JPH0816098B2 - 4-Cyclohexylmethyl-2-azetidinone derivative and process for producing the same - Google Patents

4-Cyclohexylmethyl-2-azetidinone derivative and process for producing the same

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Publication number
JPH0816098B2
JPH0816098B2 JP63275838A JP27583888A JPH0816098B2 JP H0816098 B2 JPH0816098 B2 JP H0816098B2 JP 63275838 A JP63275838 A JP 63275838A JP 27583888 A JP27583888 A JP 27583888A JP H0816098 B2 JPH0816098 B2 JP H0816098B2
Authority
JP
Japan
Prior art keywords
solvent
added
cyclohexylmethyl
reduced pressure
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.)
Expired - Lifetime
Application number
JP63275838A
Other languages
Japanese (ja)
Other versions
JPH02121963A (en
Inventor
孜郎 寺島
芳雄 伊藤
冬彦 松田
邦和 酒井
哲聖 上條
弘 原田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kissei Pharmaceutical Co Ltd
Sagami Chemical Research Institute (Sagami CRI)
Original Assignee
Kissei Pharmaceutical Co Ltd
Sagami Chemical Research Institute (Sagami CRI)
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Filing date
Publication date
Application filed by Kissei Pharmaceutical Co Ltd, Sagami Chemical Research Institute (Sagami CRI) filed Critical Kissei Pharmaceutical Co Ltd
Priority to JP63275838A priority Critical patent/JPH0816098B2/en
Publication of JPH02121963A publication Critical patent/JPH02121963A/en
Publication of JPH0816098B2 publication Critical patent/JPH0816098B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

【発明の詳細な説明】 〔産業上の利用分野〕 本発明は、一般式 （式中、R1はアラルキル基またはアシル基であり、R2は
置換あるいは無置換のアラルキル基、または置換あるい
は無置換のアリール基を表す。）で表される新規な４−
シクロヘキシルメチル−２−アゼチジノン誘導体および
その製造法に関する。前記一般式（Ｉ）で表される４−
シクロヘキシルメチル−２−アゼチジノン誘導体は、酸
処理によるラクタム環の開環とそれに続くアミノ基およ
び水酸基の保護基の除去により、式 （式中、R3は炭素数１〜７の直鎖若しくは分枝アルキル
基、アラルキル基またはアリール基を表す。）で表され
るラセミ体あるいは光学活性なβ−アミノ酸誘導体へ誘
導できる（下記参考例参照）。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] (Wherein R 1 represents an aralkyl group or an acyl group, and R 2 represents a substituted or unsubstituted aralkyl group or a substituted or unsubstituted aryl group).
The present invention relates to a cyclohexylmethyl-2-azetidinone derivative and a method for producing the same. 4-represented by the general formula (I)
The cyclohexylmethyl-2-azetidinone derivative can be prepared by subjecting a lactam ring to ring-opening by acid treatment and subsequent removal of amino and hydroxyl protecting groups. (In the formula, R 3 represents a linear or branched alkyl group having 1 to 7 carbon atoms, an aralkyl group or an aryl group.), Which can be derived to a racemic body or an optically active β-amino acid derivative (see the following reference). See example).

一般式（IV）で表されるβ−アミノ酸エステルは、ヒ
トレニン阻害活性により高血圧症治療剤として有用な、
一般式 （式中、（Ｒ）を記した炭素原子は（Ｒ）−配置であ
り、（Ｓ）を記した炭素原子は（Ｓ）−配置である。Ｙ
は酸素原子またはアミノ基、R4は炭素数１〜７の直鎖状
または分枝アルキル基を表す。）で表されるアミノ酸誘
導体の製造原料として有用である（特開昭62-234071号
報、日本薬学会第108年会講演要旨集39ページ（1988
年）参照）。The β-amino acid ester represented by the general formula (IV) is useful as a therapeutic agent for hypertension due to its human renin inhibitory activity,
General formula (In the formula, the carbon atom marked with (R) has the (R) -configuration, and the carbon atom marked with (S) has the (S) -configuration.
Represents an oxygen atom or an amino group, and R 4 represents a linear or branched alkyl group having 1 to 7 carbon atoms. ) Is useful as a raw material for producing an amino acid derivative (Japanese Patent Application Laid-Open No. 62-234071 and Japanese Society of Pharmaceutical Sciences 108th Annual Conference, 39 pages (1988)).
Year))).

〔従来の技術〕[Conventional technology]

前記一般式（Ｖ）で表されるペプチド様化合物は４個
の不斉炭素を有し、それぞれの炭素の立体配置はその活
性に影響を与えることが知られている。特にＣ末端側の
β−アミノ酸部分の２個の不斉炭素は、（2R,3S）−配
置である方が好ましいことが確認されている。しかしな
がら、これらの不斉炭素を立体選択的に構築することは
極めて難しい問題であった。特に、これらの連続する２
つの不斉炭素の相対配置を制御することは困難であっ
た。It is known that the peptidomimetic compound represented by the general formula (V) has four asymmetric carbon atoms, and the configuration of each carbon atom affects its activity. In particular, it has been confirmed that the two asymmetric carbons in the β-amino acid moiety on the C-terminal side are preferably in the (2R, 3S) -configuration. However, it has been an extremely difficult problem to stereoselectively construct these asymmetric carbons. In particular, these two consecutive
It was difficult to control the relative configuration of the two asymmetric carbons.

例えば、Ｌ−フェニルアラニンを出発原料として合成
する方法が報告されているが（特開昭62-234071号
報）、水酸基の付け根の不斉炭素の立体配置を制御する
ことは難しく、（2R）−および（2S）−配置のジアステ
レオマー混合物をシリカゲルカラムクロマトグラフィー
などで分離せざるを得なかった。この方法は高価なカラ
ムや充てん剤を要したり、大量の溶媒を用いるなどの問
題があり、しかも大量に処理することが困難なものであ
った。また、有毒なシアン化合物を使用していることも
実用化の大きな問題であった。For example, a method of synthesizing L-phenylalanine as a starting material has been reported (JP-A-62-234071), but it is difficult to control the configuration of the asymmetric carbon at the base of the hydroxyl group, and (2R)- The (2S) -configured diastereomeric mixture had to be separated by silica gel column chromatography or the like. This method has problems that an expensive column and a packing material are required and a large amount of solvent is used, and it is difficult to process a large amount. In addition, the use of a toxic cyanide compound has been a serious problem for practical use.

このため、式（IV）で表されるβ−アミノ酸誘導体の
高立体選択的合成法の開発が望まれていた。Therefore, development of a highly stereoselective synthetic method for the β-amino acid derivative represented by the formula (IV) has been desired.

〔発明が解決しようとする問題点〕[Problems to be solved by the invention]

本発明者は、上記問題点を解決すべく鋭意検討した結
果、工業的に安価に製造しうる本発明の前記一般式
（Ｉ）で表される新規な４−シクロヘキシルメチル−２
−アゼチジノン誘導体を経由することにより、前記一般
式（IV）で表されるβ−アミノ酸誘導体のラセミ体ある
いは光学活性体を高ジアステレオ選択的に合成できるこ
とを見出し、本発明を完成した。The present inventor has conducted extensive studies to solve the above-mentioned problems, and as a result, the novel 4-cyclohexylmethyl-2 represented by the general formula (I) of the present invention which can be industrially produced at low cost.
The present invention was completed by finding that a racemate or an optically active form of a β-amino acid derivative represented by the general formula (IV) can be synthesized with high diastereoselectivity by way of a -azetidinone derivative.

〔問題点を解決するための手段〕[Means for solving problems]

本発明の前記一般式（Ｉ）で表される４−シクロヘキ
シルメチル−２−アゼチジノン誘導体は、下記の製造工
程に従い製造できる。The 4-cyclohexylmethyl-2-azetidinone derivative represented by the general formula (I) of the present invention can be produced according to the following production steps.

（式中、R5は炭素数１〜７の直鎖若しくは分枝アルキル
基、アラルキル基またはアリール基、R1およびR2は前記
と同じ意味を表す。Ｘは塩素、臭素またはヨウ素を表
す。） （第１工程） 本工程は、一般式（VI）で表されるシクロヘキシル酢
酸誘導体を還元して式（VII）で表されるシクロヘキシ
ルアセトアルデヒドを製造する工程である。本反応に用
いられるシクロヘキシル酢酸誘導体としては、シクロヘ
キシル酢酸のメチルエステル、エチルエステル、プロピ
ルエステル、ベンジルエステル、フェニルエステルなど
対応するアルデヒドに変換できるものが例示できる。ま
た、本反応で用いられる還元剤としては、エステルをア
ルデヒドに還元するのに使用される如何なる還元剤も使
用することができるが、好適には水素化ジイソブチルア
ルミニウム、水素化ビス（２−メトキシ−エトキシ）ア
ルミニウムナトリウムなどが用いられる。本反応は溶媒
中で行われ、溶媒としては、通常還元反応に関与しない
ものであれば如何なる溶媒も使用できるが、好適には、
ジエチルエーテル、テトラヒドロフラン、トルエンなど
が用いられる。反応は−100℃〜20℃で円滑に進行す
る。 (In the formula, R 5 is a linear or branched alkyl group having 1 to 7 carbon atoms, an aralkyl group or an aryl group, R 1 and R 2 have the same meanings as described above, and X represents chlorine, bromine or iodine. ) (First Step) This step is a step of producing a cyclohexylacetaldehyde represented by the formula (VII) by reducing the cyclohexylacetic acid derivative represented by the general formula (VI). Examples of the cyclohexyl acetic acid derivative used in this reaction include methyl ester, ethyl ester, propyl ester, benzyl ester, phenyl ester and the like of cyclohexyl acetic acid which can be converted into corresponding aldehydes. As the reducing agent used in this reaction, any reducing agent used for reducing an ester to an aldehyde can be used, but preferably diisobutylaluminum hydride or bis (2-methoxy-hydride) is used. Ethoxy) aluminum sodium or the like is used. This reaction is carried out in a solvent, and any solvent can be used as long as it does not normally participate in the reduction reaction, but preferably,
Diethyl ether, tetrahydrofuran, toluene and the like are used. The reaction proceeds smoothly at -100 ° C to 20 ° C.

