JP3826425B2 - Method for producing optically active 2-nitro-1,3-diol derivative - Google Patents
Method for producing optically active 2-nitro-1,3-diol derivative Download PDFInfo
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- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/14—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms
- C07C205/15—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups and hydroxy groups bound to acyclic carbon atoms of a saturated carbon skeleton
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Description
【０００１】
【発明の属する技術分野】
本発明は、２−ニトロ−１，３−ジオール誘導体および該誘導体の製造法に関する。さらに詳しくは、医薬品としてプロテインキナーゼＣの阻害剤等に有用なジヒドロスフィンゴシンに代表される光学活性アミノジオールを効率良く得るのに適した中間体である２−ニトロ−１，３−ジオール誘導体および該誘導体の製造法に関する。
【０００２】
【背景技術】
光学活性アミノジオールは、通常アルドール反応によって得ることができるが、生成物としてラセミ体が合成されてしまうため、生成物から目的物をラセミ分割しなければならず、非常に手間がかかり、収率も低いという欠点を有している。この方法の例としては、Ｊ．ＣＨＥＭ．ＳＯＣ．ＰＥＲＫＩＮ ＴＲＡＮＳ．Ｉ（１９８６）１６８７−１９８６に、ニトロエタノールとアルデヒドとをニトロアルドール反応させると、ラセミ体であるジアステレオ混合物が得られてしまうので、該混合物をアセトナイドした後、ラセミ分割して目的の光学活性化合物を得るという方法が開示されている。
【０００３】
また、光学活性な原料をもとにして、光学活性アミノジオールを合成する方法がある。この方法の例として、Ａｇｒｉｃ．Ｂｉｏｌ．Ｃｈｅｍ．，５１（７），（１９８７），１９７３−１９８２に、２−エン−１−オール化合物をシャープレス酸化して得た光学活性エポキシを光学活性な原料として用い、該エポキシに対し、アミンを反応させるという方法が開示されている。しかし、この方法では、目的の光学活性アミノジオールとはアミノ基が異なる位置にある化合物も製造されるため、分割操作を行わなければならず、収率も低いものとなる。
【０００４】
【発明が解決しようとする課題】
本発明者らは、上記問題点を解決するべく鋭意検討を行った結果、２−ニトロ−１，３−ジオール誘導体を中間体として用いると、目的とする光学活性２−アミノ−１，３−ジオール誘導体が効率的に製造できることを見い出し、本発明を完成した。
本発明は、２−ニトロ−１，３−ジオール誘導体を提供することであり、不斉源を持たないアルデヒドおよびニトロエタノールから、１工程で目的の光学活性２−ニトロ−１，３−ジオール誘導体を得るための製造法を提供することである。
【０００５】
【課題を解決する為の手段】
本発明は下記の（１）ないし（４）の構成を有している。
【０００６】
（１） 式［５］で表されるアルデヒドとニトロエタノールとを、式［６］もしくは式［７］で表される光学活性１，１’−ビ−ナフトール類、希土類金属およびアルカリ金属から調製された塩基性触媒存在下で反応させることを特徴とする式［１］で表される光学活性２−ニトロ−１，３−ジオール誘導体の製造方法。
【０００７】
式中、Ｒは炭素数１２〜１８のアルキル基もしくはアルケニル基を表す。
Ｒ’は、水素、アルキル基、フェニル基、ハロゲン原子、トリアルキルシリルエチニル基、シアノ基を表し、お互いに同一でも異なっていてもかまわない。
【００１２】
（２） 式［２］で表される（２Ｓ，３Ｓ）−２−ニトロ−１，３−ジオール誘導体であることを特徴とする前記第（１）項記載の光学活性２−ニトロ−１，３−ジオール誘導体の製造方法。
【００１３】
式中、Ｒは炭素数１２〜１８のアルキル基もしくはアルケニル基を表す。
【００１５】
（３） 式［３］で表される（２Ｒ，３Ｒ）−２−ニトロ−１，３−ジオール誘導体であることを特徴とする前記第（１）項記載の光学活性２−ニトロ−１，３−ジオール誘導体の製造方法。
【００１６】
式中、Ｒは炭素数１２〜１８のアルキル基もしくはアルケニル基を表す。
【００１８】
（４） 式［４］で表されるスレオ（２Ｓ，３Ｓ）−２−ニトロ−１，３−オクタデカンジオールであることを特徴とする前記第（１）項もしくは前記第（２）項記載の光学活性２−ニトロ−１，３−ジオール誘導体の製造方法。
