JPH09278748A - Production of n-substituted-beta-lactam compound - Google Patents

Production of n-substituted-beta-lactam compound

Info

Publication number
JPH09278748A
JPH09278748A JP8090966A JP9096696A JPH09278748A JP H09278748 A JPH09278748 A JP H09278748A JP 8090966 A JP8090966 A JP 8090966A JP 9096696 A JP9096696 A JP 9096696A JP H09278748 A JPH09278748 A JP H09278748A
Authority
JP
Japan
Prior art keywords
group
lactam compound
substituted
general formula
lactam
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.)
Pending
Application number
JP8090966A
Other languages
Japanese (ja)
Inventor
Kyoji Yoshikawa
享志 吉川
Isao Kurimoto
勲 栗本
Yoji Sakito
庸治 先砥
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.)
Sumitomo Chemical Co Ltd
Original Assignee
Sumitomo Chemical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sumitomo Chemical Co Ltd filed Critical Sumitomo Chemical Co Ltd
Priority to JP8090966A priority Critical patent/JPH09278748A/en
Publication of JPH09278748A publication Critical patent/JPH09278748A/en
Pending legal-status Critical Current

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Classifications

    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Catalysts (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

PROBLEM TO BE SOLVED: To easily obtain the subject compound useful as an intermediate for carbapenem compounds in a good yield from a β-lactam compound having an arylthioester group. SOLUTION: (A) A β-lactam compound of formula I (R<1> is an OH-protecting group; R<2> is H, a lower alkyl; R<3> is an aryl) is reacted with (B) an acetic acid derivative of formula II (R<4> is a carboxyl-protecting group; X is a releasing group) (preferably a halogenoacetic acid alkyl ester) in an amount of >=5 mole times that of the component A in the presence of (C) an alkali metal hydroxide and (D) a phase transfer catalyst at <=0 deg.C, preferably at -40 to -20 deg.C, to obtain the objective compound of formula III. The components B and C are preferably used respectively in amounts of >=10 mole times and >=1 mole times, that of the component A.

Description

【発明の詳細な説明】Detailed Description of the Invention

【0001】[0001]

【発明の属する技術分野】本発明はN−置換−β−ラク
タム化合物の製造法に関する。
TECHNICAL FIELD The present invention relates to a method for producing an N-substituted-β-lactam compound.

【0002】[0002]

【従来の技術】従来より、一般式(4) で示されるβ−ラクタム類のアリールエステル化物をテ
トラヒドロフラン中、水素化ナトリウムの存在下に−5
℃でブロモ酢酸 t−ブチルと反応させてN−アルキル化
する方法や、ジクロロメタン中、5モル倍のブロモ酢酸
t−ブチルを用い、水酸化ナトリウムおよび塩化トリエ
チルベンジルアンモニウムの存在下に室温で反応させて
N−置換−β−ラクタム類を製造する方法が知られてい
る。
2. Description of the Related Art Conventionally, general formula (4) The aryl esterified product of β-lactam represented by -5 is added to tetrahydrofuran in the presence of sodium hydride to give -5.
Method of N-alkylation by reacting with t-butyl bromoacetate at ℃, or 5 mol times bromoacetic acid in dichloromethane
A method for producing N-substituted-β-lactams by reacting t-butyl in the presence of sodium hydroxide and triethylbenzylammonium chloride at room temperature is known.

【0003】一方、本発明の目的化合物である一般式
(1) (式中、R1は水酸基の保護基を、R2は水素原子または低
級アルキル基を、R3はアリール基を、R4はカルボキシル
基の保護基をそれぞれ示す。)で示されるN−置換−β
−ラクタム化合物は、抗菌剤として有用なカルバペナム
化合物の有用な中間体としてよく知られており、その製
造法としては基幹原料である前記一般式(4)で示され
るβ−ラクタム類のアリールエステル化、N−アルキル
化、アリールエステル基のアリールチオエステル基への
転換などの工程を経由して合成する方法が知られている
〔Chem. Pharm. Bull., 42(7),1381-1387(1994) 〕。し
かし、この方法は工程数が多いため工業的な製造法とし
て決して有利とは言えず、工程数が少なく、収率的にも
優れた方法の開発が望まれている。
On the other hand, the general formula (1), which is the object compound of the present invention, (Wherein R 1 represents a hydroxyl-protecting group, R 2 represents a hydrogen atom or a lower alkyl group, R 3 represents an aryl group, and R 4 represents a carboxyl-protecting group). -Β
A lactam compound is well known as a useful intermediate of a carbapenam compound useful as an antibacterial agent, and its production method is aryl esterification of β-lactams represented by the general formula (4), which is a basic raw material. , N-alkylation, conversion of aryl ester group to aryl thioester group, and the like are known [Chem. Pharm. Bull., 42 (7), 1381-1387 (1994). ]. However, since this method has a large number of steps, it cannot be said to be advantageous as an industrial manufacturing method, and it is desired to develop a method having a small number of steps and an excellent yield.

