 3380(s, OH), 3360 (m, NH), 33
10 (m,NH), 1580 (m,N-H), 1470 (m, CH2), 1130 (s, C
-O). Mass(m/z): 274 (25), 242 (100), 224 (8), 214 (6),
90 (90), 60 (100), 43 (100), 28 (70). 1 H-NMR [400 MHz, CDCl 3 / CD 3 OD (volume ratio 5 /
1), δ]; 0.88 (t, 3H, J = 6.9Hz, CH 3 ), 1.27 (br.s,
22H), 1.43-1.53 (m, 2H), 2.73-2.79 (m, 1H, CH-N),
3.55 (dd, 1H, J = 11.1Hz, J = 5.5Hz, CH-O), 3.54-3.60
(m, 1H, CH-O), 3.67 (dd, 1H, J = 11.1Hz, J = 4.4Hz, -CH
-O). IR (KBr, ν cm- 1 ); 3380 (s, OH), 3360 (m, NH), 33
10 (m, NH), 1580 (m, NH), 1470 (m, CH 2 ), 1130 (s, C
-O). Mass (m / z): 274 (25), 242 (100), 224 (8), 214 (6),
90 (90), 60 (100), 43 (100), 28 (70).
【００４４】実施例３ （２Ｒ，３Ｓ）−２−アミノヘキサデカン−１，３−ジ
オールの合成 実施例２中で得られた（２Ｓ，３Ｒ）− ２−Ｎ−アセ
トアミド−３−ヒドロキシヘキサデカン酸メチルエステ
ル ０．７３ｇ（２．００ｍｍｏｌ）の乾燥ベンゼン
（２０ｍｌ）溶液に、氷冷下に塩化チオニル １．６ｍ
ｌ（０．０２３ｍｏｌ）を３０分間で滴下し、室温下に
４時間攪拌後、氷冷下に水（２０ｍｌ）を加え、室温下
に１４時間攪拌した。有機層を分離後、水層をジエチル
エーテル（２０ｍｌ×２回) で抽出し、合わせた有機層
を減圧下に溶媒を留去し、粗反転生成物（２Ｓ，３Ｓ）
−体０．８９ｇを得た。結晶をシリカゲルカラムクロマ
トグラフィ−（ｎ−ヘキサン／ 酢酸エチル＝５／１〜
１／４（容量比））にて精製し０．７２ｇの（２Ｓ，３
Ｓ）−２−Ｎ−アセトアミド−３−ヒドロキシヘキサデ
カン酸メチルエステルを得た。収率９２％、融点８０〜
８２℃、［α]D 25＝−２４．２°(c=0.53, CHCl3) 。さ
らに（２Ｓ，３Ｓ）−体０．７２ｇを５％塩酸水（８ｍ
ｌ）と1,4-ジオキサン（８ｍｌ）の混合溶媒に加え、
２．５時間加熱還流下に攪拌した。氷冷下に６Ｎ塩酸
（８ｍｌ）を加え、冷所にて１６時間放置してアミンの
塩酸塩を析出させ、結晶を濾過後、乾燥して塩酸塩０．
４９ｇを得た、融点１３０〜１３３℃。Example 3 Synthesis of (2R, 3S) -2-aminohexadecane-1,3-diol Methyl (2S, 3R) -2-N-acetamido-3-hydroxyhexadecanoate obtained in Example 2 To a solution of 0.73 g (2.00 mmol) of ester in dry benzene (20 ml) was added thionyl chloride (1.6 m) under ice cooling.
1 (0.023 mol) was added dropwise over 30 minutes, the mixture was stirred at room temperature for 4 hours, water (20 ml) was added under ice cooling, and the mixture was stirred at room temperature for 14 hours. After separating the organic layer, the aqueous layer was extracted with diethyl ether (20 ml x 2 times), the combined organic layers were evaporated under reduced pressure to remove the crude inversion product (2S, 3S).