【００１９】
本発明の２−ニトロ−１，３−ジオール誘導体の製造方法は、次の反応である。
【００２１】
上記の反応式は、塩基性触媒の存在下で、アルデヒドとニトロエタノールを立体選択的に付加反応させ、２位および３位の立体配置を制御しながら光学活性な２−ニトロ−１，３−ジオール誘導体を生成する反応である第１工程と、さらに得られた該誘導体の立体配置を維持したままニトロ基をアミノ基へと還元し、２−アミノ−１，３−ジオール誘導体を生成する反応である第２工程を示したものである。
本発明の２−ニトロ−１，３−ジオール誘導体の製造法は、第１工程の製法である。
【００２３】
第１工程において用いられる塩基性触媒は、式［８］
Ｍ（ＯＲ”）3
（式中、Ｍは、ランタン、プラセオジウム、ネオジウム、ユーロピウム、ガドリウム、ジスプロシウム、エルビウム、イッテルビウム、イットリウム等の希土類金属を表し、Ｒ”は炭素数１〜８の置換アルキル基を表す。）
によって表される化合物と式［６］
【００２４】
もしくは式［７］
【００２６】
によって表される光学活性１，１’−ビ−２−ナフトール（以下、ビナフトールと言う。
）とアルカリ金属化合物によって調製することができる。
また、ビナフトールは、ビナフトールの５，６，７，８位および５’，６’，７’，８’位に、水素原子、（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−ブチル基等）のアルキル基、フェニル基、（クロロ、ブロモ等）のハロゲン原子、（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−ブチル基等のアルキル基を有する）トリアルキルシリルエチニル基、トリフェニルシリルエチニル基、シアノ基等の置換基が付加したものを挙げることができ、該置換基および該置換基の付加位置は５，６，７，８位および５’，６’，７’，８’位であれば特に限定はないが、６，６’位に前記置換基（二つの置換基は同一でも異なっていてもかまわない。）を有するビナフトールが好ましい。
【００２８】
アルカリ金属化合物としては、（メチルリチウム、ｔ−ブチルリチウム等の）アルキルアルカリ金属類、（水酸化リチウム、水酸化ナトリウムおよび水酸化カリウム等の）水酸化アルカリを挙げることができるが、ｎ−ブチルリチウムや水酸化リチウムが好ましい。
【００２９】
第１工程において用いられる塩基性触媒は、原料としてのアルデヒドに対し、０．００５〜０．１モル当量程度で充分反応を完結させることができるが、穏和な条件で短時間に反応を完結させるために、０．１モル当量を越える量使用しても差し支えない。
【００３０】
第１工程において用いられるアルデヒドは、式［５］
【００３１】
（式中、Ｒは炭素数１２〜１８のアルキル基もしくはアルケニル基を表す。）
で表されるものであるが、ジヒドロスフィンゴシンの製造原料となるＣＨ3（ＣＨ2）14ＣＨＯが好ましい。
【００３３】
第１工程において用いられるニトロエタノールは、アルデヒドに対して、１〜１０モル当量使用することにより、収率の高い反応が進行するが、１０モル当量を越えるニトロエタノールを使用しても副反応等の悪影響は少ない。
【００３４】
第１工程において用いられる反応溶媒としては、反応条件下において原料であるアルデヒドやニトロエタノールと反応しないものであれば特に限定はない。
具体的には、水、（メタノール、エタノール、イソプロパノールおよびエチレングリコール等の）アルコール系溶媒、（ジエチルエーテル、テトラヒドロフラン（以下、ＴＨＦという。）、１，４−ジオキサン等の）エーテル系溶媒、（塩化メチレン、クロロホルム、１，１，１−トリクロロエタンおよびモノクロロベンゼン等の）ハロゲン系溶媒、（ベンゼン、トルエン、ｎ−ヘキサン及びｎ−ヘプタン等の）炭化水素系溶媒、（酢酸エチル、酢酸メチル等の）脂肪酸エステルやジメチルスルホキシド、Ｎ，Ｎ−ジメチルホルムアミド等の極性溶媒を挙げることができる。これらの溶媒は、単独もしくは２種類以上混合物として使用して差し支えない。
また、本発明の製造法である第１工程は、−１００℃〜室温の間で反応を行うと良い。
【００３５】
本発明の２−アミノ−１，３−ジオール誘導体の製造方法である第２工程は、本発明の２−ニトロ−１，３−ジオール誘導体を中間体として、最終製品である２−アミノ−１，３−ジオール誘導体を得るための工程であり、Ｐｔ−ＣやＰｄ−Ｃ等の一般的な水添触媒を用いた接触水添反応やリチウムボロハイドライドなどを用いた還元反応である。これらの反応により、容易にニトロ基をアミノ基に変換することができる。その時、温度を室温以下に保つと、立体配置をかえることなく目的の化合物に還元することができる。
【００３６】
【実施例】
以下、本発明の２−ニトロ−１，３−ジオール誘導体の製造法を参考例および実施例を用いて詳細に説明する。なお、本実施例は本発明をなんら限定するものではない。
【００３７】