【0004】そのための方法として、前記した一般式
(4)で示されるβ−ラクタム類から予めそのアリール
チオエステル化物を製造し、これをN−置換して目的化
合物を製造する方法が考えられ、この場合のN−置換方
法として前述の一般式(4)で示されるβ−ラクタム類
のアリールエステル化物のN−置換反応を適用する方法
が考えられるが、この方法をアリールチオエステル基を
有するβ−ラクタム類に適用した場合には、該アリール
チオエステル基を有するβ−ラクタム類が塩基条件下に
おいては比較的不安定なため容易に分解し、目的化合物
の収率が非常に低いために工業的に有利な方法とはなり
得ないという問題がある。
As a method therefor, a method is conceivable in which the aryl thioester compound is prepared in advance from the β-lactam represented by the above-mentioned general formula (4), and N-substituted to produce the desired compound. As the N-substitution method in this case, a method of applying an N-substitution reaction of the aryl ester compound of the β-lactam represented by the above-mentioned general formula (4) can be considered. This method is a β-lactam having an arylthioester group. When applied to the compounds, β-lactams having the arylthioester group are relatively unstable under basic conditions and are easily decomposed, and the yield of the target compound is very low, which is industrially advantageous. There is a problem that this method cannot be used.

【0005】このため、一般式(1)で示されるN−置
換−β−ラクタム化合物を工業的に有利に製造するため
には、アリールチオエステル基を有するβ−ラクタム類
を容易に、かつ収率よくN−置換する方法の開発が極め
て重要となる。
Therefore, in order to industrially advantageously produce an N-substituted-β-lactam compound represented by the general formula (1), β-lactams having an arylthioester group can be easily and yielded. The development of well N-substitution methods is extremely important.

【0006】[0006]

【発明が解決しようとする課題】このようなことから、
本発明者らはアリールチオエステル基を有するβ−ラク
タム類を容易に、かつ収率よくN−置換して前記一般式
(1)で示されるN−置換−β−ラクタム化合物を製造
すべく検討の結果、本発明に至った。
DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present inventors have studied to easily and efficiently yield N-substituted β-lactams having an arylthioester group to produce an N-substituted-β-lactam compound represented by the general formula (1). As a result, the present invention has been achieved.

【0007】[0007]

【課題を解決するための手段】すなわち本発明は、一般
式(2) (式中、R1、R2およびR3は前記と同じ意味を有する。)
で示されるβ−ラクタム化合物と、これに対して5モル
倍以上の一般式(3) (式中、R4は前記と同じ意味を有し、Xは脱離基を示
す)で示される酢酸誘導体とを、アルカリ金属水酸化物
および相間移動触媒の存在下に、0℃以下で反応させる
ことを特徴とする前記一般式(1)で示されるN−置換
−β−ラクタム化合物の製造法を提供するものである。
That is, the present invention is based on the general formula (2): (In the formula, R 1 , R 2 and R 3 have the same meanings as described above.)
And a β-lactam compound represented by (Wherein R 4 has the same meaning as described above, and X represents a leaving group), and is reacted at 0 ° C. or lower in the presence of an alkali metal hydroxide and a phase transfer catalyst. The present invention provides a method for producing an N-substituted-β-lactam compound represented by the above general formula (1).

【0008】[0008]

