JPH06321952A - Method for removing allyl group - Google Patents
Method for removing allyl groupInfo
- Publication number
- JPH06321952A JPH06321952A JP5113205A JP11320593A JPH06321952A JP H06321952 A JPH06321952 A JP H06321952A JP 5113205 A JP5113205 A JP 5113205A JP 11320593 A JP11320593 A JP 11320593A JP H06321952 A JPH06321952 A JP H06321952A
- Authority
- JP
- Japan
- Prior art keywords
- group
- allyl
- alkali metal
- carboxylic acid
- allyl group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、β−ラクタム系抗生物
質を合成する際に、カルボキシル基等の保護基として頻
繁に利用されているアリル基を、除去する方法に関する
ものである。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for removing an allyl group frequently used as a protective group such as a carboxyl group when synthesizing a β-lactam antibiotic.
【０００２】[0002]
【従来の技術】β−ラクタム系抗生物質を合成する際
に、カルボキシル基の保護基としてアリル基を使用する
方法が有効である事は、Ｓ．Ｗ．ＭｃＣｏｍｂｉｅら
（ｊ．Ｏｒｇ．Ｃｈｅｍ．，４７，５８７（１９８
２））により、あるいは特開昭５５−９４３２１号公
報、特開昭６２−６１９８４号公報等に既に報告されて
いる。2. Description of the Related Art In the synthesis of β-lactam antibiotics, the method of using an allyl group as a protecting group for a carboxyl group is effective. W. McCombie et al. (J. Org. Chem., 47, 587 (198).
2)), or in JP-A-55-94321 and JP-A-62-61984.
【０００３】しかしながら、その結果得られるアリルエ
ステル化合物は、合成のいずれかの段階でこのアリル基
を除去しなければならない。However, the resulting allyl ester compound must remove this allyl group at any stage of the synthesis.
【０００４】このアリル基を除去する方法としては、
触媒としてトリフェニルホスフィンや亜燐酸トリエチル
を配位子として有するパラジウム錯体を用い、炭素数５
〜８のカルボン酸アルカリ金属塩（例えば２−エチルヘ
キサン酸ナトリウム）をアリル基受容体として用いて、
室温で反応させる方法（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，４
７，５８７（１９８２）、及び特開昭５５−９４３２１
号公報）、テトラキス（トリフェニルホスフィン）パ
ラジウム（０）及びトリブチル錫ヒドリドと反応させる
方法（特開昭６０−７２８９３号公報）、テトラキス
（トリフェニルホスフィン）パラジウム（０）の存在
下、アセチルアセトンまたはジメドンのアルカリ金属塩
と反応させる方法（特開昭６２−６１９８４号公報）等
が知られている。As a method for removing the allyl group,
A palladium complex having triphenylphosphine or triethyl phosphite as a ligand is used as a catalyst and has 5 carbon atoms.
~ 8 carboxylic acid alkali metal salt (for example, sodium 2-ethylhexanoate) as an allyl group acceptor,
Method of reacting at room temperature (J. Org. Chem., 4
7,587 (1982), and JP-A-55-94321.
No.), tetrakis (triphenylphosphine) palladium (0) and tributyltin hydride (JP-A-60-72893), acetylacetone or dimedone in the presence of tetrakis (triphenylphosphine) palladium (0). And the like (Japanese Patent Application Laid-Open No. 62-61984).
【０００５】[0005]
【発明が解決しようとする課題】しかしながら、これら
の方法の多くは比較的高価で空気中で不安定なテトラキ
ス（トリフェニルホスフィン）パラジウム（０）を用い
ており、経済性の面で欠点を有している上に、工業的に
テトラキス（トリフェニルホスフィン）パラジウム
（０）を保存する上での問題を有しているため工業的製
法として好ましいものではなかった。However, many of these methods use tetrakis (triphenylphosphine) palladium (0), which is relatively expensive and unstable in the air, and has a drawback in terms of economy. In addition, since it has a problem in industrially storing tetrakis (triphenylphosphine) palladium (0), it is not preferable as an industrial production method.