-0.89 g of body was obtained. The crystals are subjected to silica gel column chromatography (n-hexane / ethyl acetate = 5/1 to
Purified by 1/4 (volume ratio), 0.72 g of (2S, 3
S) -2-N-acetamido-3-hydroxyhexadecanoic acid methyl ester was obtained. Yield 92%, melting point 80 ~
82 ℃, [α] D 25 = -24.2 ° (c = 0.53, CHCl 3). Furthermore, 0.72 g of (2S, 3S) -form was added to 5% hydrochloric acid water (8 m
l) and 1,4-dioxane (8 ml) mixed solvent,
The mixture was stirred under heating under reflux for 2.5 hours. Under cooling with ice, 6N hydrochloric acid (8 ml) was added, and the mixture was allowed to stand in a cold place for 16 hours to precipitate the hydrochloride salt of the amine.
Obtained 49 g, mp 130-133 ° C.
【００４５】塩酸塩０．４９ｇを乾燥ＴＨＦ（５０ｍ
ｌ）に加え、氷冷攪拌下、水素化リチウムアルミニウム
（１．４ｇ、０．０３６ｍｏｌ）を加えた後、３時間加
熱還流下に攪拌した。反応溶液を氷冷下に１０％水酸化
ナトリウム水（２００ｍｌ）で処理した後、ジエチルエ
ーテル（２００ｍｌ×２回）で抽出し、あわせた有機層
を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、
減圧下に溶媒を留去して粗生成物０．３２ｇを得た。こ
れをｎ−ヘキサンから再結晶化し、濾過後、結晶をｎ−
ペンタンで洗浄して０．２８ｇの非天然型光学活性（２
Ｒ，３Ｓ）−２−アミノヘキサデカン−１，３−ジオー
ルを得た。収率６８％（水添化合物から）、融点８１〜
８３℃、 [α]D 24＝−３．０°(c=0.265, CHCl3)。0.49 g of the hydrochloride salt was added to dry THF (50 m
1), lithium aluminum hydride (1.4 g, 0.036 mol) was added under ice-cooling stirring, and then the mixture was heated under reflux for 3 hours with stirring. The reaction solution was treated with 10% aqueous sodium hydroxide (200 ml) under ice cooling, extracted with diethyl ether (200 ml x 2 times), and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. rear,
The solvent was distilled off under reduced pressure to obtain 0.32 g of a crude product. This was recrystallized from n-hexane and filtered to give crystals as n-hexane.
After washing with pentane, 0.28 g of non-natural optical activity (2
R, 3S) -2-Aminohexadecane-1,3-diol was obtained. Yield 68% (from hydrogenated compound), melting point 81-
83 ° C., [α] D 24 = −3.0 ° (c = 0.265, CHCl 3 ).
【００４６】1H-NMR( 400 MHz, CDCl3/CD3OD( 容量比5/
1)，δ]； 0.88 (t, 3H, J=6.9Hz,CH3), 1.27 (br.s, 2
2H), 1.42-1.55 (m, 2H), 2.78 (ddd, 1H, J=6.7Hz, J=
4.4Hz, J=3. 9Hz, CH-N), 3.56-3.62 (m, 1H, CH-O),
3.62 (dd, 1H, J=11.2Hz, J=6.7Hz, CH-O), 3.70 (dd,
1H, J=11.2Hz, J=3.9Hz, CH-O). IR(KBr，νcm-1）； 3600-3100 (s, OH,NH), 1600 (w,
NH), 1100-1000 (m,C-O ,C-N). Mass(m/z): 274 (40), 242 (100), 224 (6), 252 (6),
109 (4), 90 (40), 60(100), 43 (100), 28 (58). 1 H-NMR (400 MHz, CDCl 3 / CD 3 OD (volume ratio 5 /
1), δ]; 0.88 (t, 3H, J = 6.9Hz, CH 3 ), 1.27 (br.s, 2
2H), 1.42-1.55 (m, 2H), 2.78 (ddd, 1H, J = 6.7Hz, J =
4.4Hz, J = 3.9Hz, CH-N), 3.56-3.62 (m, 1H, CH-O),
3.62 (dd, 1H, J = 11.2Hz, J = 6.7Hz, CH-O), 3.70 (dd,
1H, J = 11.2Hz, J = 3.9Hz, CH-O). IR (KBr, νcm- 1 ); 3600-3100 (s, OH, NH), 1600 (w,
NH), 1100-1000 (m, CO, CN). Mass (m / z): 274 (40), 242 (100), 224 (6), 252 (6),
109 (4), 90 (40), 60 (100), 43 (100), 28 (58).