【発明の実施の形態】本発明において、原料であるβ−
ラクタム化合物は前記一般式(2)で示されるが、かか
る一般式において、置換基R1は水酸基の保護基であり、
水酸基の保護基として通常知られているものであれば特
に限定されないが、例えば、トリメチルシリル基、トリ
エチルシリル基、ジメチルイソプロピルシリル基、t−
ブチルジメチルシリル基、トリイソプロピルシリル基、
ジフェニル−t−ブチルシリル基などのシリル基、メト
キシメチル基、2−メトキシエトキシメチル基、メチル
チオメチル基などの置換メチル基、t−ブトキシカルボ
ニル基、2−ヨウ化エチルオキシカルボニル基、2,
2,2−トリクロロエチルオキシカルボニル基、ベンジ
ルオキシカルボニル基、o−ニトロベンジルオキシカル
ボニル基、p−ニトロベンジルオキシカルボニル基、p
−メトキシベンジルオキシカルボニル基などのアルコキ
シカルボニル基が挙げられ、置換基R2は水素原子または
低級アルキル基であって、低級アルキル基としてはメチ
ル基、エチル基、ブチル基などが挙げられる。
BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, β- which is a raw material
The lactam compound is represented by the above general formula (2), in which the substituent R 1 is a protective group for a hydroxyl group,
It is not particularly limited as long as it is commonly known as a hydroxyl-protecting group, and examples thereof include trimethylsilyl group, triethylsilyl group, dimethylisopropylsilyl group and t-
Butyldimethylsilyl group, triisopropylsilyl group,
Silyl group such as diphenyl-t-butylsilyl group, methoxymethyl group, 2-methoxyethoxymethyl group, substituted methyl group such as methylthiomethyl group, t-butoxycarbonyl group, 2-iodyloxycarbonyl group, 2,
2,2-trichloroethyloxycarbonyl group, benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p
Examples thereof include alkoxycarbonyl groups such as -methoxybenzyloxycarbonyl group, the substituent R 2 is a hydrogen atom or a lower alkyl group, and examples of the lower alkyl group include a methyl group, an ethyl group and a butyl group.

【0009】また、置換基R3はアリール基であり、具体
的にはフェニル基、トルイル基、p−クロロフェニル
基、o−クロロフェニル基、2,4,5−トリクロロフ
ェニル基、p−ニトロフェニル基、o−ニトロフェニル
基などの他、2−ピリミジニル基、2−ピリジル基など
のヘテロアリール基などが挙げられる。
The substituent R 3 is an aryl group, specifically, a phenyl group, a toluyl group, a p-chlorophenyl group, an o-chlorophenyl group, a 2,4,5-trichlorophenyl group, a p-nitrophenyl group. , O-nitrophenyl group and the like, as well as a heteroaryl group such as a 2-pyrimidinyl group and a 2-pyridyl group.

【0010】このような前記一般式(2)で示されるβ
−ラクタム化合物は公知であって、たとえば特開昭62
−103084号公報に記載の方法により、容易に製造
することができる。
Β represented by the above general formula (2)
-Lactam compounds are known and are disclosed, for example, in JP-A-62-62.
It can be easily produced by the method described in JP-A-103084.

【0011】また、もう一方の原料である酢酸誘導体は
一般式(2)で示されるが、該一般式において、脱離基
Xとしてはベンゼンスルホニルオキシ基、p−トルエン
スルホニルオキシ基、p−ニトロベンゼンスルホニルオ
キシ基などの置換もしくは無置換アリールスルホニルオ
キシ基、メタンスルホニルオキシ基、エタンスルホニル
オキシ基、トリフルオロメタンスルホニルオキシ基など
の低級アルカンあるいはハロゲノ低級アルカンスルホニ
ルオキシ基、クロロ基、ブロモ基、ヨード基などのハロ
ゲノ基などが例示される。また、カルボキシル基の保護
基である置換基R4としては、メチル基、エチル基、イソ
プロピル基、t−ブチル基などの直鎖状もしくは分枝鎖
状の低級アルキル基、2−メチルアリル基、3−メチル
アリル基、2−ペンテニル基、3−ペンテニル基、3−
フェニルアリル基などの置換されていてもよいアルケニ
ルメチル基、ベンジル基、p−メトキシベンジル基、
2,4−ジメトキシベンジル基、o−ニトロベンジル
基、p−ニトロベンジル基、p−クロロベンジル基など
の置換もしくは無置換のモノアリールアルキル基、ジフ
ェニルメチル基、ジ−p−アニシルメチル基などの置換
もしくは無置換のジアリールアルキル基、フェニル基、
p−クロロフェニル基、2,4,5−トリクロロフェニ
ル基、p−ニトロフェニル基、o−ニトロフェニル基な
どの置換もしくは無置換のアリール基、2−ピリジル
基、2−ピリミジル基などのヘテロアリール基、メトキ
シメチル基、エトキシメチル基などのアルコキシアルキ
ル基などが例示される。
The acetic acid derivative as the other raw material is represented by the general formula (2). In the general formula, the leaving group X is benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzene. Substituted or unsubstituted arylsulfonyloxy group such as sulfonyloxy group, methanesulfonyloxy group, ethanesulfonyloxy group, lower alkane such as trifluoromethanesulfonyloxy group or halogeno lower alkanesulfonyloxy group, chloro group, bromo group, iodo group, etc. And the halogeno group of is exemplified. Further, as the substituent R 4 which is a protective group for a carboxyl group, a linear or branched lower alkyl group such as a methyl group, an ethyl group, an isopropyl group and a t-butyl group, a 2-methylallyl group, 3 -Methylallyl group, 2-pentenyl group, 3-pentenyl group, 3-
An optionally substituted alkenylmethyl group such as phenylallyl group, benzyl group, p-methoxybenzyl group,
Substitution of substituted or unsubstituted monoarylalkyl group such as 2,4-dimethoxybenzyl group, o-nitrobenzyl group, p-nitrobenzyl group, p-chlorobenzyl group, diphenylmethyl group, di-p-anisylmethyl group Or an unsubstituted diarylalkyl group, a phenyl group,
Substituted or unsubstituted aryl group such as p-chlorophenyl group, 2,4,5-trichlorophenyl group, p-nitrophenyl group and o-nitrophenyl group, and heteroaryl group such as 2-pyridyl group and 2-pyrimidyl group Examples thereof include alkoxyalkyl groups such as methoxymethyl group and ethoxymethyl group.