（参考例１）塩基性触媒の調製法
（Ｒ）−６，６’−ビス（トリエチルシリルエチニル）−１，１’−ビ−２−ナフトール５８．０ｍｇ（０．１０３ｍｍｏｌ）を５０℃で２時間真空乾燥させた後、アルゴン気流下で、該ビナフトールをＴＨＦ８８０マイクロリットルに溶解した。次に、該溶解液を０℃に保ちながら、該溶解液にＬａ（Ｏ−ｉ−Ｐｒ）３１０．９ｍｇ（０．０３４４ｍｍｏｌ）の０．２ＮのＴＨＦ溶液を１７２マイクロリットル滴下した。その後、該溶解液を室温にまで昇温させ、室温において３０分間の撹拌を行った後、再び０℃にまで冷やし、０℃においてｎ−ＢｕＬｉ（０．１０３ｍｍｏｌ）の１．７２Ｎのヘキサン溶液を６０マイクロリットル滴下する。その後、室温に戻し１晩撹拌を行った後、水分（０．０３５ｍｍｏｌ）を含むＴＨＦ溶液を３５マイクロリットル加えることにより、０．０３Ｎの塩基性触媒のＴＨＦ溶液（触媒１）を調製した。
【００３８】
（実施例１）
（２Ｓ，３Ｓ）−２−ニトロ−１，３−オクタデカンジオールの合成
参考例１で調整した４００マイクロリットル（０．００１２ｍｍｏｌ）の触媒１と７０マイクロリットルのＴＨＦを、−４０℃で３０分間攪拌した後、同温度でニトロエタノールを２６マイクロリットル（０．３６ｍｍｏｌ）加えて１時間攪拌し、さらにヘキサデカナール２８．９ｍｇ（０．１２ｍｍｏｌ）を含む３００マイクロリットルのＴＨＦ溶液を添加し、１６３時間反応させ、１Ｎの塩酸を加えて反応を終了させた後、クロロホルム３０ミリリットルで抽出操作を行った。得られた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させ、溶媒を減圧留去した後、フラッシュクロマトグラフィ（ＳｉＯ２、アセトン／ヘキサン＝１／５）で精製し、白色結晶の（２Ｓ，３Ｓ）−２−ニトロ−１，３−オクタデカンジオール（化合物Ａ）を得た。化合物Ａの収率は７８モル％であった。ジアステレオ選択性は1ＨＮＭＲで確認した。
白色結晶、融点89.5-90.5℃（98%ee、エーテル−ヘキサン）、IR(KBr)3356,1561,1396cm-1
1ＨＮＭＲ（ＣＤＣｌ３）δ0.89(t,J=6.8Hz,3H),1.23-1.62(m,28H),2.26(br-dd,J=6.0,6.5Hz,1H)、2.34(d,J=7.4Hz,1H),4.03-4.25(m,3H),4.59(ddd,J=3.8,5.1,6.4Hz,1H)、13ＣＮＭＲ（ＣＤＣｌ３）δ14.11,22.70,25.29,29.27,29.36,29.44,29.53,29.60,29.65,31.92,33.62,61.91,70.42,92.06、ＦＡＢＭＳ（glycearol）m/z 332(M+1),285,41(base peak)元素分析Ｃ18Ｈ37ＮＯ4 理論値C,65.22、H,11.25、N,4.23、実測値C,65.20、H,11.37、N,4.03、［α］D 26 -4.62゜(c0.93,CHCl3)(98%ee)
光学過剰量はＨＰＬＣ（ダイセル化学工業製CHIRALPAK AD,i-PrOH/hEXANE=5/95)で決定した。
【００３９】
（２Ｓ，３Ｓ）−２−アミノ−１，３オクタデカンジオール（化合物Ｂ）の合成
水素気流下で１０％のＰｄ−Ｃ（１０ｍｇ）をエタノール０．４ミリリットルに分散させた後、該分散液に２９ｍｇ（0.087mmol,96%ee)の化合物Ａを含有するエタノール溶液を１．１ミリリットル添加し、室温で２５時間反応させた。反応終了後、反応溶液をセライトろ過し、ろ液を減圧操作により濃縮した。濃縮物をフラッシュクロマトグラフィ（ＳｉＯ２、CHCl3/6.6%NH3MeOH=100/17）で精製して、１８．７ｍｇの化合物Ｂを得た。化合物Ｂの収率は７１モル％であった。
次に、化合物Ｂを酢酸エチルで再結晶し、旋光度を測定した。［α］D 23−１１．０５゜（ｃ０．２９，ＣＨＣｌ３／ＭｅＯＨ＝１０／１、97%ee）lit.［α］D 28−１２．０゜（Stoffel,W. Bister,K. Hoppe-Seyler's Z. Physiol.Chem.1973,354,169-181)
絶対配置を確認するために、１３．７ｍｇ（０．０４５４ｍｍｏｌ）の化合物Ｂと４−メチルアミノピリジンとピリジンを含有した塩化メチレン１ミリリットル溶液を攪拌しながら、ベンゾイルクロライド５２マイクロリットル（０．４５４ｍｍｏｌ）を添加した。室温で１８時間攪拌して反応させ、メタノールを加えて反応を終了させた後、ジエチルエーテルで抽出作業を行なって得た有機層を１Ｎ塩酸と飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥させた。その溶媒を減圧留去後、フラッシュクロマトグラフィ（ＳｉＯ2、酢酸エチル／ヘキサン＝１／１０）で精製して２−アミノ−１，３−オクタデカンジオール Ｎ，Ｏ，Ｏ−トリベンゾエートを２６ｍｇ（収率９４モル％）得た。この物の1ＨＮＭＲと市販のＤＬ−スレオ−２−アミノ−１，３−オクタデカンジオール Ｎ，Ｏ，Ｏ−トリベンゾエート（Ｓｉｇｍａ社製）を比較した。