（第２工程） 本工程は、式（VII）で表されるシクロヘキシルアセ
トアルデヒドと一般式（VIII）で表される第１アミン化
合物とを反応させ、副生する水を除去して一般式（II）
で表されるイミン誘導体を製造するものである。第一ア
ミン化合物としては、置換基としてアラルキル基あるい
はアリール基を有するものが用いられる。アラルキル基
としては、ベンジル、ｐ−メトキシベンジル、2,4−ジ
メトキシベンジル、ｏ−ニトロベンジル、ｐ−ニトロベ
ンジルのような置換あるいは無置換のモノアリールメチ
ル基、ジフェニルメチル、ジ−ｐ−アニシルメチルのよ
うなジアリールメチル基、トリチルのようなトリアリー
ルメチル基などを挙げることができ、アリール基として
は、フェニル、ｐ−アニシル、ｏ−アニシル、2,4−ジ
メトキシフェニル、ｐ−ニトロフェニルなどの置換、あ
るいは無置換アリール基を挙げることができる。脱水反
応である本工程を行うための反応条件としては、溶媒と
の共沸蒸留による方法、脱水剤を用いる方法およびこれ
らを組み合わせる方法が可能である。脱水剤としては、
反応系中で脱水以外の反応を起こさないものであれば如
何なる脱水剤も使用できるが、好適には、無水硫酸ナト
リウム、無水硫酸マグネシウム、塩化カルシウム、モレ
キュラーシーブスなどが用いられる。溶媒としては、メ
タノール、エタノール、プロパノール、ブタノールなど
のアルコール系溶媒、ベンゼン、トルエン、シクロヘキ
サンなどの炭化水素系溶媒、ジエチルエーテル、テトラ
ヒドロフランなどのエーテル系溶媒、クロロホルム、ジ
クロロメタン、四塩化炭素などのハロゲン化炭化水素系
溶媒などを例示できる。反応は−20℃〜100℃で円滑に
進行する。(Second Step) In this step, cyclohexylacetaldehyde represented by the formula (VII) is reacted with the primary amine compound represented by the general formula (VIII) to remove water produced as a by-product, and then the general formula (II )
The imine derivative represented by As the primary amine compound, a compound having an aralkyl group or an aryl group as a substituent is used. Examples of the aralkyl group include substituted or unsubstituted monoarylmethyl groups such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, o-nitrobenzyl and p-nitrobenzyl, diphenylmethyl and di-p-anisylmethyl. Examples of the aryl group include a diarylmethyl group, a triarylmethyl group such as trityl, and the like. As the aryl group, phenyl, p-anisyl, o-anisyl, 2,4-dimethoxyphenyl, p-nitrophenyl and the like are substituted. Or an unsubstituted aryl group. The reaction conditions for carrying out this step, which is a dehydration reaction, include a method by azeotropic distillation with a solvent, a method using a dehydrating agent, and a method combining these. As a dehydrating agent,
Any dehydrating agent can be used as long as it does not cause a reaction other than dehydration in the reaction system, but anhydrous sodium sulfate, anhydrous magnesium sulfate, calcium chloride, molecular sieves and the like are preferably used. As the solvent, alcohol solvents such as methanol, ethanol, propanol and butanol, hydrocarbon solvents such as benzene, toluene and cyclohexane, ether solvents such as diethyl ether and tetrahydrofuran, halogenated halogen compounds such as chloroform, dichloromethane and carbon tetrachloride. Examples include hydrocarbon solvents. The reaction proceeds smoothly at -20 ° C to 100 ° C.

（第３工程） 本工程は、第２工程で得られた一般式（II）で表され
るイミン誘導体と、一般式（III）で表されるグリコー
ル酸誘導体とを塩基存在下反応させ、一般式（Ｉ）で表
される４−シクロヘキシルメチル−２−アゼチジノン誘
導体を製造するものである。用いるグリコール酸誘導体
としては、塩化ベンジルオキシアセチル、臭化ベンジル
オキシアセチル、ヨウ化ベンジルオキシアセチル、塩化
アセトキシアセチル、臭化アセトキシアセチル、ヨウ化
アセトキシアセチルなどのハロゲン化アラルキルオキシ
アセチルあるいはハロゲン化アシルオキシアセチルが挙
げられる。また、用いる塩基としては、トリメチルアミ
ン、トリエチルアミン、トリプロピルアミン、ジイソプ
ロピルエチルアミンなどの第３アミン類、ピリジン、コ
リジン、ルチジンなどの芳香族アミンが用いられ、好適
にはトリエチルアミンが用いられる。反応は溶媒中で行
われることが好ましく、溶媒としては、ジエチルエーテ
ル、テトラヒドロフラン、ジオキサン、1,2−ジメトキ
シエタンなどのエーテル系溶媒、ベンゼン、トルエン、
ヘキサン、シクロヘキサンなどの炭化水素系溶媒、ジク
ロロメタン、ジクロロエタン、クロロホルム、四塩化炭
素などのハロゲン化炭化水素系溶媒、N,N−ジメチルホ
ルムアミド、N,N−ジメチルアセトアミド、ヘキサメチ
ルホスホリックトリアミドなどの極性非プロトン性溶媒
が挙げられる。反応は−40℃〜100℃で円滑に進行す
る。(Third Step) In this step, the imine derivative represented by the general formula (II) obtained in the second step is reacted with the glycolic acid derivative represented by the general formula (III) in the presence of a base, It is intended to produce a 4-cyclohexylmethyl-2-azetidinone derivative represented by the formula (I). Examples of the glycolic acid derivative used include aralkyloxyacetyl halides or acyloxyacetyl halides such as benzyloxyacetyl chloride, benzyloxyacetyl bromide, benzyloxyacetyl iodide, acetoxyacetyl chloride, acetoxyacetyl bromide, and acetoxyacetyl iodide. Can be mentioned. As the base used, tertiary amines such as trimethylamine, triethylamine, tripropylamine and diisopropylethylamine, aromatic amines such as pyridine, collidine and lutidine are used, and triethylamine is preferably used. The reaction is preferably carried out in a solvent, and as the solvent, diethyl ether, tetrahydrofuran, dioxane, ether solvents such as 1,2-dimethoxyethane, benzene, toluene,
Hexane, hydrocarbon solvents such as cyclohexane, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, etc. Examples include polar aprotic solvents. The reaction proceeds smoothly at -40 ° C to 100 ° C.

以上の製造工程によって製造された本発明化合物であ
る一般式（Ｉ）で表される４−シクロヘキシルメチル−
２−アゼチジノン誘導体は、下記工程により高血圧治療
剤である一般式（Ｖ）で表される化合物の製造原料であ
る一般式（IV）で表されるβ−アミノ酸誘導体に誘導で
きる。4-Cyclohexylmethyl- represented by the general formula (I), which is the compound of the present invention, produced by the above production process
The 2-azetidinone derivative can be derived into the β-amino acid derivative represented by the general formula (IV) which is a raw material for producing the compound represented by the general formula (V) which is a therapeutic agent for hypertension by the following steps.