【0012】一般式(2)で示されるβ−ラクタム化合
物と一般式(3)で示される酢酸誘導体との反応は、ア
ルカリ金属水酸化物および相間移動触媒の存在下に行わ
れる。ここで、アルカリ金属水酸化物としては、水酸化
カリウム、水酸化ナトリウム、水酸化ルビジウム、水酸
化セシウムなどが例示され、これらは固体または水溶液
として使用される。また、相間移動触媒としてはヨウ化
テトラn−ブチルアンモニウム、臭化テトラn−ブチル
アンモニウム、塩化テトラn−ブチルアンモニウム、臭
化テトライソプロピルアンモニウム、塩化テトライソプ
ロピルアンモニウム、塩化テトラメチルアンモニウム、
塩化テトラエチルアンモニウム、塩化トリエチルベンジ
ルアンモニウムなどの4級アンモニウム塩が挙げられ
る。
The reaction between the β-lactam compound represented by the general formula (2) and the acetic acid derivative represented by the general formula (3) is carried out in the presence of an alkali metal hydroxide and a phase transfer catalyst. Here, examples of the alkali metal hydroxide include potassium hydroxide, sodium hydroxide, rubidium hydroxide, and cesium hydroxide, and these are used as solids or aqueous solutions. Further, as the phase transfer catalyst, tetra n-butyl ammonium iodide, tetra n-butyl ammonium bromide, tetra n-butyl ammonium chloride, tetraisopropyl ammonium bromide, tetraisopropyl ammonium chloride, tetramethyl ammonium chloride,
Examples thereof include quaternary ammonium salts such as tetraethylammonium chloride and triethylbenzylammonium chloride.

【0013】かかる反応において、酢酸誘導体の使用量
はβ−ラクタム化合物に対して5モル倍以上、好ましく
は10モル倍以上は必要であり、これより少なくなると
収率が低下する傾向にある。アルカリ金属水酸化物や相
間移動触媒の使用量は特に限定されないが、アルカリ金
属水酸化物についてはβ−ラクタム化合物に対して通常
1〜10モル倍、好ましくは2〜6モル倍、相間移動触
媒についてはβ−ラクタム化合物に対して通常0.01
〜1モル倍、好ましくは0.05〜0.2モル倍であ
る。
In such a reaction, the amount of the acetic acid derivative used is required to be 5 mol times or more, preferably 10 mol times or more with respect to the β-lactam compound, and if it is less than this, the yield tends to be lowered. The amount of the alkali metal hydroxide or the phase transfer catalyst used is not particularly limited, but the alkali metal hydroxide is usually 1 to 10 mol times, preferably 2 to 6 mol times, the phase transfer catalyst with respect to the β-lactam compound. Is usually 0.01 for β-lactam compounds.
-1 mol times, preferably 0.05-0.2 mol times.

【0014】この反応は、通常はトルエン、ベンゼン、
テトラヒドルフラン、ジクロロメタン、1,2−ジクロ
ロエタン、モノクロロベゼンなどの反応に不活性な溶媒
中で行われ、その使用量は特に制限されるものではない
が通常は原料β−ラクタム化合物に対して1〜100重
量倍の範囲である。反応原料である酢酸誘導体が液状で
ある場合には、このような溶媒を用いることなく、該酢
酸誘導体を溶媒を兼ねて反応を行うこともできる。
This reaction is usually carried out with toluene, benzene,
The reaction is carried out in a solvent inert to the reaction such as tetrahydrofuran, dichloromethane, 1,2-dichloroethane, monochlorobezene, etc. Although the amount used is not particularly limited, it is usually relative to the raw material β-lactam compound. It is in the range of 1 to 100 times by weight. When the acetic acid derivative, which is a reaction raw material, is in a liquid state, the reaction can be carried out by using the acetic acid derivative also as a solvent without using such a solvent.