透明粘性オイル、IR(neat)3354,3063,2924,2853,1722,1644,1109,1070,1027cm-1、1ＨＮＭＲ（ＣＤＣｌ3）δ0.88(t,J=6.2Hz,3H),1.17-1.52(m,26H),1.78-1.96(m,2H),4.49(dd,J=5.0,11.4Hz,1H),4.57(dd,J=6.0,11.4Hz,1H),4.89(dddd,J=5.0,5.0,6.0,9.4Hz,1H), 5.55(dt,J=5.0,7.1Hz,1H),6.65(br-d,J=9.4Hz,1H),7.34-7.61(m,9H),7.70-7.77(m,2H),7.95-8.06(m,4H)、13ＣＮＭＲ（ＣＤＣｌ３）δ14.09,22.66,25.21,29.27,29.33,29.49,29.49,29.56,29.63,31.56,31.90,51.38,64.40,73.57,126.88,128.39,128.50,128.64,129.65,131.64,133.15,133.30,134.12,166.41,166.50,167.44、ＭＳ m/z 613(M+),146(base peak),
105
【００４０】
【発明の効果】
医薬品の中間体として有用な２−アミノ−１，３−ジオール誘導体を合成するのに、大変有用な２−ニトロ−１，３−ジオール誘導体と該誘導体を容易にかつ収率良く得ることのできる製造法を開発することができた。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a 2-nitro-1,3-diol derivative and a method for producing the derivative. More specifically, a 2-nitro-1,3-diol derivative which is an intermediate suitable for efficiently obtaining an optically active aminodiol typified by dihydrosphingosine useful as an inhibitor of protein kinase C as a pharmaceutical, and the like The present invention relates to a method for producing a derivative.
[0002]
[Background]
Optically active amino diol can usually be obtained by aldol reaction, but since a racemate is synthesized as a product, the target product must be racemically resolved from the product, which is very laborious and yields. Has the disadvantage of being low. Examples of this method include J. CHEM. SOC. PERKIN TRANS. When I (1986) 1687-1986 is reacted with nitroethanol and an aldehyde with a nitroaldol reaction, a racemic diastereomeric mixture is obtained. After the mixture is acetonated, the desired optical activity is obtained by racemic resolution. A method of obtaining a compound is disclosed.
[0003]
There is also a method for synthesizing an optically active aminodiol based on an optically active raw material. As an example of this method, Agric. Biol. Chem. 51 (7), (1987), 1973-1982, an optically active epoxy obtained by sharp pressing oxidation of a 2-en-1-ol compound is used as an optically active raw material, and an amine is reacted with the epoxy. A method of making it happen is disclosed. However, in this method, a compound having an amino group at a position different from that of the target optically active aminodiol is also produced, so that a division operation must be performed and the yield is low.