【０００６】また、上記問題を解決する方法として、酢
酸パラジウムにトリフェニルホスフィンや亜燐酸トリエ
チルを加えて反応系内において相当するパラジウム錯体
を調製後に反応する方法が示されているが、一般式
（Ｉ）で表わされる化合物にこの方法を適用した場合、
それらの反応は反応が遅く、アリルエステルの品位によ
っては反応が完結しにくいという欠点が判明した。As a method for solving the above-mentioned problem, a method of adding triphenylphosphine or triethyl phosphite to palladium acetate to prepare a corresponding palladium complex in the reaction system and then reacting it is shown. When this method is applied to the compound represented by I),
It was revealed that these reactions are slow and it is difficult to complete the reactions depending on the quality of the allyl ester.
【０００７】[0007]
【課題を解決するための手段】本発明者らは上記欠点を
解決するために鋭意研究を行った結果、ペネム化合物の
アリルエステルを、カルボン酸アルカリ金属塩をアリル
基受容体として、触媒量の酢酸パラジウム（II）と触媒
量のアルキル基の炭素数３〜８の亜燐酸トリアルキルを
用い反応する事でアリル基除去の反応は、室温で素早く
完結する事を見いだし、本発明を完成した。Means for Solving the Problems As a result of intensive studies to solve the above-mentioned drawbacks, the present inventors have found that an allyl ester of a penem compound is used as an allyl group acceptor with an alkali metal carboxylate as an allyl group acceptor. The inventors have found that the reaction for removing an allyl group can be completed quickly at room temperature by reacting palladium (II) acetate with a catalytic amount of a trialkyl phosphite having an alkyl group having 3 to 8 carbon atoms, and completed the present invention.
【０００８】すなわち、本発明は、一般式（Ｉ）：That is, the present invention has the general formula (I):
【化３】 （式中、ｍは０または１を表し、Ｒ1は置換されてもよ
いアリル基を表す。）で示されるペネム化合物のアリル
エステルを、有機溶媒中で酢酸パラジウム（II）とアル
キル基の炭素数３〜８の亜燐酸トリアルキルの存在下、
炭素数１〜８のカルボン酸のアルカリ金属塩または炭素
数１〜８のカルボン酸及びアルカリ金属塩とを反応せし
めて、一般式（II）：[Chemical 3] (In the formula, m represents 0 or 1, and R 1 represents an optionally substituted allyl group.) An allyl ester of a penem compound represented by the formula: palladium (II) acetate and carbon of an alkyl group in an organic solvent. In the presence of the number 3-8 trialkyl phosphite,
A general formula (II):
【化４】 （式中、Ｒ2はアルカリ金属を示し、ｍは前記と同じも
のを示す。）で表されるペネム化合物とするアリル基の
除去方法である。本発明の方法は酢酸パラジウムとアル
キル基の炭素数３〜８の亜燐酸トリアルキルとで、反応
系内に於いて相当するパラジウム錯体を形成するもので
ある。[Chemical 4] (In the formula, R 2 represents an alkali metal and m represents the same as described above.) The method of removing an allyl group as a penem compound. In the method of the present invention, palladium acetate and a trialkyl phosphite having an alkyl group having 3 to 8 carbon atoms form a corresponding palladium complex in the reaction system.
【０００９】ペネム化合物のアリルエステルからアリル
基を除去する反応に於いて、アルキル基の炭素数３〜８
の亜燐酸トリアルキルを配位子として有するパラジウム
錯体を用いた反応は新規なものであり、これらのパラジ
ウム錯体を用いる事でアリル基の除去の反応は、今まで
公知の反応に比べて早く進行し、室温で素早く完結す
る。In the reaction for removing an allyl group from an allyl ester of a penem compound, the alkyl group has 3 to 8 carbon atoms.
The reaction using a palladium complex having trialkyl phosphite as a ligand is novel, and the reaction for removing the allyl group proceeds faster than known reactions by using these palladium complexes. And complete quickly at room temperature.