（式中、R1およびR2は前記と同じ意味を表し、R3は炭素
数１〜７の直鎖若しくは分枝アルキル基、アラルキル基
またはアリール基を表す。） （第４工程） 本工程は、一般式（Ｉ）で表される４−シクロヘキシ
ルメチル−２−アゼチジノンをアルコール中、酸処理し
てラクタム環を開いて、一般式（IX）で表されるβ−ア
ミノ酸エステルを製造する工程である。用いるアルコー
ルとしては、メタノール、エタノール、プロパノール、
ブタノール、アミルアルコール、ベンジルアルコール、
β−ニトロベンジルアルコール、フェノールなどが挙げ
られ、酸としては、塩酸、硫酸、ホウ酸、リン酸、ｐ−
トルエンスルホン酸などが挙げられる。本反応は溶媒中
で行われ、溶媒としては、メタノール、エタノール、プ
ロパノール、ブタノール、アミルアルコールなどのアル
コール系溶媒、ベンゼン、トルエン、キシレンなどの芳
香族炭化水素系溶媒、ジクロロメタン、クロロホルム、
四塩化炭素などのハロゲン化炭化水素系溶媒が用いられ
る。反応は−20℃〜100℃で円滑に進行する。 (In the formula, R 1 and R 2 have the same meanings as described above, and R 3 represents a linear or branched alkyl group having 1 to 7 carbon atoms, an aralkyl group, or an aryl group.) (Fourth Step) This Step Is a process for producing a β-amino acid ester represented by the general formula (IX) by treating 4-cyclohexylmethyl-2-azetidinone represented by the general formula (I) with an acid in an alcohol to open a lactam ring. Is. The alcohol used is methanol, ethanol, propanol,
Butanol, amyl alcohol, benzyl alcohol,
Examples of the acid include β-nitrobenzyl alcohol and phenol. Examples of the acid include hydrochloric acid, sulfuric acid, boric acid, phosphoric acid, p-
Examples include toluene sulfonic acid. This reaction is carried out in a solvent, and as the solvent, alcohol solvents such as methanol, ethanol, propanol, butanol, and amyl alcohol, benzene, toluene, aromatic hydrocarbon solvents such as xylene, dichloromethane, chloroform,
A halogenated hydrocarbon solvent such as carbon tetrachloride is used. The reaction proceeds smoothly at -20 ° C to 100 ° C.

（第５工程） 本工程は、一般式（IX）で表されるβ−アミノ酸エス
テルの水酸基の保護基、R1とアミノ基の保護基、R2を除
去し、一般式（IV）で表されるβ−アミノ酸誘導体を製
造する工程である。R1およびR2は、通常の脱保護する方
法に従って容易に除去することができ（Protective Gro
ups in Organic Synthesis John-Wiley ＆ Sons,New Yo
rk,1981,参照）、遊離の水酸基やアミノ基に変換でき
る。(Fifth Step) In this step, the protecting group for the hydroxyl group, the protecting group for R 1 and the amino group, and R 2 of the β-amino acid ester represented by the general formula (IX) are removed to obtain the compound represented by the general formula (IV). Is a step of producing a β-amino acid derivative. R 1 and R 2 can be easily removed by conventional deprotection methods (Protective Gro
ups in Organic Synthesis John-Wiley & Sons, New Yo
rk, 1981)), and can be converted into free hydroxyl and amino groups.

例えば、R1、R2がともにアリールメチル基の場合は、
触媒存在下、水素で加水素分解することにより保護基が
除去できる。触媒としては炭素上に担持したパラジウ
ム、白金、ロジウムなどが用いられ、溶媒としてはメタ
ノール、エタノール、プロパノールなどのアルコール系
溶媒、酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ア
ミルなどのエステル系溶媒、ベンゼン、トルエンなどの
炭化水素系溶媒などが用いられる。反応は常圧の水素雰
囲気下、０℃〜100℃で円滑に進行する。For example, when R 1 and R 2 are both arylmethyl groups,
The protecting group can be removed by hydrogenolysis with hydrogen in the presence of a catalyst. As the catalyst, palladium supported on carbon, platinum, rhodium or the like is used, and as the solvent, an alcohol solvent such as methanol, ethanol or propanol, an ester solvent such as methyl acetate, ethyl acetate, propyl acetate or amyl acetate, benzene. Hydrocarbon solvents such as toluene and the like are used. The reaction proceeds smoothly at 0 ° C to 100 ° C under a hydrogen atmosphere at atmospheric pressure.

以下、実施例、参考例により本発明を詳細に説明する
が、本発明はこれらに限定されるものではない。Hereinafter, the present invention will be described in detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

なお、略号の意味は次の通りである。 The abbreviations have the following meanings.

Bn:ベンジル基 Ac:アセチル基 DAM:ジ−ｐ−アニシルメチル基 参考例１ シクロヘキシル酢酸エチル11.2g（65.6mmol）を無水
エーテル131mlに溶かし、−78℃に冷却して水素化ジイ
ソブチルアルミニウムの1M−ヘキサン溶液72.2ml（72.2
mmol）を滴下した。同温度で１時間後ロッシェル塩水溶
液（40g/200ml）に反応液を移し、室温で２時間攪拌し
た。エーテルを加えて分液し、有機層を0.5N塩酸、飽和
食塩水、飽和炭酸水素ナトリウム水、飽和食塩水で順次
洗浄した。硫酸マグネシウムで乾燥後、溶媒を減圧留去
して得られた残渣をカラム精製し、（シリカゲル、ヘキ
サン：エーテル＝1:0〜19:1）、シクロヘキシルアセト
アルデヒド7.10g（収率85％）を無色油状物して得た。Bn: benzyl group Ac: acetyl group DAM: di-p-anisylmethyl group Reference example 1 11.2 g (65.6 mmol) of cyclohexyl ethyl acetate was dissolved in 131 ml of anhydrous ether, cooled to -78 ° C and 72.2 ml of a 1M hexane solution of diisobutylaluminum hydride (72.2
mmol) was added dropwise. After 1 hour at the same temperature, the reaction solution was transferred to a Rochelle salt aqueous solution (40 g / 200 ml) and stirred at room temperature for 2 hours. Ether was added and the layers were separated, and the organic layer was washed successively with 0.5N hydrochloric acid, saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was purified by column. Obtained as an oil.

IR（neat）:2930,2860,1722,1445 cm-1 Ｈ−NMR（CDCl3） δ:0.7〜2.0（11H,m,c-C6H11）,2.28（2H,m,CH2 CHO）,
9.75（1H,dt,J＝0.7,2.3Hz,CHO） GC-MS m/e:126（M+）,108（M-H2O）,97（M-CHO） 参考例２ シクロヘキシルアセトアルデヒド2.08g（16.5mmol）
と硫酸マグネシウム3.96g（33mmol）をトルエン16.5ml
に加え、ベンジルアミン1.64ml（15.0mmol）を０℃にて
加えた。同温度で２時間後、不溶物をろ別し、溶媒を減
圧留去し、Ｎ−ベンジル−シクロヘキシルアセトアルド
イミン3.29g（定量的収率）を無色油状物として得た。IR (neat): 2930,2860,1722,1445 cm -1 H-NMR (CDCl 3 ) δ: 0.7 to 2.0 (11H, m, cC 6 H 11 ), 2.28 (2H, m, CH 2 CHO),
9.75 (1H, dt, J = 0.7,2.3Hz, CHO) GC-MS m / e: 126 (M + ), 108 (MH 2 O), 97 (M-CHO) Reference example 2 Cyclohexylacetaldehyde 2.08g (16.5mmol)
And magnesium sulfate 3.96 g (33 mmol) in toluene 16.5 ml
In addition, 1.64 ml (15.0 mmol) of benzylamine was added at 0 ° C. After 2 hours at the same temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure to obtain 3.29 g (quantitative yield) of N-benzyl-cyclohexylacetoaldimine as a colorless oil.

Ｈ−NMR（CDCl3） δ:0.8〜1.9（11H,m,c-C6H11）,2.21（2H,t,J＝5.6Hz,N
CHCH2）,4.56（2H,s,PhCH2）,7.27（5H,s,Ph）,7.78（1
H,t,J＝5.3Hz,NCH） 実施例１ 参考例２で得られたＮ−ベンジルシクロヘキシルアセ
トアルドイミン0.324g（1.63mmol）にジクロロメタン1.
5mlとトリエチルアミン1.03ml（14.0mmol）を加えて溶
かした後、氷冷下、塩化ベンジルオキシ酢酸0.350ml
（2.22mmol）のジクロロメタン溶液（0.35ml）を30分か
けて滴下した。徐々に室温まで昇温した後、同温度で一
夜攪拌した。1N塩酸8mlとエーテルを加えて攪拌し、分
液した。有機層を飽和食塩水、飽和炭酸水素ナトリウム
水、飽和食塩水で順次洗浄した後、硫酸マグネシウムで
乾燥した。溶媒を減圧留去して得られた残渣をカラム精
製し（シリカゲル、ヘキサン：酢酸エチル＝20:1〜15:
1）、（3R*,4S*）−１−ベンジル−３−ベンジルオキシ
−４−シクロヘキシルメチル−２−アゼチジノン0.218g
（収率41％）を無色油状物として得た。H-NMR (CDCl 3 ) δ: 0.8 to 1.9 (11H, m, cC 6 H 11 ), 2.21 (2H, t, J = 5.6Hz, N
CHCH 2 ), 4.56 (2H, s, PhCH 2 ), 7.27 (5H, s, Ph), 7.78 (1
H, t, J = 5.3Hz, NCH) Example 1 Dichloromethane was added to 0.324 g (1.63 mmol) of N-benzylcyclohexylacetoaldimine obtained in Reference Example 2.
After adding 5 ml and 1.03 ml (14.0 mmol) of triethylamine to dissolve, 0.350 ml of benzyloxyacetic acid chloride under ice cooling.
A solution of (2.22 mmol) in dichloromethane (0.35 ml) was added dropwise over 30 minutes. After gradually warming to room temperature, the mixture was stirred overnight at the same temperature. 8 ml of 1N hydrochloric acid and ether were added, and the mixture was stirred and separated. The organic layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 20: 1 to 15:
1), (3R * , 4S * )-1-benzyl-3-benzyloxy-4-cyclohexylmethyl-2-azetidinone 0.218 g
(Yield 41%) was obtained as a colorless oil.