【００４７】参考例３ （２Ｒ，３Ｓ）−２−Ｎ−ベンズアミド−３−ヒドロキ
シオクタデカン酸メチルエステルの合成 あらかじめ窒素置換を行った３００ｍｌのステンレスオ
ートクレ−ブに、２−Ｎ−ベンズアミド−ヘキサデカノ
イル酢酸メチルエステル９．６０ｇ（２３．７ｍｍｏ
ｌ) 及び参考例１に準じて合成したルテニウム−光学活
性ホスフィン錯体Ru2Cl4［(-)T-BINAP］2(NEt3) １０７
ｍｇ（０．０６０ｍｍｏｌ）を二塩化メチレン５０ｍｌ
に溶かしたものを加え、５０℃、水素圧５０ａｔｍで８
４時間攪拌して反応させた。水添反応物の溶媒を留去
し、残留物をＮ−ヘキサンから結晶化して９．２６ｇの
結晶を得た。この結晶をシリカゲルカラムクロマトグラ
フィー（ｎ−ヘキサン／酢酸エチル＝５／１〜１／４
（容量比））にて精製し９．２０ｇの（２Ｒ，３Ｓ）−
２−Ｎ−ベンズアミド−３−ヒドロキシオクタデカン酸
メチルエステルを得た。収率９５％、融点７６〜７８
℃、[α]D 25＝−４．９°(c=0.265,CHCl3) 、光学純度
７４％ｅ．ｅ．。Reference Example 3 Synthesis of (2R, 3S) -2-N-benzamido-3-hydroxyoctadecanoic acid methyl ester 2-N-benzamide-hexadeca was added to a 300 ml stainless steel autoclave which had been previously substituted with nitrogen. Noyl acetic acid methyl ester 9.60 g (23.7 mmo
l) and a ruthenium-optically active phosphine complex Ru 2 Cl 4 [(-) T-BINAP] 2 (NEt 3 ) 107 synthesized according to Reference Example 1
mg (0.060 mmol) 50 ml of methylene dichloride
Add the one melted at 8 ℃ at 50 ℃, hydrogen pressure 50atm.
The reaction was carried out by stirring for 4 hours. The solvent of the hydrogenation reaction product was distilled off, and the residue was crystallized from N-hexane to obtain 9.26 g of crystals. This crystal was subjected to silica gel column chromatography (n-hexane / ethyl acetate = 5/1 to 1/4).
(Volume ratio)) and 9.20 g of (2R, 3S)-
2-N-benzamido-3-hydroxyoctadecanoic acid methyl ester was obtained. Yield 95%, melting point 76-78
℃, [α] D 25 = -4.9 ° (c = 0.265, CHCl 3), optical purity 74% e. e. .