【００１０】本発明のペネム化合物のアリルエステル
（Ｉ）（以下アリルエステル化合物と称する）のＲ1で
示される置換されていてもよいアリル基としては、例え
ばアリル基、あるいはアリルアルコール、ハロアリルア
ルコール、メチルアリルアルコール、クロチルアルコー
ル、これらの低級アルコキシ酸誘導体、シンナミルアル
コール、シンナミルアルコールの活性エステルから誘導
される基などが挙げられる。The optionally substituted allyl group represented by R 1 of the allyl ester (I) of the penem compound of the present invention (hereinafter referred to as an allyl ester compound) is, for example, allyl group, allyl alcohol, haloallyl alcohol. , Methylallyl alcohol, crotyl alcohol, lower alkoxy acid derivatives thereof, cinnamyl alcohol, and groups derived from cinnamyl alcohol active ester.
【００１１】触媒として用いる亜燐酸トリアルキルとし
ては、そのエステル基に同一または異なる炭素数３〜８
のアルコールから誘導される基を有する化合物が挙げら
れ、例えば亜燐酸トリブチル、亜燐酸トリプロピル、亜
燐酸トリペンチル、亜燐酸トリヘキシルまたは亜燐酸ト
リオクチルが例示できる。The trialkyl phosphite used as the catalyst has 3 to 8 carbon atoms which are the same or different in the ester group.
Examples thereof include compounds having a group derived from alcohol, and examples thereof include tributyl phosphite, tripropyl phosphite, tripentyl phosphite, trihexyl phosphite, and trioctyl phosphite.
【００１２】アリル基受容体として用いる炭素数１〜８
のカルボン酸のアルカリ金属塩としては、例えば、酢
酸、プロピオン酸、酪酸、ヘキサン酸もしくはエチルヘ
キサン酸のナトリウム塩またはカリウム塩が挙げられ、
また、アリル基受容体として炭素数１〜８のカルボン酸
及びアルカリ金属塩を用いる場合のカルボン酸として
は、上に例示したものと同様のカルボン酸が、アルカリ
金属塩としては該カルボン酸と金属塩を形成するもの、
例えばナトリウムまたはカリウムの炭酸水素塩あるいは
炭酸塩が例示できる。1 to 8 carbon atoms used as an allyl group acceptor
Examples of the alkali metal salt of carboxylic acid include, for example, acetic acid, propionic acid, butyric acid, sodium salt or potassium salt of hexanoic acid or ethylhexanoic acid,
When using a carboxylic acid having 1 to 8 carbon atoms and an alkali metal salt as an allyl group acceptor, the same carboxylic acids as those exemplified above are used, and the alkali metal salt is the carboxylic acid and a metal. Those that form salts,
Examples thereof include sodium or potassium hydrogen carbonate or carbonate.
【００１３】反応は、まずアリル基受容体とアリルエス
テル化合物（Ｉ）を有機溶媒中で混合する。また必要に
応じて水を添加するが、水を添加する場合の水の添加量
はアリルエステル化合物（Ｉ）１モルに対し、２．５モ
ル以上あれば良いが、余り水の量が多いと後処理で生成
物が水に溶解して収率が低下するため、２．５〜１０モ
ル程度が好ましい。In the reaction, first, the allyl group acceptor and the allyl ester compound (I) are mixed in an organic solvent. Water is added as necessary. When water is added, the amount of water added may be 2.5 mol or more per 1 mol of the allyl ester compound (I), but if the amount of water is too large, Since the product is dissolved in water in the post-treatment to reduce the yield, it is preferably about 2.5 to 10 mol.
【００１４】アリル基受容体の使用量はアリルエステル
化合物（Ｉ）１モルに対して１〜１．５モルが好まし
い。The amount of the allyl group acceptor used is preferably 1 to 1.5 mol per 1 mol of the allyl ester compound (I).
【００１５】このように調製された溶液に触媒量の亜燐
酸トリアルキルと触媒量の酢酸パラジウムを添加し、−
１０℃から用いる溶媒の沸点までの範囲で、好ましくは
５℃から４０℃で反応させる。A catalytic amount of trialkyl phosphite and a catalytic amount of palladium acetate were added to the solution thus prepared,
The reaction is carried out in the range of 10 ° C to the boiling point of the solvent used, preferably 5 ° C to 40 ° C.
【００１６】亜燐酸トリアルキルの使用量はアリルエス
テル化合物（Ｉ）１モルに対して１モル％〜５モル％が
好ましいが、更に増量して反応時間を短縮することもで
きる。The amount of trialkyl phosphite used is preferably 1 mol% to 5 mol% with respect to 1 mol of allyl ester compound (I), but the reaction time can be shortened by further increasing the amount.