IR（neat）:3050,2930,2865,1750,1499,1448,1403,134
5,1160,1075,1023,736,699 cm-1 Ｈ−NMR（CDCl3） δ:0.5〜1.8（13H,m,c-C6H11CH2）,3.63（1H,dt,J＝5.
1,6.6Hz,NCH）,4.08,4.66（2H,d,J＝15.2Hz,OCH2）,4.6
1（1H,d,J＝5.1Hz,OCH）,4.67,4.90（2H,d,J＝11.9Hz,N
CH2）,7.30（10H,m,aromatics） MS m/e:454(M+Bn)+,4.26(M+Bn-CO)+,364(M+1)+ 参考例３ （3R*,4S*）−１−ベンジル−３−ベンジルオキシ−
４−シクロヘキシルメチル−２−アゼチジノン0.118g
（0.325mmol）を２−プロパノール5mlに溶かし、氷冷
下、塩化水素約200mlを吹き込んだ。徐々に室温まで昇
温し、さらに一夜攪拌した。溶媒を減圧留去後、トルエ
ンを加えて再び減圧留去した。残渣にエーテルと飽和炭
酸水素ナトリウム水を加えて分液し、有機層を飽和食塩
水で洗浄した。硫酸マグネシウムで乾燥後、溶媒を減圧
留去して得られた残渣をカラム精製し（シリカゲル、ヘ
キサン：酢酸エチル＝1:0〜30:1）、（2R*,3S*）−２−
ベンジルオキシ−３−ベンジルアミノ−４−シクロヘキ
シル酪酸イソプロピル0.129g（収率94％）を無色油状物
として得た。IR (neat): 3050,2930,2865,1750,1499,1448,1403,134
5,1160,1075,1023,736,699 cm −1 H-NMR (CDCl 3 ) δ: 0.5 to 1.8 (13H, m, cC 6 H 11 CH 2 ), 3.63 (1H, dt, J = 5.
1,6.6Hz, NCH), 4.08,4.66 (2H, d, J = 15.2Hz, OCH 2 ), 4.6
1 (1H, d, J = 5.1Hz, OCH), 4.67,4.90 (2H, d, J = 11.9Hz, N
CH 2 ), 7.30 (10H, m, aromatics) MS m / e: 454 (M + Bn) + , 4.26 (M + Bn-CO) + , 364 (M + 1) + Reference Example 3 (3R * , 4S * )-1-benzyl-3-benzyloxy-
4-cyclohexylmethyl-2-azetidinone 0.118 g
(0.325 mmol) was dissolved in 5 ml of 2-propanol, and about 200 ml of hydrogen chloride was blown therein under ice cooling. The temperature was gradually raised to room temperature, and the mixture was further stirred overnight. After the solvent was distilled off under reduced pressure, toluene was added and the solvent was distilled off under reduced pressure again. Ether and saturated aqueous sodium hydrogencarbonate were added to the residue for liquid separation, and the organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 1: 0 to 30: 1), (2R * , 3S * )-2-
0.129 g (yield 94%) of isopropyl benzyloxy-3-benzylamino-4-cyclohexylbutyrate was obtained as a colorless oil.

IR（neat）:2930,2860,1739,1449,1372,1262,1196,114
3,1102,1026,732,698 cm-1 Ｈ−NMR（CDCl3） δ:0.6〜1.8（14H,m,c-C6H11CH2とNH）,1.23（3H,d,J＝
6.2Hz,(CH3 )2CHの一方）,1.29（3H,d,J＝6.2Hz,(CH3 )2C
Hの一方）,3.05（1H,m,NCH）,3.72（2H,s,NCH2）,3.90
（1H,d,J＝4.0Hz,BnOCH）,4.37,4.81（2H,d,J＝11.9Hz,
OCH2）,5.12（1H,quint,J＝6.2Hz），CH3 CH）,7.25,7.3
2（10H,s,C6H5 x 2） MS m/e:424(M+1)+,336（Ｍ-CO2(CH3)2）,326,216 参考例４ （2R*,3S*）−２−ベンジルオキシ−３−ベンジルア
ミノ−４−シクロヘキシル酪酸イソプロピル57.1mg（0.
135mmol）を２−プロパノール1.5mlに溶かし、10％パラ
ジウムカーボン20mgを加えて水素雰囲気下、室温で１日
攪拌した。触媒をろ別し、ろ液を減圧濃縮して（2R*,3S
*）−３−アミノ−４−シクロヘキシル−２−ヒドロキ
シ酪酸イソプロピル31.2mg（収率95％）を無色結晶とし
て得た。IR (neat): 2930,2860,1739,1449,1372,1262,1196,114
3,1102,1026,732,698 cm −1 H-NMR (CDCl 3 ) δ: 0.6 to 1.8 (14H, m, cC 6 H 11 CH 2 and NH), 1.23 (3H, d, J =
6.2Hz, ( CH 3 ) 2 CH one), 1.29 (3H, d, J = 6.2Hz, ( CH 3 ) 2 C
H side), 3.05 (1H, m, NCH), 3.72 (2H, s, NCH 2 ), 3.90
(1H, d, J = 4.0Hz, BnOCH), 4.37,4.81 (2H, d, J = 11.9Hz,
OCH 2 ), 5.12 (1H, quint, J = 6.2Hz), CH 3 CH ), 7.25,7.3
2 (10H, s, C 6 H 5 x 2) MS m / e: 424 (M + 1) + , 336 (M-CO 2 (CH 3 ) 2 ), 326,216 Reference Example 4 (2R * , 3S * )-2-benzyloxy-3-benzylamino-4-cyclohexylbutyrate isopropyl 57.1 mg (0.
(135 mmol) was dissolved in 1.5 ml of 2-propanol, 20 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 day. The catalyst was filtered off and the filtrate was concentrated under reduced pressure (2R * , 3S
* ) 31.2 mg (yield 95%) of isopropyl-3-amino-4-cyclohexyl-2-hydroxybutyrate was obtained as colorless crystals.

融点:73〜75℃ IR（neat）:3450,2930,2860,1738,1596,1441,1380,122
2,1196,1146,1110,985 cm-1 Ｈ−NMR（CDCl3） δ:0.7〜2.0（16H,m,c-C6H11CH2，NH2,OH）,1.29（6H,
d,J＝6.4Hz,CH3 x 2）,3.15（1H,m,NCH）,3.96（1H,d,J
＝2.4Hz,CHOH）,5.13（1H,quint,J＝6.4Hz,CH3 CH） MS m/e:244(M+1)+,184（Ｍ−OCH(CH3)2)+,156 元素分析値：（C13H25NO3として） Ｃ％ Ｈ％ Ｎ％ 計算値 64.17 10.35 5.76 実測値 63.91 10.21 5.63 参考例５ （3R*,4S*）−１−ベンジル−３−ベンジルオキシ−
４−シクロヘキシルメチル−２−アゼチジノン89.9mg
（0.248mmol）をメタノール5mlに溶かし、氷冷下、塩化
水素約200mlを吹き込んだ。徐々に室温まで昇温し、さ
らに一夜攪拌した。溶媒を減圧留去して得られた残渣に
メタノール5mlを加えて溶かし、10％パラジウムカーボ
ン10mgと5N塩酸メタノール溶液0.5mlを加えて水素雰囲
気下１日攪拌した。触媒をろ別後、ろ液を減圧濃縮し
た。残渣にピリジン1.0mlと無水酢酸0.3mlを加え室温で
１日攪拌した。溶媒を減圧留去後、残渣にエーテルと1N
塩酸を加えて攪拌し分液した。有機層を飽和食塩水、飽
和炭酸水素ナトリウム水、飽和食塩水で順次洗浄後、硫
酸マグネシウムで乾燥した。溶媒を減圧留去して得られ
た残渣をカラム精製し（シリカゲル、ヘキサン：酢酸エ
チル＝7:3〜1:1）、（2R*,3S*）−２−アセトキシ−３
−アセチルアミノ−４−シクロヘキシル酪酸メチル66.4
mg（収率90％）を無色結晶して得た。Melting point: 73-75 ° C IR (neat): 3450,2930,2860,1738,1596,1441,1380,122
2,1196,1146,1110,985 cm −1 H-NMR (CDCl 3 ) δ: 0.7 to 2.0 (16H, m, cC 6 H 11 CH 2 , NH 2 , OH), 1.29 (6H,
d, J = 6.4Hz, CH 3 x 2), 3.15 (1H, m, NCH), 3.96 (1H, d, J
= 2.4Hz, CH OH), 5.13 (1H, quint, J = 6.4Hz, CH 3 CH ) MS m / e: 244 (M + 1) + , 184 (M-OCH (CH 3 ) 2 ) + , 156 Elemental analysis value: (as C 13 H 25 NO 3 ) C% H% N% Calculated value 64.17 10.35 5.76 Measured value 63.91 10.21 5.63 Reference example 5 (3R * , 4S * )-1-benzyl-3-benzyloxy-
4-Cyclohexylmethyl-2-azetidinone 89.9mg
(0.248 mmol) was dissolved in 5 ml of methanol, and about 200 ml of hydrogen chloride was blown therein under ice cooling. The temperature was gradually raised to room temperature, and the mixture was further stirred overnight. The solvent was distilled off under reduced pressure and 5 ml of methanol was added to the residue to dissolve it, 10 mg of 10% palladium carbon and 0.5 ml of 5N hydrochloric acid methanol solution were added, and the mixture was stirred for one day in a hydrogen atmosphere. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. 1.0 ml of pyridine and 0.3 ml of acetic anhydride were added to the residue, and the mixture was stirred at room temperature for 1 day. After the solvent was distilled off under reduced pressure, ether and 1N were added to the residue.
Hydrochloric acid was added, and the mixture was stirred and separated. The organic layer was washed successively with saturated saline, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 7: 3-1: 1), (2R * , 3S * )-2-acetoxy-3.
-Acetylamino-4-cyclohexyl methyl butyrate 66.4
mg (yield 90%) was obtained as colorless crystals.