【００４８】1H-NMR(400 MHz,CDCl3，δ）； 0.88 (t,
3H, J=6.9Hz, CH3), 1.25 (br.s, 24H), 1.35-1.65 (m,
4H), 3.80 (s, 3H, CO2CH3), 4.22-4.28 (m, 1H, CH-
O), 4.88 (dd, 1H, J=8.9Hz, J=2.0Hz, CH-N), 6.87
(d, 1H, J=8.9Hz, NH), 7.42-7.56 (m, 3H, m-2H, p-1
H), 7.82-7.88 (m, 2H, o-2H). IR(KBr，ν cm-1 ）； 3370(s, OH, NH), 1750 (s, CO2
Me), 1635 (s, CON),1545 (s, NH). Mass(m/z): 434 (10), 433 (2), 415 (40), 356 (22),
310 (20), 252 (6), 222 (6), 193 (98), 161 (100), 1
34 (55), 105 (98), 96 (58), 83 (90), 68 (45), 57
(45), 31(98), 28(98) 1 H-NMR (400 MHz, CDCl 3 , δ); 0.88 (t,
3H, J = 6.9Hz, CH 3 ), 1.25 (br.s, 24H), 1.35-1.65 (m,
4H), 3.80 (s, 3H, CO 2 CH 3 ), 4.22-4.28 (m, 1H, CH-
O), 4.88 (dd, 1H, J = 8.9Hz, J = 2.0Hz, CH-N), 6.87
(d, 1H, J = 8.9Hz, NH), 7.42-7.56 (m, 3H, m-2H, p-1
H), 7.82-7.88 (m, 2H, o-2H). IR (KBr, ν cm- 1 ); 3370 (s, OH, NH), 1750 (s, CO 2
Me), 1635 (s, CON), 1545 (s, NH). Mass (m / z): 434 (10), 433 (2), 415 (40), 356 (22),
310 (20), 252 (6), 222 (6), 193 (98), 161 (100), 1
34 (55), 105 (98), 96 (58), 83 (90), 68 (45), 57
(45), 31 (98), 28 (98)
【００４９】参考例４ （２Ｒ，３Ｓ）−２−Ｎ−アセトアミド−３−ヒドロキ
シオクタデカン酸エチルエステルの合成 あらかじめ窒素置換を行った３００ｍｌのステンレスオ
ートクレーブに、２−Ｎ−アセトアミド−ヘキサデカノ
イル酢酸エチルエステル９．９０ｇ（２５．８ｍｍｏ
ｌ） 及び参考例１に準じて合成したルテニウム−光学
活性ホスフィン錯体Ru2Cl4［(-)T-BINAP］2(NEt3)１１
７ｍｇ（０．０６５ｍｍｏｌ）を二塩化メチレン４０ｍ
ｌに溶かしたものを加え、５０℃、水素圧５０ａｔｍで
29時間攪拌して反応させた。水添反応物の溶媒を留去
し、残留物をｎ−ヘキサンと酢酸エチルの２０：１の混
合溶媒から結晶化して８．２ｇの結晶を得た。この結晶
をシリカゲルカラムクロマトグラフィ−（ｎ−ヘキサン
／ 酢酸エチル＝５／１〜１／４（容量比））にて精製
し８．０ｇの（２Ｒ，３Ｓ）−２−Ｎ−アセトアミド−
３−ヒドロキシオクタデカン酸エチルエステルを得た。
収率８１％、融点８６〜８８℃、[α]D 25＝−１２．３
°(c=0.235,CHCl3)、光学純度９２％ｅ．ｅ．。Reference Example 4 Synthesis of (2R, 3S) -2-N-acetamido-3-hydroxyoctadecanoic acid ethyl ester In a 300 ml stainless steel autoclave previously substituted with nitrogen, ethyl 2-N-acetamido-hexadecanoyl acetate was added. 9.90 g of ester (25.8 mmo
l) and a ruthenium-optically active phosphine complex Ru 2 Cl 4 [(-) T-BINAP] 2 (NEt 3 ) 11 synthesized according to Reference Example 1
7 mg (0.065 mmol) of methylene dichloride 40 m
Add the one dissolved in l, at 50 ℃, hydrogen pressure 50 atm
The reaction was allowed to stir for 29 hours. The solvent of the hydrogenation reaction product was distilled off, and the residue was crystallized from a 20: 1 mixed solvent of n-hexane and ethyl acetate to obtain 8.2 g of crystals. This crystal was purified by silica gel column chromatography (n-hexane / ethyl acetate = 5/1 to 1/4 (volume ratio)) and 8.0 g of (2R, 3S) -2-N-acetamide-
3-Hydroxyoctadecanoic acid ethyl ester was obtained.
Yield 81%, melting point 86-88 ° C, [α] D 25 = -12.3.
(C = 0.235, CHCl 3 ), optical purity 92% e. e. .