【００１７】酢酸パラジウム（II）の使用量はアリルエ
ステル化合物（Ｉ）１モルに対して０．５モル％〜２．
５モル％で充分である。酢酸パラジウム（II）の添加方
法としては、反応の初期に全量を添加してもよいが、必
要に応じて添加時期を２回以上に分けて反応の初期に一
定量を加えた後に反応の途中で残りの量を添加すること
もできる。このようにする事で、反応の途中で反応の速
度が遅くなったり進行しなくなった反応を更に進めるこ
とが出来る。The amount of palladium (II) acetate used is 0.5 mol% to 2. mol per 1 mol of the allyl ester compound (I).
5 mol% is sufficient. As a method for adding palladium (II) acetate, the whole amount may be added at the initial stage of the reaction, but if necessary, the addition timing may be divided into two or more times, and a fixed amount may be added at the initial stage of the reaction before the reaction is completed. Alternatively, the remaining amount can be added. By doing so, it is possible to further advance the reaction that has slowed down or stopped progressing during the reaction.
【００１８】用いる有機溶媒としてはアリルエステル化
合物（Ｉ）及び触媒の酢酸パラジウムと亜燐酸トリアル
キルを溶解できるものであれば特に限定されないが、例
えば、ジクロロメタン、クロロホルム等のハロゲン化ア
ルキル；酢酸メチル、酢酸エチル等のエステル類；ジエ
チルエーテル、エチレングリコールジメチルエーテル、
テトラヒドロフラン、１，４−ジオキサン等のエーテル
類；メタノール、エタノール等のアルコール類；アセト
ニトリル、プロピオニトリル等のニトリル類；アセト
ン、メチルエチルケトン、メチルイソブチルケトン等の
ケトン類；またはベンゼン、トルエン、キシレン等の芳
香族炭化水素類が挙げられ、これらは単独もしくは必要
に応じて二種以上混合して用いられる。The organic solvent to be used is not particularly limited as long as it can dissolve the allyl ester compound (I) and the catalyst palladium acetate and trialkyl phosphite, for example, alkyl halides such as dichloromethane and chloroform; methyl acetate, Esters such as ethyl acetate; diethyl ether, ethylene glycol dimethyl ether,
Ethers such as tetrahydrofuran and 1,4-dioxane; alcohols such as methanol and ethanol; nitriles such as acetonitrile and propionitrile; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; or benzene, toluene, xylene and the like. Aromatic hydrocarbons may be mentioned, and these may be used alone or in admixture of two or more as necessary.
【００１９】反応により生成する一般式（II）で表され
るペネム化合物は、有機溶媒に水を添加した反応では、
通常水和物の形で存在し、使用した溶剤に難溶な場合に
は生成物が水和物の結晶となって析出する。また、有機
溶媒に水を添加しない場合には、一般に結晶が析出しに
くい為に、反応の終了後に水を添加する事で目的化合物
の水和物の結晶を析出させる事ができる。The penem compound represented by the general formula (II) produced by the reaction is obtained by adding water to an organic solvent,
It usually exists in the form of a hydrate, and when it is poorly soluble in the solvent used, the product precipitates as hydrate crystals. In addition, when water is not added to the organic solvent, crystals generally do not easily precipitate, so that it is possible to precipitate crystals of a hydrate of the target compound by adding water after the reaction.
【００２０】このようにして得られた目的化合物の結晶
は、必要に応じて、再結晶等の操作で更に精製する事も
出来る。The crystals of the target compound thus obtained can be further purified by an operation such as recrystallization, if necessary.
【００２１】[0021]
【実施例】次に実施例を挙げて本発明を詳細に説明する
が、本発明はこれらの実施例のみに限定されるものでは
ない。The present invention will now be described in detail with reference to examples, but the present invention is not limited to these examples.