融点:107〜108℃ IR（KBr）:3280,3100,2940,2870,1750,1650,1560,1440,
1378,1300,1229,1180,1080 cm-1 Ｈ−NMR（CDCl3） δ:0.7〜1.9（13H,m,c-C6H11CH2）,1.96（3H,s,CH3CO
N）,2.18（3H,s,CH3COO）,3.73（3H,s、OCH3）,4.64（1
H,m,NCH）,5.00（1H,d,J＝2.4Hz,OCH）,5.52（1H,bd,J
＝9.7Hz,NH） MS m/e:300(M+1)+,257(M+1-CH3CO)+,256 参考例６ シクロヘキシルアセトアルデヒド0.196g（1.55mmol）
と硫酸マグネシウム0.30gをトルエン2mlに加え、ｐ−ア
ニシジン0.172g（1.40mmol）を０℃にて加えた。同温度
で２時間後、不溶物をろ別し、溶媒を減圧留去し、Ｎ−
ｐ−メトキシフェニル−シクロヘキシルアセトアルドイ
ミン0.340g（定量的収率）を得た。Melting point: 107-108 ° C IR (KBr): 3280,3100,2940,2870,1750,1650,1560,1440,
1378,1300,1229,1180,1080 cm -1 H-NMR (CDCl 3 ) δ: 0.7 to 1.9 (13H, m, cC 6 H 11 CH 2 ), 1.96 (3H, s, CH 3 CO
N), 2.18 (3H, s, CH 3 COO), 3.73 (3H, s, OCH 3 ), 4.64 (1
H, m, NCH), 5.00 (1H, d, J = 2.4Hz, OCH), 5.52 (1H, bd, J
= 9.7Hz, NH) MS m / e: 300 (M + 1) + , 257 (M + 1-CH 3 CO) + , 256 Reference example 6 Cyclohexylacetaldehyde 0.196g (1.55mmol)
And magnesium sulfate 0.30 g were added to toluene 2 ml, and p-anisidine 0.172 g (1.40 mmol) was added at 0 ° C. After 2 hours at the same temperature, the insoluble matter was filtered off, the solvent was distilled off under reduced pressure, and N-
0.340 g (quantitative yield) of p-methoxyphenyl-cyclohexylacetoaldimine was obtained.

Ｈ−NMR（CDCl3） δ:0.7〜2.0（11H,m,c-C6H11）,2.34（2H,t,J＝5.4Hz,N
CHCH2 ）,3.79（3H,s,CH3O）,6.94（4H,m,aromatics）,
7.86（1H,t,J＝5.5Hz,N＝CH） 実施例２ 参考例６で得た粗製Ｎ−ｐ−メトキシフェニル−シク
ロヘキシルアセトアルデヒド0.340gにジクロロメタン1.
7mlとトリエチルアミン1.08mlを加えて溶かした後、氷
冷下、塩化ベンジルオキシ酢酸0.367ml（2.33mmol）を
滴下した。徐々に室温まで昇温した後、同温度で一夜攪
拌した。飽和炭酸水素ナトリウム水6mlとエーテルを加
えて攪拌し分液した。有機層を飽和食塩水、1N塩酸、飽
和食塩水で洗浄した後、硫酸マグネシウムで乾燥した。
溶媒を減圧留去して得られた残渣をカラム精製し（シリ
カゲル、ヘキサン：酢酸エチル＝20:1〜9:1）、（3R*,4
S*）−３−ベンジルオキシ−４−シクロヘキシルメチル
−１−ｐ−メトキシフェニル−２−アゼチジノン0.175g
（収率30％）を無色油状物として得た。H-NMR (CDCl 3 ) δ: 0.7 to 2.0 (11H, m, cC 6 H 11 ), 2.34 (2H, t, J = 5.4Hz, N
CH CH 2 ), 3.79 (3H, s, CH 3 O), 6.94 (4H, m, aromatics),
7.86 (1H, t, J = 5.5Hz, N = CH) Example 2 Dichloromethane was added to 0.340 g of the crude Np-methoxyphenyl-cyclohexylacetaldehyde obtained in Reference Example 6.
After 7 ml and 1.08 ml of triethylamine were added and dissolved, 0.367 ml (2.33 mmol) of benzyloxyacetic acid chloride was added dropwise under ice cooling. After gradually warming to room temperature, the mixture was stirred overnight at the same temperature. 6 ml of saturated aqueous sodium hydrogencarbonate and ether were added, and the mixture was stirred and separated. The organic layer was washed with saturated saline, 1N hydrochloric acid and saturated saline, and then dried over magnesium sulfate.
The solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 20: 1 to 9: 1), (3R * , 4
S * )-3-Benzyloxy-4-cyclohexylmethyl-1-p-methoxyphenyl-2-azetidinone 0.175 g
(Yield 30%) was obtained as a colorless oil.

IR（neat）:2930,2852,1740,1510,1442,1390,1299,124
2,1175,1123,1028,827,734,697,620,520 cm-1 Ｈ−NMR（CDCl3） δ:0.8〜2.0（13H,m,c-C6H11CH2）,3.78（3H,s,CH3O）,
4.21（1H,m,NCH）,4.73（1H,d,J＝5.3Hz,OCH）,4.74,4.
97（2H,d,J＝11.9Hz），PhCH2 ）,6.86,7.30（4H,d,J＝
9.0Hz,C6H4）,7.36（5H,s,Ph） MS m/e:379（M+）,260(M-119)+ 参考例７ シクロヘキシルアセトアルデヒド0.740g（5.87mmol）
と硫酸マグネシウム1.43gをベンゼン5mlに溶かし、ジ−
ｐ−アニシルメチルアミン（DAM−NH2）1.30g（5.34mmo
l）を０℃にて加えた。同温度で１時間後、不溶物をろ
別し、溶媒を減圧留去し、Ｎ−（ジ−ｐ−アニシルメチ
ル）シクロヘキシルアセトアルドイミン1.98g（定量的
収率）を得た。IR (neat): 2930,2852,1740,1510,1442,1390,1299,124
2,1175,1123,1028,827,734,697,620,520 cm −1 H-NMR (CDCl 3 ) δ: 0.8 to 2.0 (13H, m, cC 6 H 11 CH 2 ), 3.78 (3H, s, CH 3 O),
4.21 (1H, m, NCH), 4.73 (1H, d, J = 5.3Hz, OCH), 4.74,4.
97 (2H, d, J = 11.9Hz), Ph CH 2 ), 6.86,7.30 (4H, d, J =
9.0Hz, C 6 H 4 ), 7.36 (5H, s, Ph) MS m / e: 379 (M + ), 260 (M-119) + Reference Example 7 Cyclohexylacetaldehyde 0.740 g (5.87 mmol)
Dissolve 1.43 g of magnesium sulfate in 5 ml of benzene,
p- anisyl methylamine (DAM-NH 2) 1.30g ( 5.34mmo
l) was added at 0 ° C. After 1 hour at the same temperature, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure to obtain 1.98 g (quantitative yield) of N- (di-p-anisylmethyl) cyclohexylacetoaldimine.