【００５０】1H-NMR(400 MHz,CDCl3，δ）； 0.88 (t,
3H, J=6.9Hz, CH3), 1.26 (br.s, 26H), 1.30 (t, 3H,
J=7.2Hz, O-C-CH3),1.45-1.52 (m, 2H), 2.07 (s, 3H,
AcN), 4.08-4.14 (m, 1H, CH-O), 4.23 (dq, 2H, J=7.2
Hz, J=2.1Hz, CO2CH3), 4.64(dd, 1H, J=9.0Hz, J=2.2H
z, CH-N), 6.17 (d, 1H, J=9.0Hz, NH). IR(KBr，ν cm-1）；3510(s, OH), 3290 (s, NH), 1720
(s, CO2Et), 1655 (s, CON), 1555 (s, NH), 1290 (s,
C-O). Mass(m/z): 386 (6), 367 (8), 324 (20), 312 (40), 2
94 (92), 270 (35),252 (10), 222 (6), 196 (8), 174
(20), 145 (100), 124 (12), 110 (20), 103(100), 99
(100), 82 (99), 72 (66), 56 (52), 32 (100), 28 (10
0). 1 H-NMR (400 MHz, CDCl 3 , δ); 0.88 (t,
3H, J = 6.9Hz, CH 3 ), 1.26 (br.s, 26H), 1.30 (t, 3H,
J = 7.2Hz, OC-CH 3 ), 1.45-1.52 (m, 2H), 2.07 (s, 3H,
AcN), 4.08-4.14 (m, 1H, CH-O), 4.23 (dq, 2H, J = 7.2
Hz, J = 2.1Hz, CO 2 CH 3 ), 4.64 (dd, 1H, J = 9.0Hz, J = 2.2H
z, CH-N), 6.17 (d, 1H, J = 9.0Hz, NH). IR (KBr, ν cm- 1 ); 3510 (s, OH), 3290 (s, NH), 1720
(s, CO 2 Et), 1655 (s, CON), 1555 (s, NH), 1290 (s,
CO). Mass (m / z): 386 (6), 367 (8), 324 (20), 312 (40), 2
94 (92), 270 (35), 252 (10), 222 (6), 196 (8), 174
(20), 145 (100), 124 (12), 110 (20), 103 (100), 99
(100), 82 (99), 72 (66), 56 (52), 32 (100), 28 (10
0).
【００５１】[0051]
【発明の効果】本発明は、安全で簡便に光学活性ジヒド
ロスフィンゴシン類を高い光学純度で得ることを可能に
する。INDUSTRIAL APPLICABILITY The present invention makes it possible to obtain optically active dihydrosphingosines with high optical purity safely and conveniently.
Claims (2)
キル基を示し、Ｒ2 は低級アルキル基、低級アルキル基
もしくは低級アルコキシ基で置換されていてもよいフェ
ニル基、または低級アルキル基もしくは低級アルコキシ
基で置換されていてもよいベンジル基を示し、Ｒ3 は水
素原子、低級アルキル基、低級アルコキシ基、低級アル
キル基もしくは低級アルコキシ基で置換されていてもよ
いフェニル基、または低級アルキル基もしくは低級アル
コキシ基で置換されていてもよいベンジルオキシ基を示
す）で表わされる２−Ｎ−アシルアミノ−高級アシル酢
酸エステル化合物を、ルテニウム−光学活性ホスフィン
錯体を触媒として不斉水素化を行い、次の一般式（２） 【化２】 （式中、＊印は光学活性であることを示し、Ｒ1 ，Ｒ2
及びＲ3 は上記と同じ意義を有する）で表わされる光学
活性２−Ｎ−アシルアミノ−３−ヒドロキシ高級カルボ
ン酸誘導体を得、ついでこれを必要に応じて３位水酸基
の立体配置を反転した後、加水分解及び還元することを
特徴とする次の一般式（３） 【化３】 （式中、Ｒ1 及び＊印は上記と同じ意義を有する）で表
わされる光学活性ジヒドロスフィンゴシン類の製造方
法。1. The following general formula (1): (In the formula, R 1 represents a higher alkyl group having 11 to 21 carbon atoms, and R 2 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, or a lower alkyl group. Group or a benzyl group which may be substituted with a lower alkoxy group, R 3 is a hydrogen atom, a lower alkyl group, a lower alkoxy group, a phenyl group which may be substituted with a lower alkyl group or a lower alkoxy group, or a lower group A 2-N-acylamino-higher acylacetic acid ester compound represented by the formula (which represents a benzyloxy group which may be substituted with an alkyl group or a lower alkoxy group) is subjected to asymmetric hydrogenation using a ruthenium-optically active phosphine complex as a catalyst. , The following general formula (2): (In the formula, * indicates that it is optically active, and R 1 , R 2
And R 3 have the same meaning as described above) to obtain an optically active 2-N-acylamino-3-hydroxy higher carboxylic acid derivative, which is then optionally inverted in the configuration of the 3-position hydroxyl group, The following general formula (3) characterized by hydrolysis and reduction: (In the formula, R 1 and * have the same meaning as described above) A method for producing an optically active dihydrosphingosine.