【００２２】実施例１ （１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸ナトリウム塩の合成 Example 1 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro)
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt
【化５】 （１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸アリルエステル６．５１ｇ（２０
ｍｍｏｌ）をテトラヒドロフラン３０ｍｌに溶解し、水
１．８ｍｌ、プロピオン酸ナトリウム２．５０ｇ（２６
ｍｍｏｌ）および亜燐酸トリブチル０．２５ｇ（１ｍｍ
ｏｌ）を撹拌下に順次添加した。溶液を１５℃に冷却
し、酢酸パラジウム０．０４ｇ（０．２ｍｍｏｌ）を撹
拌下に添加した後、２５℃まで昇温して同温度で１．５
時間撹拌して反応を完結させた。反応液を−５℃まで冷
却した後、反応液を濾過して得られた結晶を０℃に冷却
したＴＨＦ２０ｍｌとアセトン１２．５ｍｌで順次洗浄
した。得られた結晶を減圧下で乾燥し、６．８０ｇの白
色結晶を得た。内部標準法による高速液体クロマトグラ
フィーによる測定を行い、結晶中の（１’Ｒ，２”Ｒ，
５Ｒ，６Ｓ）−６−（１’−ヒドロキシエチル）−２−
（２”−テトラヒドロフラニル）ペネム−３−カルボン
酸のナトリウム塩の２．５水和物の純度は９８．５％で
あった。（収率：９４％）1 Ｈ−ＮＭＲ（ＣＤＣｌ3，δｐｐｍ，ＴＭＳ標準） １．７１（３Ｈ，ｄ，Ｊ＝６Ｈｚ），１．７３−２．０
３（３Ｈ，ｍ），２．１８−２．３５（１Ｈ，ｍ），
３．６７−３．９２（３Ｈ，ｍ），４．０５−４．１９
（１Ｈ，ｍ），５．３８（１Ｈ，ｄ，ｄ，Ｊ＝７Ｈ
ｚ），５．４６（１Ｈ，ｓ）実施例２〜５ （１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸ナトリウム塩の合成 実施例１と同様の手順で第１表に示す条件で亜燐酸トリ
アルキルの種類を変えて反応を行った結果、得られた
（１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸ナトリウム塩の２．５水和物の純
度及び収率は以下の表１の通りであった。[Chemical 5] (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl ester 6.51 g (20
mmol) was dissolved in 30 ml of tetrahydrofuran, 1.8 ml of water and 2.50 g of sodium propionate (26
mmol) and tributyl phosphite 0.25 g (1 mm
ol) was added sequentially with stirring. The solution was cooled to 15 ° C., 0.04 g (0.2 mmol) of palladium acetate was added with stirring, then the temperature was raised to 25 ° C. and the temperature was increased to 1.5.
The reaction was completed by stirring for a period of time. The reaction solution was cooled to -5 ° C, and the crystals obtained by filtering the reaction solution were washed successively with 20 ml of THF cooled to 0 ° C and 12.5 ml of acetone. The crystals obtained were dried under reduced pressure to obtain 6.80 g of white crystals. Measurement by high performance liquid chromatography by the internal standard method was performed to find (1'R, 2 "R,
5R, 6S) -6- (1′-hydroxyethyl) -2-
The purity of the hydrate of the sodium salt of (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid was 98.5%. (Yield: 94%) 1 H-NMR (CDCl 3 , δppm) , TMS standard) 1.71 (3H, d, J = 6 Hz), 1.73-2.0
3 (3H, m), 2.18-2.35 (1H, m),
3.67-3.92 (3H, m), 4.05-4.19
(1H, m), 5.38 (1H, d, d, J = 7H
z), 5.46 (1H, s) Examples 2-5 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro)
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt The reaction was carried out in the same procedure as in Example 1 under the conditions shown in Table 1 by changing the type of trialkyl phosphite, and the result was (1′R, 2 ″). R, 5R, 6S) -6- (1'-Hydroxyethyl) -2- (2 "-tetrahydrofuranyl) penem-3-carboxylic acid sodium salt 2.5 hydrate purity and yield are shown in the table below. It was as 1.