Ｈ−NMR（CDCl3） δ:0.8〜1.9（11H,m,c-C6H11）,2.27（2H,m,NCHCH2 ）,
3.76（6H,s,CH3 x 2）,5.26（1H,s,Ar2CH）,6.82,7.19
（8H,d,J＝8.8Hz,aromatics）,7.80（1H,t,J＝5.3Hz,N
＝CH） 実施例３ 参考例７で得た粗製Ｎ−（ジ−ｐ−アニシルメチル）
−シクロヘキシルアセトアルドイミン0.396gにジクロロ
メタン1mlとトリエチルアミン0.696mlを加えて溶かした
後、氷冷下、塩化ベンジルオキシ酢酸0.237ml（1.50mmo
l）のジクロロメタン溶液（0.24ml）を30分かけて滴下
した。徐々に室温まで昇温した後、同温度で一夜攪拌し
た。1N塩酸とエーテルを加えて攪拌し、分液した。有機
層を飽和食塩水、飽和炭酸水素ナトリウム水溶液、飽和
食塩水で順次洗浄した後、硫酸マグネシウムで乾燥し
た。溶媒を減圧留去して得られた残渣をカラム精製し
（シリカゲル、ヘキサン：酢酸エチル＝19:1〜17:3）、
低極性成分として（3R*,4R*）−３−ベンジルオキシ−
４−シクロヘキシルメチル−１−ジ−ｐ−アニシルメチ
ル−２−アゼチジノン68.8mg（収率14％）、高極性成分
として（3R*,4S*）−３−ベンジルオキシ−４−シクロ
ヘキシルメチル−１−ジ−ｐ−アニシルメチル−２−ア
ゼチジノン395mg（収率80％）を無色カラメルとして得
た。 H-NMR (CDCl 3) δ : 0.8~1.9 (11H, m, cC 6 H 11), 2.27 (2H, m, NCH CH 2),
3.76 (6H, s, CH 3 x 2), 5.26 (1H, s, Ar 2 CH), 6.82,7.19
(8H, d, J = 8.8Hz, aromatics), 7.80 (1H, t, J = 5.3Hz, N
= CH) Example 3 Crude N- (di-p-anisylmethyl) obtained in Reference Example 7
-Cyclohexylacetoaldimine 0.396 g was added with dichloromethane 1 ml and triethylamine 0.696 ml to dissolve, and then, under ice cooling, 0.237 ml of benzyloxyacetic acid chloride (1.50 mmo
A solution of l) in dichloromethane (0.24 ml) was added dropwise over 30 minutes. After gradually warming to room temperature, the mixture was stirred overnight at the same temperature. 1N hydrochloric acid and ether were added, and the mixture was stirred and separated. The organic layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 19: 1 to 17: 3),
(3R * , 4R * )-3-benzyloxy-
4-Cyclohexylmethyl-1-di-p-anisylmethyl-2-azetidinone 68.8 mg (14% yield), (3R * , 4S * )-3-benzyloxy-4-cyclohexylmethyl-1-di as highly polar component 395 mg (yield 80%) of -p-anisylmethyl-2-azetidinone was obtained as a colorless caramel.

（3R*,4R*）−体のスペクトル IR（neat）:2930,2850,1750,1610,1585,1511,1449,138
0,1330,1302,1248,1174,1109,1029,821,735,698 cm-1 Ｈ−NMR（CDCl3） δ:0.6〜1.8（13H,m,c-C6H11CH2）,3.55（1H,m,N-CH）,
3.80（6H,s,CH3 x 2）,4.26（1H,d,J＝1.5Hz,OCH）,4.6
4,4.85（2H,d,J＝11.7Hz,PhCH2 ）,5.81（1H,Ar2CH）,6.
8〜7.3（8H,m,C6H4 x 2）,7.33（5H,s,Ph） MS m/e:530(M+CH3O)+,500(M+1)+ （3R*,4S*）−体のスペクトル IR（neat）:2930,2860,1743,1610,1583,1511,1446,133
9,1302,1247,1175,1029,821,736,698,570 cm-1 Ｈ−NMR（CDCl3） δ:0.6〜1.8（13H,m,c-C6H11CH2）,3.70（1H,m,NCH）,
3.79（6H,s,CH3 x 2）,4.56（1H,d,J＝5.1Hz,OCH）,4.6
8,4.92（2H,d,J＝12.1Hz,PhCH2 ）,5.83（1H,s,Ar2CH）,
6.8〜7.3（8H,m,C6H4 x 2）,7.33（5H,s,Ph） MS m/e:530(M+CH3O)+,500(M+1)+ 参考例８ （3R*,4S*）−３−ベンジルオキシ−４−シクロヘキ
シルメチル−１−ジ−ｐ−アニシルメチル−２−アゼチ
ジノン0.266g（0.533mmol）を２−プロパノール5mlに溶
かし、氷冷下、塩化水素約200mlを吹き込んだ。徐々に
室温まで昇温し、さらに４時間攪拌した。溶媒を減圧留
去後、残渣にエーテルと飽和炭酸水素ナトリウム水溶液
を加えて分液し、有機層を飽和食塩水で洗浄した。硫酸
マグネシウムで乾燥後、溶媒を減圧留去して得られた残
渣をカラム精製し（シリカゲル、ヘキサン：酢酸エチル
＝19:1〜9:1）、（2R*,3S*）−２−ベンジルオキシ−４
−シクロヘキシル−３−（ジ−ｐ−アニシルメチルアミ
ノ）酪酸イソプロピル0.288g（収率96％）を無色油状物
として得た。(3R * , 4R * )-Spectral spectrum IR (neat): 2930,2850,1750,1610,1585,1511,1449,138
0,1330,1302,1248,1174,1109,1029,821,735,698 cm −1 H-NMR (CDCl 3 ) δ: 0.6 to 1.8 (13H, m, cC 6 H 11 CH 2 ), 3.55 (1H, m, N -CH),
3.80 (6H, s, CH 3 x 2), 4.26 (1H, d, J = 1.5Hz, OCH), 4.6
4,4.85 (2H, d, J = 11.7Hz, Ph CH 2 ), 5.81 (1H, Ar 2 CH), 6.
8 to 7.3 (8H, m, C 6 H 4 x 2), 7.33 (5H, s, Ph) MS m / e: 530 (M + CH 3 O) + , 500 (M + 1) + (3R * , 4S * )-body spectrum IR (neat): 2930,2860,1743,1610,1583,1511,1446,133
9,1302,1247,1175,1029,821,736,698,570 cm -1 H-NMR (CDCl 3 ) δ: 0.6 to 1.8 (13H, m, cC 6 H 11 CH 2 ), 3.70 (1H, m, NCH),
3.79 (6H, s, CH 3 x 2), 4.56 (1H, d, J = 5.1Hz, OCH), 4.6
8,4.92 (2H, d, J = 12.1Hz, Ph CH 2 ), 5.83 (1H, s, Ar 2 CH),
6.8 to 7.3 (8H, m, C 6 H 4 x 2), 7.33 (5H, s, Ph) MS m / e: 530 (M + CH 3 O) + , 500 (M + 1) + Reference Example 8 (3R * , 4S * )-3-Benzyloxy-4-cyclohexylmethyl-1-di-p-anisylmethyl-2-azetidinone (0.266 g, 0.533 mmol) was dissolved in 2-propanol (5 ml), and cooled with ice to about hydrogen chloride. Bubbled 200 ml. The temperature was gradually raised to room temperature, and the mixture was further stirred for 4 hours. After evaporating the solvent under reduced pressure, ether and saturated aqueous sodium hydrogen carbonate solution were added to the residue for partitioning the mixture, and the organic layer was washed with saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 19: 1 to 9: 1) and (2R * , 3S * )-2-benzyloxy. -4
0.288 g (yield 96%) of isopropyl cyclohexyl-3- (di-p-anisylmethylamino) butyrate was obtained as a colorless oil.

IR（neat）:2930,2860,1740,1610,1509,1450,1243,119
5,1174,1102,1032,820,740,698,558 cm-1 Ｈ−NMR（CDCl3） δ:0.6〜2.0（13H,m,c-C6H11CH2）,1.19,1.29（6H,d,J
＝6.2Hz,CH3 x 2）,2.95（1H,m,NCH）,3.74,3.76（6H,
s,CH3O x 2）,3.95（1H,d,J＝3.0,OCH）,4.34,4.78（2
H,d,J＝12.3Hz,PhCH2）,4.84（1H,s,Ar2CH）,5.10（1H,
quint,J＝6.2Hz,CH(CH3)2）,6.72〜7.26（8H,m,C6H4 x
2）,7.30（5H,s,Ph） MS m/e:558(M-1)+,516(M-CH3-CO)+ 参考例９ （3R*,4S*）−２−ベンジルオキシ−４−シクロヘキ
シル−３−（ジ−ｐ−アニシルメチルアミノ）酪酸イソ
プロピル60.5mg（0.108mmol）を２−プロパノール2mlに
溶かし、10％パラジウムカーボン10mgを加えて水素雰囲
気下３日間攪拌した。触媒をろ別し、ろ液を減圧濃縮し
て得られた残渣をカラム精製し（シリカゲル、ヘキサ
ン：酢酸エチル＝3:2〜2:3）、（3R*,4S*）−３−アミ
ノ−４−シクロヘキシル−２−ヒドロキシ酪酸イソプロ
ピル18.0mg（収率67％）を無色結晶として得た。IR (neat): 2930,2860,1740,1610,1509,1450,1243,119
5,1174,1102,1032,820,740,698,558 cm −1 H-NMR (CDCl 3 ) δ: 0.6 to 2.0 (13H, m, cC 6 H 11 CH 2 ), 1.19,1.29 (6H, d, J
= 6.2Hz, CH 3 x 2), 2.95 (1H, m, NCH), 3.74,3.76 (6H,
s, CH 3 O x 2), 3.95 (1H, d, J = 3.0, OCH), 4.34,4.78 (2
H, d, J = 12.3Hz, PhCH 2 ), 4.84 (1H, s, Ar 2 CH), 5.10 (1H,
quint, J = 6.2Hz, CH ( CH 3) 2), 6.72~7.26 (8H, m, C 6 H 4 x
2), 7.30 (5H, s, Ph) MS m / e: 558 (M-1) + , 516 (M-CH 3 -CO) + Reference Example 9 60.5 mg (0.108 mmol) of isopropyl (3R * , 4S * )-2-benzyloxy-4-cyclohexyl-3- (di-p-anisylmethylamino) butyrate was dissolved in 2 ml of 2-propanol and 10 mg of 10% palladium carbon was dissolved. Was added and the mixture was stirred under a hydrogen atmosphere for 3 days. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 3: 2 to 2: 3), and (3R * , 4S * )-3-amino- Isopropyl 4-cyclohexyl-2-hydroxybutyrate (18.0 mg, yield 67%) was obtained as colorless crystals.