【0015】この反応における反応方法は任意である
が、通常は、β−ラクタム化合物、酢酸誘導体および相
間移動触媒を不活性溶媒に溶解し、これにアルカリ金属
水酸化物を加えることにより行われ、不活性溶媒を使用
しない場合にはβ−ラクタム化合物および相間移動触媒
を酢酸誘導体に溶解し、これにアルカリ金属水酸化物を
加えて反応を行えばよい。
Although the reaction method in this reaction is arbitrary, it is usually carried out by dissolving the β-lactam compound, the acetic acid derivative and the phase transfer catalyst in an inert solvent and adding an alkali metal hydroxide thereto. When an inert solvent is not used, the β-lactam compound and the phase transfer catalyst may be dissolved in an acetic acid derivative, and an alkali metal hydroxide may be added thereto to carry out the reaction.

【0016】この反応において、反応温度は酢酸誘導体
の使用量とともに極めて重要な要件であって、0℃以
下、好ましくは−20℃以下であることが必要であり、
0℃を越えると収率が低下して所望の効果を得ることが
できない。反応温度の下限は特に限定されないが、一般
的には−50℃、好ましくは−40℃である。
In this reaction, the reaction temperature is a very important requirement together with the amount of the acetic acid derivative used, and it is necessary that the reaction temperature is 0 ° C. or lower, preferably −20 ° C. or lower,
If the temperature exceeds 0 ° C, the yield is lowered and the desired effect cannot be obtained. The lower limit of the reaction temperature is not particularly limited, but it is generally -50 ° C, preferably -40 ° C.

【0017】反応終了後は、生成した一般式(1)で示
されるN−置換−β−ラクタム化合物の水酸基の保護基
である置換基R1がはずれないように、該反応混合物を酢
酸、希塩酸、希硫酸、燐酸、塩化アンモニウムなどの弱
酸で中和し、その後水を加えて洗浄、分液した後、有機
層を脱水剤などで脱水処理し、これを減圧濃縮するなど
の方法により目的化合物を得ることができる。尚、上記
反応において不活性溶媒を使用しなかった場合には、水
による洗浄の際にトルエン、ベンゼン、ジクロロメタ
ン、1,2−ジクロロエタン、モノクロロベゼンなどの
水と分液する有機溶媒を加えることが操作上好まれる。
After completion of the reaction, the reaction mixture is treated with acetic acid and dilute hydrochloric acid so that the substituent R 1 which is a protective group for the hydroxyl group of the N-substituted-β-lactam compound represented by the general formula (1) does not come off. The target compound is neutralized with a weak acid such as dilute sulfuric acid, phosphoric acid, or ammonium chloride, washed with water and then separated, and then the organic layer is dehydrated with a dehydrating agent and concentrated under reduced pressure. Can be obtained. When an inert solvent is not used in the above reaction, an organic solvent that separates from water such as toluene, benzene, dichloromethane, 1,2-dichloroethane and monochlorobezene should be added when washing with water. Is preferred for operation.

【0018】[0018]

【発明の効果】本発明の方法によれば、一般式(2)で
示されるアリールチオエステル基を有するβ−ラクタム
化合物から、容易に、好収率で一般式(1)で示される
N−置換−β−ラクタム化合物を得ることができ、その
結果、基幹原料である一般式(4)で示されるβ−ラク
タム類から少ない工程数で、カルバペネムの重要な中間
体であるN−置換−β−ラクタム化合物を製造すること
が可能となる。
According to the method of the present invention, a β-lactam compound having an arylthioester group represented by the general formula (2) can be easily and favorably yielded by N-substitution represented by the general formula (1). It is possible to obtain a -β-lactam compound, and as a result, N-substituted-β- which is an important intermediate of carbapenem can be obtained from the β-lactam represented by the general formula (4) which is a basic material in a small number of steps. It becomes possible to produce a lactam compound.

【0019】[0019]

【実施例】以下、実施例により本発明をさらに詳細に説
明するが、本発明がこれによって限定されるものでない
ことはいうまでもない。
EXAMPLES The present invention will be described in more detail with reference to the following examples, but it goes without saying that the present invention is not limited thereto.