次の一般式（４） Ｒｕx Ｈy Ｃｌz （Ｒ4 −ＢＩＮＡＰ）2 （Ｓ）p （４） （式中、Ｒ4 −ＢＩＮＡＰは次の一般式（５） 【化４】 で表わされる光学活性三級ホスフィンを示し、Ｒ4 は水
素原子、メチル基又はｔｅｒｔ−ブチル基を示し、Ｓは
三級アミンを示し、ｙが０のときｘは２、ｚは４、ｐは
１を示し、ｙが１のときｘは１、ｚは１、ｐは０を示
す）で表わされるものである請求項１記載の製造方法。2. A ruthenium-optically active phosphine complex having the following general formula (4) Ru x H y Cl z (R 4 -BINAP) 2 (S) p (4) (wherein R 4 -BINAP is General formula (5) Represents an optically active tertiary phosphine, R 4 represents a hydrogen atom, a methyl group or a tert-butyl group, S represents a tertiary amine, and when y is 0, x is 2, z is 4, and p is 1 is represented, and when y is 1, x is 1, z is 1, and p is 0).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4255443A JP2976214B2 (en) | 1992-09-01 | 1992-09-01 | Method for producing optically active dihydrosphingosines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4255443A JP2976214B2 (en) | 1992-09-01 | 1992-09-01 | Method for producing optically active dihydrosphingosines |
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| Publication Number | Publication Date |
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| JPH0680617A true JPH0680617A (en) | 1994-03-22 |
| JP2976214B2 JP2976214B2 (en) | 1999-11-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4255443A Expired - Fee Related JP2976214B2 (en) | 1992-09-01 | 1992-09-01 | Method for producing optically active dihydrosphingosines |
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| Country | Link |
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| JP (1) | JP2976214B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184008B1 (en) | 1997-03-03 | 2001-02-06 | Sumitomo Chemical Company Ltd. | Production of optically active sphingoid compound |
| EP1146037A1 (en) * | 1999-01-18 | 2001-10-17 | Nippon Soda Co., Ltd. | Process for the preparation of optically active amino alcohols |
| WO2002004401A1 (en) * | 2000-07-10 | 2002-01-17 | Nippon Soda Co., Ltd. | PROCESS FOR THE PREPARATION OF β-AMINO ALCOHOLS IN SYN CONFIGURATION |
| JP2002020359A (en) * | 2000-07-10 | 2002-01-23 | Nippon Soda Co Ltd | METHOD FOR PRODUCING OPTICALLY ACTIVE beta-AMINOALCOHOL HAVING ANTI-CONFIGURATION |
| WO2004076391A1 (en) * | 2003-02-28 | 2004-09-10 | Japan Science And Technology Agency | Process for producing optically active compound |
| WO2005005371A1 (en) | 2003-07-10 | 2005-01-20 | Nissan Chemical Industries, Ltd. | PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE β-HYDROXY-α-AMINOCARBOXYLIC ACID DERIVATIVES |
| JP2005536556A (en) * | 2002-08-27 | 2005-12-02 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Enantioselective hydrogenation of aminoalcohols. |
| WO2006075651A1 (en) | 2005-01-12 | 2006-07-20 | Nissan Chemical Industries, Ltd. | PROCESS FOR PRODUCING OPTICALLY ACTIVE β-HYDROXY-α-AMINOCARBOXYLIC ACID DERIVATIVE |
| WO2008041571A1 (en) * | 2006-09-26 | 2008-04-10 | Kaneka Corporation | Process for producing optically active beta-hydroxy-alpha-aminocarboxylic acid ester |
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1992