物性値は参考例４で得たサンプルと一致した。 The physical property values corresponded to those of the sample obtained in Reference Example 4.

参考例10 シクロヘキシルアセトアルデヒド0.159g（1.26mmol）
と硫酸マグネシウム0.3gをベンゼン2mlに加え、氷冷
下、（Ｓ）−１−フェニルエチルアミン0.156ml（1.26m
mol）を加えた。同温度で２時間後不溶物をろ別し、溶
媒を減圧留去し、Ｎ−〔（Ｓ）−１−フェニルエチル〕
シクロヘキシルアセトアルドイミン0.300g（定量的収
率）を無色油状物として得た。Reference example 10 Cyclohexylacetaldehyde 0.159g (1.26mmol)
And magnesium sulfate 0.3 g were added to benzene 2 ml, and (S) -1-phenylethylamine 0.156 ml (1.26 m
mol) was added. After 2 hours at the same temperature, the insoluble matter was filtered off, the solvent was distilled off under reduced pressure, and N-[(S) -1-phenylethyl]
0.300 g (quantitative yield) of cyclohexylacetoaldimine was obtained as a colorless oil.

Ｈ−NMR（CDCCl3） δ:0.8〜2.0（11H,m,c-C6H11）,1.49（3H,d,J＝6.8Hz,C
H3）,2.17（1H,t,J＝5.5Hz,NCHCH2 ）,4.28（1H,q,J＝6.
8Hz,PhCH）,7.30（5H,s,Ph）,7.74（1H,t,J＝5.5Hz,N＝
CH） 実施例４ 参考例10で得られたＮ−〔（Ｓ）−１−フェニルエチ
ル〕シクロヘキシルアセトアルドイミン0.300gにジクロ
ロメタン1.5mlおよびトリエチルアミン0.876ml（6.30mm
ol）を加えて溶かした後、氷冷下、塩化ベンジルオキシ
酢酸0.298ml（1.89mmol）のジクロロメタン溶液（0.3m
l）を30分かけて滴下した。徐々に室温まで昇温した
後、室温で一夜攪拌した。1N塩酸とエーテルを加えて分
液し、有機層を飽和食塩水、飽和炭酸水素ナトリウム水
溶液、飽和食塩水で順次洗浄した。硫酸マグネシウムで
乾燥した後、溶媒を減圧留去して得られた残渣をカラム
精製し（シリカゲル、ヘキサン：酢酸エチル＝9:1）、
３−ベンジルオキシ−４−シクロヘキシルメチル−１−
〔（Ｓ）−１−フェニルエチル〕−２−アゼチジノン0.
401g（収率84％）を無色油状物として得た。本品の400M
Hz、Ｈ−NMR（CDCl3）を測定したところ、δ:3.42ppm、
3.47ppm、3.56ppmおよび3.63ppmの位置にβ−ラクタム
環の立体異性体に基づく４種類のC4−Ｈのシグナルが観
測された。これらのシグナルの積分比より、その生成比
は6:10:52:32であることが判明した。これらの異性体は
混合物のまま、次の参考例11の原料として用いた。ま
た、参考例11、12、13の結果より所望の立体配置である
（3R,4S）−配置の異性体が主成績体であることが明ら
かとなった。H-NMR (CDCCl 3 ) δ: 0.8 to 2.0 (11H, m, cC 6 H 11 ), 1.49 (3H, d, J = 6.8Hz, C
H 3), 2.17 (1H, t, J = 5.5Hz, NCH CH 2), 4.28 (1H, q, J = 6.
8Hz, PhCH), 7.30 (5H, s, Ph), 7.74 (1H, t, J = 5.5Hz, N =
CH) Example 4 To 0.300 g of N-[(S) -1-phenylethyl] cyclohexylacetoaldimine obtained in Reference Example 10, 1.5 ml of dichloromethane and 0.876 ml of triethylamine (6.30 mm
ol) was added and dissolved, and then under ice-cooling, a solution of 0.298 ml (1.89 mmol) of benzyloxyacetic acid chloride in dichloromethane (0.3 m
l) was added dropwise over 30 minutes. After gradually warming to room temperature, the mixture was stirred overnight at room temperature. 1N Hydrochloric acid and ether were added and the layers were separated, and the organic layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the obtained residue was purified by column (silica gel, hexane: ethyl acetate = 9: 1),
3-benzyloxy-4-cyclohexylmethyl-1-
[(S) -1-Phenylethyl] -2-azetidinone 0.
401 g (84% yield) was obtained as a colorless oil. 400M of this product
When Hz and H-NMR (CDCl 3 ) were measured, δ: 3.42 ppm,
Four kinds of C 4 -H signals based on the stereoisomer of the β-lactam ring were observed at the positions of 3.47 ppm, 3.56 ppm and 3.63 ppm. From the integral ratio of these signals, it was found that the production ratio was 6: 10: 52: 32. These isomers were used as raw materials in the following Reference Example 11 as they were as a mixture. Further, from the results of Reference Examples 11, 12, and 13, it was revealed that the isomer having the desired configuration (3R, 4S) -configuration is the main product.

IR（neat）;3050,2930,2865,1750,1499,1448,1403,134
5,1160,1075,1023,736,699 cm-1 Ｈ−NMR（CDCl3） δ:0.6〜2.0（16H,m,c-C6H11CH2,CH3）,3.42,3.47,3.5
6,3.63（1H,m,NCH,積分比:6:10:52:32）,4.0〜4.9（4H,
m,その他のプロトン）,7.2〜7.4（10H,m,aromatics） MS m/e:377(M+),294(M-C-C6H11)+,286(M-Bn)+,272(M-Ph
CHCH3)+ 参考例11 実施例４で得られた３−ベンジルオキシ−４−シクロ
ヘキシルメチル−１−〔（Ｓ）−１−フェニルエチル〕
−２−アゼチジノンの４種の立体異性体混合物0.193g
（0.512mmol）を２−プロパノール1mlに溶かし、氷冷
下、塩化水素約50mlを吹き込んだ。徐々に室温まで昇温
し、さらに６時間攪拌した。溶媒を減圧留去後、残渣に
エーテルと飽和炭酸水素ナトリウム水溶液を加えて攪拌
し、分液した。有機層を飽和食塩水で洗浄し、硫酸マグ
ネシウムで乾燥した。溶媒を減圧留去して得られた残渣
をカラム分離し（シリカゲル、ヘキサン：エーテル＝1:
0〜20:1〜15:1）、主生成物として、（2R,3S）−２−ベ
ンジルオキシ−４−シクロヘキシル−３−〔（Ｓ）−１
−フェニルエチルアミノ〕酪酸イソプロピル0.110g（収
率49％）を無色油状物として得た。なお、本品の立体化
学は、以下の参考例12および13に示した方法で既知物質
へ誘導して、（2R,3S）であることが明らかとなった。
また、本品の収率が49％であることから、本品は実施例
４で得られた４種類のジアステレオマーのうちの主成績
体から誘導されたものであることは明らかである。IR (neat); 3050,2930,2865,1750,1499,1448,1403,134
5,1160,1075,1023,736,699 cm -1 H-NMR (CDCl 3 ) δ: 0.6 to 2.0 (16H, m, cC 6 H 11 CH 2 , CH 3 ), 3.42,3.47,3.5
6,3.63 (1H, m, NCH, integration ratio: 6: 10: 52: 32), 4.0 ~ 4.9 (4H,
m, other protons), 7.2 to 7.4 (10H, m, aromatics) MS m / e: 377 (M + ), 294 (MCC 6 H 11 ) + , 286 (M-Bn) + , 272 (M-Ph
CHCH 3 ) + Reference example 11 3-Benzyloxy-4-cyclohexylmethyl-1-[(S) -1-phenylethyl] obtained in Example 4
-2-azetidinone 4 stereoisomer mixture 0.193g
(0.512 mmol) was dissolved in 1 ml of 2-propanol, and about 50 ml of hydrogen chloride was blown therein under ice cooling. The temperature was gradually raised to room temperature, and the mixture was further stirred for 6 hours. After evaporating the solvent under reduced pressure, ether and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was stirred and separated. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated by column (silica gel, hexane: ether = 1: 2).
0-20: 1 to 15: 1), as a main product, (2R, 3S) -2-benzyloxy-4-cyclohexyl-3-[(S) -1
0.110 g (yield 49%) of isopropyl-phenylethylamino] butyrate was obtained as a colorless oil. The stereochemistry of this product was (2R, 3S), which was derived from known substances by the methods shown in Reference Examples 12 and 13 below.
Further, since the yield of this product was 49%, it is clear that this product was derived from the main product of the four diastereomers obtained in Example 4.