[0004]
[Problems to be solved by the invention]
As a result of intensive studies to solve the above problems, the present inventors have found that when a 2-nitro-1,3-diol derivative is used as an intermediate, the objective optically active 2-amino-1,3- The present inventors have found that a diol derivative can be produced efficiently and completed the present invention.
The present invention provides a 2-nitro-1,3-diol derivative, which is a target optically active 2-nitro-1,3-diol derivative in one step from aldehyde and nitroethanol having no asymmetric source. It is to provide a manufacturing method for obtaining the above.
[0005]
[Means for solving the problems]
The present invention has the following configurations (1) to (4) .
[0006]
(1) An aldehyde represented by formula [5] and nitroethanol are prepared from optically active 1,1′-binaphthols represented by formula [6] or formula [7], rare earth metals and alkali metals. A method for producing an optically active 2-nitro-1,3-diol derivative represented by the formula [1] , wherein the reaction is carried out in the presence of a prepared basic catalyst .
[0007]
In the formula, R represents an alkyl group or alkenyl group having 12 to 18 carbon atoms.
R ′ represents hydrogen, an alkyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group, or a cyano group, and may be the same or different from each other.
[0012]
(2) The optically active 2-nitro-1, as described in (1) above, which is a (2S, 3S) -2-nitro-1,3-diol derivative represented by the formula [2] A method for producing a 3-diol derivative.
[0013]
In the formula, R represents an alkyl group or alkenyl group having 12 to 18 carbon atoms.
[0015]
(3) The optically active 2-nitro-1, as described in (1) above, which is a (2R, 3R) -2-nitro-1,3-diol derivative represented by the formula [3] A method for producing a 3-diol derivative.
[0016]
In the formula, R represents an alkyl group or alkenyl group having 12 to 18 carbon atoms.