【００２３】[0023]
【表１】 実施例６ （１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸ナトリウム塩の合成 （１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−（１’−ヒドロ
キシエチル）−２−（２”−テトラヒドロフラニル）ペ
ネム−３−カルボン酸アリルエステル３．２５ｇ（１０
ｍｍｏｌ）をメチルイソブチルケトン１０ｍｌに溶解
し、水０．９ｍｌ、ヘキサン酸ナトリウム１．８０ｇ
（１３ｍｍｏｌ）および亜燐酸トリブチル０．１２５ｇ
（０．５ｍｍｏｌ）を撹拌下に順次添加した。溶液を１
５℃に冷却し、酢酸パラジウム２２．５ｍｇ（０．１ｍ
ｍｏｌ）を撹拌下に添加した後、２５℃まで昇温して同
温度で１時間撹拌した。撹拌後に亜燐酸トリブチル０．
１２５ｇ（０．５ｍｍｏｌ）と酢酸パラジウム２２．５
ｍｇ（０．１ｍｍｏｌ）を再度添加し、同温度で更に
５．５時間撹拌した。反応液を−５℃まで冷却した後、
反応液を濾過して得られた結晶を０℃に冷却したＴＨＦ
５ｍｌとアセトン３ｍｌで順次洗浄した。得られた結晶
を減圧下で乾燥し、３．３７ｇの白色結晶を得た。内部
標準法による高速液体クロマトグラフィーによる測定を
行い、結晶中の（１’Ｒ，２”Ｒ，５Ｒ，６Ｓ）−６−
（１’−ヒドロキシエチル）−２−（２”−テトラヒド
ロフラニル）ペネム−３−カルボン酸のナトリウム塩の
２．５水和物の純度は９６．２％であった。（収率：９
２％）[Table 1] Example 6 (1'R, 2 "R, 5R, 6S) -6- (1'-hydro
Xyethyl) -2- (2 "-tetrahydrofuranyl) pe
Synthesis of nem-3-carboxylic acid sodium salt (1′R, 2 ″ R, 5R, 6S) -6- (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid allyl 3.25 g of ester (10
mmol) dissolved in 10 ml of methyl isobutyl ketone, 0.9 ml of water, 1.80 g of sodium hexanoate.
(13 mmol) and tributyl phosphite 0.125 g
(0.5 mmol) was added sequentially with stirring. 1 solution
After cooling to 5 ° C., 22.5 mg (0.1 m of palladium acetate)
(mol) was added under stirring, the temperature was raised to 25 ° C., and the mixture was stirred at the same temperature for 1 hour. After stirring, tributyl phosphite was added.
125 g (0.5 mmol) and palladium acetate 22.5
mg (0.1 mmol) was added again, and the mixture was further stirred at the same temperature for 5.5 hours. After cooling the reaction solution to -5 ° C,
The crystals obtained by filtering the reaction solution were cooled to 0 ° C in THF.
It was washed successively with 5 ml and 3 ml of acetone. The crystals obtained were dried under reduced pressure to obtain 3.37 g of white crystals. Measurement by high performance liquid chromatography by the internal standard method showed that (1'R, 2 "R, 5R, 6S) -6-
The purity of the hydrate of the sodium salt of (1′-hydroxyethyl) -2- (2 ″ -tetrahydrofuranyl) penem-3-carboxylic acid was 96.2%. (Yield: 9
2%)
【００２４】[0024]
【発明の効果】本発明方法は、比較的安価で空気中で安
定な原料を用いて高収率で、しかも素早くペネム化合物
のアリルエステルのアリル基を除去することが出来、工
業的に極めて有効である。INDUSTRIAL APPLICABILITY The method of the present invention is capable of removing the allyl group of the allyl ester of a penem compound rapidly with a high yield by using a relatively inexpensive raw material which is stable in air, and is industrially very effective. Is.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 // Ａ６１Ｋ 31/43 ＡＤＺ 9454−4Ｃ Ｃ０７Ｂ 61/00 ３００ Ｃ０７Ｄ 499/00 Ｚ (72)発明者 飯吉 幸之 新潟県中頸城郡中郷村大字藤沢950 日本 曹達株式会社二本木工場内 (72)発明者 豊岡 誠 新潟県中頸城郡中郷村大字藤沢950 日本 曹達株式会社二本木工場内 (72)発明者 石黒 正路 大阪府三島郡島本町若山台１丁目１番１号 サントリー株式会社生物医学研究所内 (72)発明者 中塚 隆 大阪府三島郡島本町若山台１丁目１番１号 サントリー株式会社生物医学研究所内─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display location // A61K 31/43 ADZ 9454-4C C07B 61/00 300 C07D 499/00 Z (72) Inventor Yukiyuki Iiyoshi 950 Fujisawa, Nakago-mura, Nakakubiki-gun, Niigata Inside Nihongi Plant, Soda Co., Ltd. (72) Inventor Makoto Toyooka 950 Fujisawa, Nakago-mura, Nakakubiki-gun, Niigata Prefecture In Nihongi Plant, Japan Soda Co., Ltd. (72) Masaji Ishiguro 1-1 1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Suntory Ltd. Biomedical Research Institute (72) Inventor Takashi Nakatsuka 1-1-1 Wakayamadai, Shimamoto-cho Mishima-gun Osaka Prefecture Suntory Ltd.