IR（neat）:2940,2860,1740,1447,1372,1268,1195,100
2,735,699 cm-1 Ｈ−NMR（CDCl3） δ:0.4〜1.8（22H,m,c-C6H11CH2,CH3 x 3）,2.88（1H,
m,NCH）,3.81（1H,q,J＝6.4Hz,PhCHN）,3.93（1H,d,J＝
3.1Hz,OCH）,4.35,4.77（2H,d,J＝12.2Hz,PhCH2）,5.15
（1H,quint,J＝6.2Hz,CH(CH3)2）,7.25,7.30（10H,s,Ph
x 2） MS m/e:438(M+1)+,422(M-CH3)+,350(M-COOCH(CH3)2)+ ▲〔α〕20 D▼−1.5°（C 1.18,CHCl3） 参考例12 （2R,3S）−２−ベンジルオキシ−４−シクロヘキシ
ル−３−〔（Ｓ）−１−フェニルエチルアミノ）酪酸イ
ソプロピル74.3mg（0.170mmol）を２−プロパノール5ml
に溶かし、10％パラジウムカーボン20mgを加えて水素雰
囲気下、室温で１日攪拌した。触媒をろ別し、ろ液を減
圧濃縮して、（2R,3S）−３−アミノ−４−シクロヘキ
シル−２−ヒドロキシ酪酸イソプロピル40.0mg（収率99
％）を無色結晶として得た。IR (neat): 2940,2860,1740,1447,1372,1268,1195,100
2,735,699 cm -1 H-NMR (CDCl 3 ) δ: 0.4 to 1.8 (22H, m, cC 6 H 11 CH 2 , CH 3 x 3), 2.88 (1H,
m, NCH), 3.81 (1H, q, J = 6.4Hz, PhCHN), 3.93 (1H, d, J =
3.1Hz, OCH), 4.35, 4.77 (2H, d, J = 12.2Hz, PhCH 2 ), 5.15
(1H, quint, J = 6.2Hz, CH (CH 3 ) 2 ), 7.25,7.30 (10H, s, Ph
x 2) MS m / e: 438 (M + 1) +, 422 (M-CH 3) +, 350 (M-COOCH (CH 3) 2) + ▲ [α] 20 D ▼ -1.5 ° (C 1.18 , CHCl 3 ) Reference example 12 74.3 mg (0.170 mmol) of isopropyl (2R, 3S) -2-benzyloxy-4-cyclohexyl-3-[(S) -1-phenylethylamino) butyrate was added to 5 ml of 2-propanol.
20 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 1 day in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2R, 3S) -3-amino-4-cyclohexyl-2-hydroxybutyrate isopropyl 40.0 mg (yield 99
%) As colorless crystals.

融点:86〜87℃ IR（KBr）:3450,2920,2850,1734,1593,1440,1373,1220,
1192,1142,1102,980,822,790,661 cm-1 Ｈ−NMR（CDCl3）は参考例４のデータと一致した。Melting point: 86-87 ° C IR (KBr): 3450,2920,2850,1734,1593,1440,1373,1220,
1192,1142,1102,980,822,790,661 cm -1 H-NMR (CDCl 3 ) was in agreement with the data of Reference Example 4.

MS m/e:243（M+）,184(M-OCH(CH3)2),156 ▲〔α〕20 D▼−22.0°（C 1.08,CHCl3） 参考例13 （2R,3S）−３−アミノ−４−シクロヘキシル−２−
ヒドロキシ酪酸イソプロピル10.8mg（0.0444mmol）をベ
ンゼン1mlに溶かし、5N塩酸エタノール溶液44μｌを加
えた。減圧で溶媒を留去後、ベンゼン1mlを加えて攪拌
した。減圧で溶媒で留去後、酢酸エチル0.5mlを加えて
攪拌した。減圧で溶媒を留去して（2R,3S）−３−アミ
ノ−４−シクロヘキシル−２−ヒドロキシ酪酸イソプロ
ピル塩酸塩を12.4mg（定量的収率）を得た。MS m / e: 243 (M +), 184 (M-OCH (CH 3) 2), 156 ▲ [α] 20 D ▼ -22.0 ° (C 1.08 , CHCl 3) Reference Example 13 (2R, 3S) -3-Amino-4-cyclohexyl-2-
10.8 mg (0.0444 mmol) of isopropyl hydroxybutyrate was dissolved in 1 ml of benzene, and 44 μl of 5N hydrochloric acid ethanol solution was added. After the solvent was distilled off under reduced pressure, 1 ml of benzene was added and stirred. After the solvent was distilled off under reduced pressure, 0.5 ml of ethyl acetate was added and the mixture was stirred. The solvent was distilled off under reduced pressure to obtain 12.4 mg (quantitative yield) of (2R, 3S) -3-amino-4-cyclohexyl-2-hydroxybutyrate isopropyl hydrochloride.

Ｈ−NMR（D2O） δ:0.8〜2.0（13H,m,C6H11CH2）,1.31（6H,d,J＝6.2Hz,
CH3 x 2）,3.71（1H,m,NCH）,4.38（1H,d,J＝4.6Hz,OC
H）,5.11（1H,m,CH3CH） ▲〔α〕20 D▼−9.8°（C 1.24,H2O） これらの物性値は、特開昭62-234071号報記載の方法
で合成したサンプルの物性値と一致した。H-NMR (D 2 O) δ: 0.8 to 2.0 (13H, m, C 6 H 11 CH 2 ), 1.31 (6H, d, J = 6.2Hz,
CH 3 x 2), 3.71 (1H, m, NCH), 4.38 (1H, d, J = 4.6Hz, OC
H), 5.11 (1H, m, CH 3 CH) ▲ [α] 20 D ▼ -9.8 ° (C 1.24, H 2 O) These physical properties were synthesized by the method described in JP-A-62-234071. It was in agreement with the physical properties of the sample.

フロントページの続き (72)発明者 原田 弘 長野県東筑摩郡四賀村大字中川8054番地 審査官 星野 紹英 (56)参考文献 特開 平３−236371（ＪＰ，Ａ) 特開 平３−284665（ＪＰ，Ａ)Front page continued (72) Inventor Hiroshi Harada 8054 Nakagawa, Shiga-mura, Higashichikuma-gun, Nagano Examiner Shoei Hoshino (56) References JP-A-3-236371 (JP, A) JP-A-3-284665 (JP , A)

Claims (2)

【特許請求の範囲】[Claims] 【請求項１】一般式 （式中、R1はアラルキル基またはアシル基であり、R2は
置換あるいは無置換のアラルキル基、または置換あるい
は無置換のアリール基を表す。）で表される４−シクロ
ヘキシルメチル−２−アゼチジノン誘導体。1. A general formula (In the formula, R 1 represents an aralkyl group or an acyl group, and R 2 represents a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.) 4-cyclohexylmethyl-2-azetidinone Derivative. 【請求項２】一般式 （式中、R2は置換あるいは無置換のアラルキル基、また
は置換あるいは無置換のアリール基を表す。）で表され
るイミン誘導体と、一般式 R1OCH2COX （III） （式中、R1はアラルキル基またはアシル基を表し、Ｘは
塩素、臭素またはヨウ素を表す。）で表されるグリコー
ル酸誘導体とを塩基の存在下反応させることを特徴とす
る、一般式 （式中、R1、R2は前記と同じ意味を表す。）で表される
４−シクロヘキシルメチル−２−アゼチジノンの製造方
法。2. General formula (In the formula, R 2 represents a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted aryl group.), And an imine derivative represented by the general formula R 1 OCH 2 COX (III) 1 represents an aralkyl group or an acyl group, X represents chlorine, bromine or iodine), and a glycolic acid derivative represented by the formula) is reacted in the presence of a base. (In the formula, R 1 and R 2 have the same meanings as described above.) A method for producing 4-cyclohexylmethyl-2-azetidinone.
JP63275838A 1988-10-31 1988-10-31 4-Cyclohexylmethyl-2-azetidinone derivative and process for producing the same Expired - Lifetime JPH0816098B2 (en)

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JPH0816098B2 true JPH0816098B2 (en) 1996-02-21

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Publication number Priority date Publication date Assignee Title
US5442105A (en) * 1991-06-21 1995-08-15 Takasago International Corporation Process for producing cyclohexylbutyric acid derivative

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