[0018]
(4) The threo (2S, 3S) -2-nitro-1,3-octadecanediol represented by the formula [4] , the item (1) or the item (2) A method for producing an optically active 2-nitro-1,3-diol derivative.
[0019]
Method for producing a 2-nitro-1,3-diol derivatives of the present invention is the following reaction.
[0021]
In the above reaction formula, aldehyde and nitroethanol are stereoselectively added in the presence of a basic catalyst, and the optically active 2-nitro-1,3-3- is controlled while controlling the configuration at the 2- and 3-positions. The first step, which is a reaction for producing a diol derivative, and a reaction for producing a 2-amino-1,3-diol derivative by reducing the nitro group to an amino group while maintaining the configuration of the obtained derivative. The 2nd process which is is shown.
The production method of the 2-nitro-1,3-diol derivative of the present invention is the production method of the first step.
[0023]
The basic catalyst used in the first step is represented by the formula [8].
M (OR ") 3
(In the formula, M represents a rare earth metal such as lanthanum, praseodymium, neodymium, europium, gadolinium, dysprosium, erbium, ytterbium, yttrium, and R ″ represents a substituted alkyl group having 1 to 8 carbon atoms.)
And a compound represented by the formula [6]
[0024]
Or the formula [7]
[0026]
The optically active 1,1′-bi-2-naphthol represented by (hereinafter referred to as binaphthol).
) And an alkali metal compound.
Binaphthol has hydrogen atoms (methyl group, ethyl group, propyl group, isopropyl group, butyl group, s) at the 5, 6, 7, 8 position and 5 ′, 6 ′, 7 ′, 8 ′ position of binaphthol. -Butyl group, t-butyl group, etc.) alkyl group, phenyl group, (chloro, bromo etc.) halogen atom, (methyl group, ethyl group, propyl group, isopropyl group, butyl group, s-butyl group, t- And those having a substituent such as a trialkylsilylethynyl group, a triphenylsilylethynyl group, or a cyano group (having an alkyl group such as a butyl group) added. There is no particular limitation as long as it is in the 6,7,8 position and 5 ′, 6 ′, 7 ′, 8 ′ position, but the substituents in the 6,6 ′ position (the two substituents may be the same or different). Is not preferred.) .
[0028]
Examples of the alkali metal compound include alkyl alkali metals (such as methyl lithium and t-butyl lithium) and alkali hydroxides (such as lithium hydroxide, sodium hydroxide and potassium hydroxide), but n-butyl. Lithium and lithium hydroxide are preferred.
[0029]
The basic catalyst used in the first step can sufficiently complete the reaction at about 0.005 to 0.1 molar equivalent to the aldehyde as a raw material, but completes the reaction in a short time under mild conditions. Therefore, an amount exceeding 0.1 molar equivalent may be used.
[0030]
The aldehyde used in the first step is represented by the formula [5].
[0031]
(In the formula, R represents an alkyl or alkenyl group having 12 to 18 carbon atoms.)
However, CH 3 (CH 2 ) 14 CHO, which is a raw material for producing dihydrosphingosine, is preferable.
[0033]
The nitroethanol used in the first step proceeds at a high yield by using 1 to 10 molar equivalents relative to the aldehyde, but side reactions and the like even if nitroethanol exceeding 10 molar equivalents is used. There are few adverse effects.
[0034]
The reaction solvent used in the first step is not particularly limited as long as it does not react with the raw material aldehyde or nitroethanol under the reaction conditions.
Specifically, water, alcohol solvents (such as methanol, ethanol, isopropanol and ethylene glycol), ether solvents (such as diethyl ether, tetrahydrofuran (hereinafter referred to as THF), 1,4-dioxane), Halogenated solvents (such as methylene, chloroform, 1,1,1-trichloroethane and monochlorobenzene), hydrocarbon solvents (such as benzene, toluene, n-hexane and n-heptane), (such as ethyl acetate, methyl acetate) Examples include polar solvents such as fatty acid esters, dimethyl sulfoxide, and N, N-dimethylformamide. These solvents may be used alone or as a mixture of two or more.