- 1992-09-01 JP JP4255443A patent/JP2976214B2/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6184008B1 (en) | 1997-03-03 | 2001-02-06 | Sumitomo Chemical Company Ltd. | Production of optically active sphingoid compound |
| EP1146037A1 (en) * | 1999-01-18 | 2001-10-17 | Nippon Soda Co., Ltd. | Process for the preparation of optically active amino alcohols |
| EP1146037A4 (en) * | 1999-01-18 | 2002-07-17 | Nippon Soda Co | Process for the preparation of optically active amino alcohols |
| JP4746749B2 (en) * | 1999-01-18 | 2011-08-10 | 日本曹達株式会社 | Process for producing optically active amino alcohols |
| WO2002004401A1 (en) * | 2000-07-10 | 2002-01-17 | Nippon Soda Co., Ltd. | PROCESS FOR THE PREPARATION OF β-AMINO ALCOHOLS IN SYN CONFIGURATION |
| JP2002020359A (en) * | 2000-07-10 | 2002-01-23 | Nippon Soda Co Ltd | METHOD FOR PRODUCING OPTICALLY ACTIVE beta-AMINOALCOHOL HAVING ANTI-CONFIGURATION |
| JP5042438B2 (en) * | 2000-07-10 | 2012-10-03 | 日本曹達株式会社 | Process for producing β-aminoalcohols having a syn configuration |
| JP2012116853A (en) * | 2000-07-10 | 2012-06-21 | Nippon Soda Co Ltd | METHOD FOR PRODUCING β-AMINO ALCOHOL HAVING SYN STERIC ARRANGEMENT |
| JP4658293B2 (en) * | 2000-07-10 | 2011-03-23 | 日本曹達株式会社 | Process for producing optically active β-amino alcohols having anti-configuration |
| JP2005536556A (en) * | 2002-08-27 | 2005-12-02 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Enantioselective hydrogenation of aminoalcohols. |
| WO2004076391A1 (en) * | 2003-02-28 | 2004-09-10 | Japan Science And Technology Agency | Process for producing optically active compound |
| US7619003B2 (en) | 2003-02-28 | 2009-11-17 | Japan Science And Technology Agency | Process for producing optically active compound |
| US7799941B2 (en) | 2003-07-10 | 2010-09-21 | Nissan Chemical Industries, Ltd. | Process for producing optically active β-hydroxy-α-aminocarboxylic acid derivative |
| WO2005005371A1 (en) | 2003-07-10 | 2005-01-20 | Nissan Chemical Industries, Ltd. | PROCESS FOR PRODUCTION OF OPTICALLY ACTIVE β-HYDROXY-α-AMINOCARBOXYLIC ACID DERIVATIVES |
| US7781609B2 (en) | 2005-01-12 | 2010-08-24 | Nissan Chemical Industries, Ltd. | Process for producing optically active β-hydroxy-α-aminocarboxylic acid derivative |
| WO2006075651A1 (en) | 2005-01-12 | 2006-07-20 | Nissan Chemical Industries, Ltd. | PROCESS FOR PRODUCING OPTICALLY ACTIVE β-HYDROXY-α-AMINOCARBOXYLIC ACID DERIVATIVE |
| WO2008041571A1 (en) * | 2006-09-26 | 2008-04-10 | Kaneka Corporation | Process for producing optically active beta-hydroxy-alpha-aminocarboxylic acid ester |
| US8207370B2 (en) | 2006-09-26 | 2012-06-26 | Kaneka Corporation | Process for producing optically active beta-hydroxy-alpha-aminocarboxylic acid ester |
| JP5274256B2 (en) * | 2006-09-26 | 2013-08-28 | 株式会社カネカ | Process for producing optically active β-hydroxy-α-aminocarboxylic acid ester |
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| JP2976214B2 (en) | 1999-11-10 |
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