【0020】実施例1 (3S,4S)−3−〔(1R)−1−t−ブチルジメ
チルシリルオキシエチル〕−4−〔(1R)−1−p−
クロロフェニルチオカルボニルエチル〕−2−アゼチジ
ノン2g(純度 96.9%)、ブロム酢酸t−ブチル
5.9g(6.7モル倍)およびヨウ化テトラn−ブチ
ルアンモニウム1.7gをトルエン30mlに溶解し、
−27℃で51%水酸化カリウム2gを加えたのち、同
温度で2時間攪拌した。その後、反応混合物に水20m
lを加えて洗浄、分液し、水層とトルエン層を得る。水
層をトルエン10mlで抽出処理し、このトルエン層を
先のトルエン層と合わせる。トルエン層を飽和塩化アン
モニウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後
減圧濃縮して、(3S,4S)−3−〔(1R)−1−
t−ブチルジメチルシリルオキシエチル〕−4−〔(1
R)−1−p−クロロフェニルチオカルボニルエチル〕
−1−t−ブトキシカルボニルメチル−2−アゼチジノ
ンを33.7重量%含む油状物6.2gを得た。(収率
85.1%)
Example 1 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -2-azetidinone 2 g (purity 96.9%), t-butyl bromacetate 5.9 g (6.7 mol times) and tetra-n-butylammonium iodide 1.7 g were dissolved in toluene 30 ml. ,
After adding 2 g of 51% potassium hydroxide at -27 ° C, the mixture was stirred at the same temperature for 2 hours. Then, 20m of water was added to the reaction mixture.
l was added thereto for washing and liquid separation to obtain an aqueous layer and a toluene layer. The aqueous layer was extracted with 10 ml of toluene, and this toluene layer was combined with the previous toluene layer. The toluene layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (3S, 4S) -3-[(1R) -1-
t-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
6.2 g of an oily substance containing 33.7% by weight of -1-t-butoxycarbonylmethyl-2-azetidinone was obtained. (Yield 85.1%)

【0021】実施例2 ブロム酢酸t−ブチルを11.5g(13モル倍)使用
する以外は実施例1と同様に反応、後処理を行い、(3
S,4S)−3−〔(1R)−1−t−ブチルジメチル
シリルオキシエチル〕−4−〔(1R)−1−p−クロ
ロフェニルチオカルボニルエチル〕−1−t−ブトキシ
カルボニルメチル−2−アゼチジノンを21.9重量%
含む油状物10.0gを得た。(収率89.2%)
Example 2 Reaction and post-treatment were carried out in the same manner as in Example 1 except that 11.5 g (13 mole times) of t-butyl bromoacetate was used, and (3
S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2- 21.9% by weight of azetidinone
An oily substance containing 10.0 g was obtained. (Yield 89.2%)

【0022】実施例3 (3S,4S)−3−〔(1R)−1−t−ブチルジメ
チルシリルオキシエチル〕−4−〔(1R)−1−p−
クロロフェニルチオカルボニルエチル〕−2−アゼチジ
ノン2g(純度 96.9%)および臭化テトラn−ブ
チルアンモニウム0.1gをブロム酢酸t−ブチル1
1.5g(13モル倍)に溶解し、−27℃で51%水
酸化カリウム1.2gを加えたのち、同温度で4時間攪
拌した。その後、反応混合物に4%酢酸/トルエン溶液
26gを加えて中和し、水25gで2回洗浄した。洗浄
後の有機層を無水硫酸ナトリウムで乾燥後減圧濃縮し
て、(3S,4S)−3−〔(1R)−1−t−ブチル
ジメチルシリルオキシエチル〕−4−〔(1R)−1−
p−クロロフェニルチオカルボニルエチル〕−1−t−
ブトキシカルボニルメチル−2−アゼチジノンを24.
2重量%含む油状物8.9gを得た。(収率87.7
%) この油状物をシリカゲルクロマトグラフィーによりヘキ
サン/酢酸エチルで精製して純度90.1%の目的化合
物を得た。
Example 3 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -2-azetidinone (2 g, purity 96.9%) and tetra-n-butylammonium bromide (0.1 g) were added to t-butyl 1-bromoacetate.
It was dissolved in 1.5 g (13 mol times), 1.2 g of 51% potassium hydroxide was added at -27 ° C, and the mixture was stirred at the same temperature for 4 hours. Then, the reaction mixture was neutralized by adding 26 g of a 4% acetic acid / toluene solution, and washed twice with 25 g of water. The washed organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
p-chlorophenylthiocarbonylethyl] -1-t-
24. butoxycarbonylmethyl-2-azetidinone.
8.9 g of an oil containing 2% by weight was obtained. (Yield 87.7
This oily matter was purified by silica gel chromatography with hexane / ethyl acetate to obtain a target compound having a purity of 90.1%.