Moreover, the 1st process which is a manufacturing method of this invention is good to react between -100 degreeC-room temperature.
[0035]
2-amino-1 of the present invention, the second step is a method for producing 3-diol derivative, the 2-nitro-1,3-diol derivatives of the present invention as an intermediate, is the final product 2-amino-1 , 3-diol derivatives, a catalytic hydrogenation reaction using a general hydrogenation catalyst such as Pt—C or Pd—C, or a reduction reaction using lithium borohydride. By these reactions, a nitro group can be easily converted into an amino group. At that time, if the temperature is kept at room temperature or lower, the compound can be reduced to the target compound without changing the configuration.
[0036]
【Example】
Hereafter, the manufacturing method of the 2-nitro- 1, 3-diol derivative of this invention is demonstrated in detail using a reference example and an Example. In addition, a present Example does not limit this invention at all.
[0037]
Reference Example 1 Preparation Method of Basic Catalyst 2R of 58.0 mg (0.103 mmol) of (R) -6,6′-bis (triethylsilylethynyl) -1,1′-bi-2-naphthol at 50 ° C. After being vacuum-dried for an hour, the binaphthol was dissolved in 880 microliters of THF under an argon stream. Next, 172 microliters of a solution of La (Oi-Pr) 310.9 mg (0.0344 mmol) in 0.2N THF was added dropwise to the solution while keeping the solution at 0 ° C. Thereafter, the solution was heated to room temperature, stirred for 30 minutes at room temperature, then cooled to 0 ° C. again, and a 1.72N hexane solution of n-BuLi (0.103 mmol) was added at 0 ° C. Add 60 microliters dropwise. After returning to room temperature and stirring overnight, 35 microliters of a THF solution containing water (0.035 mmol) was added to prepare a THF solution (catalyst 1) of 0.03N basic catalyst.
[0038]
Example 1
Synthesis of (2S, 3S) -2-nitro-1,3-octadecanediol 400 microliters (0.0012 mmol) of catalyst 1 prepared in Reference Example 1 and 70 microliters of THF were stirred at −40 ° C. for 30 minutes. Then, 26 microliters (0.36 mmol) of nitroethanol was added at the same temperature and stirred for 1 hour, and 300 microliters of THF solution containing 28.9 mg (0.12 mmol) of hexadecanal was further added, and 163 hours. After the reaction, 1N hydrochloric acid was added to terminate the reaction, extraction was performed with 30 ml of chloroform. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by flash chromatography (SiO 2, acetone / hexane = 1/5) to give white crystalline ( 2S, 3S) -2-nitro-1,3-octadecanediol (Compound A) was obtained. The yield of Compound A was 78 mol%. Diastereoselectivity was confirmed by 1 HNMR.
White crystals, melting point 89.5-90.5 ° C (98% ee, ether-hexane), IR (KBr) 3356,1561,1396cm -1
1 HNMR (CDCl 3) δ 0.89 (t, J = 6.8 Hz, 3H), 1.23-1.62 (m, 28H), 2.26 (br-dd, J = 6.0, 6.5 Hz, 1H), 2.34 (d, J = 7.4 Hz, 1H), 4.03-4.25 (m, 3H), 4.59 (ddd, J = 3.8, 5.1, 6.4 Hz, 1H), 13 C NMR (CDCl3) δ 14.11, 22.70, 25.29, 29.27, 29.36, 29.44, 29.53, 29.60, 29.65, 31.92, 33.62, 61.91, 70.42, 92.06, FABMS (glycearol) m / z 332 (M + 1), 285, 41 (base peak) elemental analysis C 18 H 37 NO 4 Theoretical value C, 65.22 , H, 11.25, N, 4.23, measured C, 65.20, H, 11.37, N, 4.03, [α] D 26 -4.62 ° (c0.93, CHCl3) (98% ee)
The optical excess amount was determined by HPLC (CHIRALPAK AD, i-PrOH / hEXANE = 5/95 manufactured by Daicel Chemical Industries).