Claims (5)
もよいアリル基を表す。）で示されるペネム化合物のア
リルエステル化合物を、有機溶媒中で酢酸パラジウム
（II）とアルキル基の炭素数３〜８の亜燐酸トリアルキ
ルの存在下、炭素数１〜８のカルボン酸のアルカリ金属
塩または炭素数１〜８のカルボン酸及びアルカリ金属塩
とを反応せしめて一般式（II）： 【化２】 （式中、Ｒ2はアルカリ金属を示し、ｍは前記と同じも
のを示す。）で表されるペネム化合物とするアリル基の
除去方法。1. A compound represented by the general formula (I): (In the formula, m represents 0 or 1, and R 1 represents an optionally substituted allyl group.) The allene ester compound of the penem compound represented by the formula ( 1 ) was treated with palladium (II) acetate and an alkyl group in an organic solvent. In the presence of trialkyl phosphite having 3 to 8 carbon atoms and reacting with an alkali metal salt of a carboxylic acid having 1 to 8 carbon atoms or a carboxylic acid having 1 to 8 carbon atoms and an alkali metal salt, : [Chemical 2] (In the formula, R 2 represents an alkali metal and m represents the same as above.) A method for removing an allyl group, which is a penem compound.
ルアリル基、クロチル基またはシンナミル基である請求
項１記載の方法。2. The method according to claim 1, wherein R 1 is an allyl group, a haloallyl group, a methylallyl group, a crotyl group or a cinnamyl group.
サン酸もしくはエチルヘキサン酸である請求項１記載の
方法。3. The method according to claim 1, wherein the carboxylic acid is propionic acid, butyric acid, hexanoic acid or ethylhexanoic acid.
ウム塩またはカリウム塩である請求項１記載の方法。4. The method according to claim 1, wherein the alkali metal salt of carboxylic acid is a sodium salt or a potassium salt.
である請求項１記載の方法。5. The method of claim 1, wherein the trialkyl phosphite is tributyl phosphite.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11320593A JP3488263B2 (en) | 1993-05-14 | 1993-05-14 | Allyl group removal method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11320593A JP3488263B2 (en) | 1993-05-14 | 1993-05-14 | Allyl group removal method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06321952A true JPH06321952A (en) | 1994-11-22 |
| JP3488263B2 JP3488263B2 (en) | 2004-01-19 |
Family
ID=14606225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11320593A Expired - Lifetime JP3488263B2 (en) | 1993-05-14 | 1993-05-14 | Allyl group removal method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3488263B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5621084A (en) * | 1994-04-05 | 1997-04-15 | Pfizer Inc. | Process for removal of allyl group or allyloxycarbonyl group |
| EP0774465A1 (en) | 1995-11-20 | 1997-05-21 | Suntory Limited | Penem derivatives and antimicrobial agents containing the same |
| CN1314691C (en) * | 2005-08-22 | 2007-05-09 | 鲁南制药集团股份有限公司 | Faropenem sodium preparation method |
-
1993
- 1993-05-14 JP JP11320593A patent/JP3488263B2/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5621084A (en) * | 1994-04-05 | 1997-04-15 | Pfizer Inc. | Process for removal of allyl group or allyloxycarbonyl group |
| EP0774465A1 (en) | 1995-11-20 | 1997-05-21 | Suntory Limited | Penem derivatives and antimicrobial agents containing the same |
| CN1314691C (en) * | 2005-08-22 | 2007-05-09 | 鲁南制药集团股份有限公司 | Faropenem sodium preparation method |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3488263B2 (en) | 2004-01-19 |
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