【0023】比較例1 (3S,4S)−3−〔(1R)−1−t−ブチルジメ
チルシリルオキシエチル〕−4−〔(1R)−1−p−
クロロフェニルチオカルボニルエチル〕−2−アゼチジ
ノン2g(純度 96.9%)、ブロム酢酸t−ブチル
2.3g(2.6モル倍)およびヨウ化テトラn−ブチ
ルアンモニウム0.63gをジクロロメタン30mlに
溶解し、25℃で27%水酸化ナトリウム2.6gを加
えたのち、同温度で3.5時間攪拌した。その後、反応
混合物に水20mlを加えて洗浄、分液し、水層とジク
ロロメタン層を得る。水層をジクロロメタン10mlで
抽出処理し、このジクロロメタン層を先のジクロロメタ
ン層と合わせる。ジクロロメタン層を飽和塩化アンモニ
ウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後減圧
濃縮して、(3S,4S)−3−〔(1R)−1−t−
ブチルジメチルシリルオキシエチル〕−4−〔(1R)
−1−p−クロロフェニルチオカルボニルエチル〕−1
−t−ブトキシカルボニルメチル−2−アゼチジノンを
15.1重量%含む油状物4.7gを得た。(収率2
8.9%)
Comparative Example 1 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -2-azetidinone 2 g (purity 96.9%), t-butyl bromacetate 2.3 g (2.6 mole times) and tetran-butylammonium iodide 0.63 g were dissolved in dichloromethane 30 ml. After adding 2.6 g of 27% sodium hydroxide at 25 ° C., the mixture was stirred at the same temperature for 3.5 hours. Then, 20 ml of water is added to the reaction mixture for washing and liquid separation to obtain an aqueous layer and a dichloromethane layer. The aqueous layer was extracted with 10 ml of dichloromethane, and this dichloromethane layer was combined with the previous dichloromethane layer. The dichloromethane layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (3S, 4S) -3-[(1R) -1-t-
Butyldimethylsilyloxyethyl] -4-[(1R)
-1-p-Chlorophenylthiocarbonylethyl] -1
4.7 g of an oily substance containing 15.1% by weight of -t-butoxycarbonylmethyl-2-azetidinone was obtained. (Yield 2
(8.9%)

【0024】比較例2 ヨウ化テトラn−ブチルアンモニウムを0.8g使用
し、27%水酸化ナトリウム2.6gに代えて8.4M
水酸化カリウム2.2mlを使用し、反応温度を0℃、
反応時間を4.5時間とする以外は比較例1と同様に反
応、後処理して、(3S,4S)−3−〔(1R)−1
−t−ブチルジメチルシリルオキシエチル〕−4−
〔(1R)−1−p−クロロフェニルチオカルボニルエ
チル〕−1−t−ブトキシカルボニルメチル−2−アゼ
チジノンを25.1重量%含む油状物4.5gを得た。
(収率46.0%)
Comparative Example 2 Tetra n-butylammonium iodide (0.8 g) was used, and 8.4M was used instead of 27% sodium hydroxide (2.6 g).
Using 2.2 ml of potassium hydroxide, the reaction temperature is 0 ° C,
The reaction and post-treatment were carried out in the same manner as in Comparative Example 1 except that the reaction time was 4.5 hours, and then (3S, 4S) -3-[(1R) -1
-T-butyldimethylsilyloxyethyl] -4-
4.5 g of an oily matter containing 25.1% by weight of [(1R) -1-p-chlorophenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-azetidinone was obtained.
(Yield 46.0%)

【0025】比較例3 ヨウ化テトラn−ブチルアンモニウムを0.83g使用
し、27%水酸化ナトリウム2.6gに代えて8.4M
水酸化カリウム2.2mlを使用し、反応温度を−15
℃、反応時間を10.5時間とする以外は比較例1と同
様に反応、後処理して、(3S,4S)−3−〔(1
R)−1−t−ブチルジメチルシリルオキシエチル〕−
4−〔(1R)−1−p−クロロフェニルチオカルボニ
ルエチル〕−1−t−ブトキシカルボニルメチル−2−
アゼチジノンを33.0重量%含む油状物4.0gを得
た。(収率53.8%)
Comparative Example 3 0.83 g of tetra-n-butylammonium iodide was used, and 8.4M was used instead of 2.6 g of 27% sodium hydroxide.
Using 2.2 ml of potassium hydroxide, the reaction temperature was -15
The reaction and post-treatment were carried out in the same manner as in Comparative Example 1 except that the reaction temperature was 10.5 hours and the reaction temperature was 10.5 hours.
R) -1-t-Butyldimethylsilyloxyethyl]-
4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -1-t-butoxycarbonylmethyl-2-
4.0 g of an oily substance containing 33.0% by weight of azetidinone was obtained. (Yield 53.8%)