[0039]
Synthesis of (2S, 3S) -2-amino-1,3 octadecanediol (Compound B) 10% Pd—C (10 mg) was dispersed in 0.4 ml of ethanol under a hydrogen stream, 1.1 ml of an ethanol solution containing 29 mg (0.087 mmol, 96% ee) of Compound A was added and reacted at room temperature for 25 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The concentrate was purified by flash chromatography (SiO2, CHCl3 / 6.6% NH3MeOH = 100/17) to give 18.7 mg of compound B. The yield of compound B was 71 mol%.
Next, Compound B was recrystallized with ethyl acetate, and the optical rotation was measured. [Α] D 23 -11.05 ° (c0.29, CHCl 3 /MeOH=10/1,97%ee)lit.[α] D 28 -12.0 ° (Stoffel, W. Bister, K . Hoppe -Seyler's Z. Physiol.Chem. 1973, 354, 169-181)
To confirm the absolute configuration, 52 microliters (0.454 mmol) of benzoyl chloride was stirred while stirring a 1 ml solution of methylene chloride containing 13.7 mg (0.0454 mmol) of Compound B, 4-methylaminopyridine and pyridine. Was added. The reaction was stirred for 18 hours at room temperature, and the reaction was completed by adding methanol, followed by extraction with diethyl ether. The organic layer obtained was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. I let you. The solvent was distilled off under reduced pressure and purified by flash chromatography (SiO 2 , ethyl acetate / hexane = 1/10) to obtain 26 mg of 2-amino-1,3-octadecanediol N, O, O-tribenzoate (yield) 94 mol%). 1 HNMR of this product was compared with commercially available DL-threo-2-amino-1,3-octadecanediol N, O, O-tribenzoate (manufactured by Sigma).
Transparent viscous oil, IR (neat) 3354,3063,2924,2853,1722,1644,1109,1070,1027 cm −1 , 1 HNMR (CDCl 3 ) δ0.88 (t, J = 6.2Hz, 3H), 1.17- 1.52 (m, 26H), 1.78-1.96 (m, 2H), 4.49 (dd, J = 5.0,11.4Hz, 1H), 4.57 (dd, J = 6.0,11.4Hz, 1H), 4.89 (dddd, J = 5.0,5.0,6.0,9.4Hz, 1H), 5.55 (dt, J = 5.0,7.1Hz, 1H), 6.65 (br-d, J = 9.4Hz, 1H), 7.34-7.61 (m, 9H), 7.70 -7.77 (m, 2H), 7.95-8.06 (m, 4H), 13 C NMR (CDCl3) δ 14.09, 22.66, 25.21, 29.27, 29.33, 29.49, 29.49, 29.56, 29.63, 31.56, 31.90, 51.38, 64.40, 73.57,126.88,128.39,128.50,128.64,129.65,131.64,133.15,133.30,134.12,166.41,166.50,167.44, MS m / z 613 (M + ), 146 (base peak),
105
[0040]
【The invention's effect】
A very useful 2-nitro-1,3-diol derivative and the derivative can be easily obtained in a high yield for synthesizing a 2-amino-1,3-diol derivative useful as an intermediate of a pharmaceutical product. A manufacturing method could be developed.
Claims (4)
Ｒ’は、水素、アルキル基、フェニル基、ハロゲン原子、トリアルキルシリルエチニル基、シアノ基を表し、お互いに同一でも異なっていてもかまわない。 A base prepared from an aldehyde represented by the formula [5] and nitroethanol from an optically active 1,1′-binaphthol represented by the formula [6] or the formula [7], a rare earth metal and an alkali metal A method for producing an optically active 2-nitro-1,3-diol derivative represented by the formula [1], wherein the reaction is carried out in the presence of a neutral catalyst .
R ′ represents hydrogen, an alkyl group, a phenyl group, a halogen atom, a trialkylsilylethynyl group, or a cyano group, and may be the same or different from each other.
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