Claims (5)

【特許請求の範囲】[Claims] 【請求項1】一般式(2) (式中、R1は水酸基の保護基を、R2は水素原子または低
級アルキル基を、R3はアリール基をそれぞれ示す。)で
示されるβ−ラクタム化合物と、これに対して5モル倍
以上の一般式(3) (式中、R4はカルボキシル基の保護基を、Xは脱離基を
示す)で示される酢酸誘導体とを、アルカリ金属水酸化
物および相間移動触媒の存在下に、0℃以下で反応させ
ることを特徴とする一般式(1) (式中、R1、R2、R3およびR4は前記と同じ意味を有す
る。)で示されるN−置換−β−ラクタム化合物の製造
法。
1. The general formula (2) (In the formula, R 1 represents a hydroxyl-protecting group, R 2 represents a hydrogen atom or a lower alkyl group, and R 3 represents an aryl group.) And a β-lactam compound represented by 5 mole times The above general formula (3) (Wherein R 4 represents a protecting group for a carboxyl group, and X represents a leaving group) is reacted at 0 ° C. or lower in the presence of an alkali metal hydroxide and a phase transfer catalyst. General formula (1) characterized by (In the formula, R 1 , R 2 , R 3 and R 4 have the same meanings as described above.) A method for producing an N-substituted-β-lactam compound.
【請求項2】酢酸誘導体の使用量がβ−ラクタム化合物
に対して10モル倍以上である請求項1に記載のN−置
換−β−ラクタム化合物の製造法。
2. The method for producing an N-substituted-β-lactam compound according to claim 1, wherein the amount of the acetic acid derivative used is 10 times or more the molar amount of the β-lactam compound.
【請求項3】酢酸誘導体がハロゲノ酢酸アルキルエステ
ルである請求項1または2に記載のN−置換−β−ラク
タム化合物の製造法。
3. The method for producing an N-substituted-β-lactam compound according to claim 1, wherein the acetic acid derivative is a halogenoacetic acid alkyl ester.
【請求項4】アルカリ金属水酸化物の使用量がβ−ラク
タム化合物に対して1モル倍以上である請求項1に記載
のN−置換−β−ラクタム化合物の製造法。
4. The method for producing an N-substituted-β-lactam compound according to claim 1, wherein the amount of the alkali metal hydroxide used is 1 mole times or more the amount of the β-lactam compound.
【請求項5】反応温度が−40℃〜−20℃である請求
項1に記載のN−置換−β−ラクタム化合物の製造法。
5. The method for producing an N-substituted-β-lactam compound according to claim 1, wherein the reaction temperature is −40 ° C. to −20 ° C.
JP8090966A 1996-04-12 1996-04-12 Production of n-substituted-beta-lactam compound Pending JPH09278748A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP8090966A JPH09278748A (en) 1996-04-12 1996-04-12 Production of n-substituted-beta-lactam compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP8090966A JPH09278748A (en) 1996-04-12 1996-04-12 Production of n-substituted-beta-lactam compound

Publications (1)

Publication Number Publication Date
JPH09278748A true JPH09278748A (en) 1997-10-28

Family

ID=14013248

Family Applications (1)

Application Number Title Priority Date Filing Date
JP8090966A Pending JPH09278748A (en) 1996-04-12 1996-04-12 Production of n-substituted-beta-lactam compound

Country Status (1)

Country Link
JP (1) JPH09278748A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002326985A (en) * 2001-04-27 2002-11-15 Sumitomo Pharmaceut Co Ltd Azetidinone derivative and method for producing the same
WO2005005446A1 (en) * 2003-07-11 2005-01-20 Nippon Soda Co., Ltd. Processes for producing carbapenem intermediate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002326985A (en) * 2001-04-27 2002-11-15 Sumitomo Pharmaceut Co Ltd Azetidinone derivative and method for producing the same
WO2005005446A1 (en) * 2003-07-11 2005-01-20 Nippon Soda Co., Ltd. Processes for producing carbapenem intermediate
JPWO2005005446A1 (en) * 2003-07-11 2006-08-24 日本曹達株式会社 Method for producing carbapenem intermediate
JP4552231B2 (en) * 2003-07-11 2010-09-29 日本曹達株式会社 Method for producing carbapenem intermediate

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