JP4294124B2 - Method for producing azetidinone derivative - Google Patents
Method for producing azetidinone derivative Download PDFInfo
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- JP4294124B2 JP4294124B2 JP19238798A JP19238798A JP4294124B2 JP 4294124 B2 JP4294124 B2 JP 4294124B2 JP 19238798 A JP19238798 A JP 19238798A JP 19238798 A JP19238798 A JP 19238798A JP 4294124 B2 JP4294124 B2 JP 4294124B2
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- 0 C[C@@]([*+])[C@]([C@@](*)N1)C1=O Chemical compound C[C@@]([*+])[C@]([C@@](*)N1)C1=O 0.000 description 2
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- 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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Description
【0001】
【産業上の利用分野】
本発明は優れた抗菌作用を有するカルバペネム系抗生物質の中間体として有用なアゼチジノン誘導体の製造方法に関する。
【0002】
【従来の技術】
優れた抗菌剤であるカルバペネム系抗生物質を製造するための中間体として式〔VIII〕
【化7】
(式中、r1、r2は同一または相異なって、水素または低級アルキル基を、T1 、T2 は同一または相異なって酸素原子または硫黄原子を示す。)で表される化合物を始め、種々の化合物が提案され合成されている(特開昭63−284176号、Tetrahedron Letters,vol27(47),5687−5690(1986),PTC/J92/01698等)。これらの化合物は加水分解してカルボン酸誘導体等に変換でき、カルバペネム系抗生物質合成上極めて有用な中間体である。これらの化合物のより実用的な製造方法として例えば式〔IX〕
【化8】
で表されるアゼチジノン化合物と、式〔X〕
【化9】
(式中、r1、r2、T1、T2は前記と同じ意味を示す。 )で表される化合物をスズトリフラート、四塩化チタン等のルイス酸及びアミン存在下に反応させる、いわゆるアルドール型反応を応用した方法、あるいは式〔XI〕
【化10】
(式中、r1、r2、T1、T2は前記と同じ意味を示す。)で表される化合物と式〔IX〕
【化11】
で表される化合物とを反応させるいわゆるリホルマツキー反応を応用した方法が報告されている。
【0003】
【発明が解決しようとする課題】
しかしながら、アルドール型反応ではその反応溶媒として種々の溶媒が可能であるとの記載は有るものの、反応の途中で生成する金属錯体の溶解度、収率面での優位性から、近年、環境問題上規制が厳しくなっている塩素系溶媒、とりわけ塩化メチレンが好適に使用されており、実際の報告例は塩化メチレンがほとんどである。また、リホルマツキー反応では溶媒は主にTHFが使用されているが、無水でのTHF回収が容易でないことから、実用上は好ましくない。
【0004】
【課題を解決するための手段】
本発明者らは、このような状況下、高収率、高選択率でかつ安価に製造する方法を鋭意検討した結果、本発明を完成するに至った。
【0005】
即ち、本発明は式〔I〕
【化12】
(式中、R1は水酸基の保護基をZは脱離基を示す。)で表される化合物と、式〔II〕
【化13】
(式中、R2は水素原子または低級アルキル基を示し、R3は置換されていてもよい低級アルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアラルキル基、置換されていてもよい芳香族基を示し、R4は置換されていてもよい低級アルキル基、置換されていてもよいシクロアルキル基、置換されていてもよいアラルキル基、置換されていてもよいアルケニル基、置換されていてもよい芳香族基、または−YR5(Yは酸素原子、硫黄原子、置換されていてもよいアルキルアミノ基、置換されていてもよいアニリノ基を示し、R5は置換されていてもよい低級アルキル基、置換されていてもよいアラルキル基、置換されていてもよいアルケニル基、置換されていてもよい芳香族基を示す。)を示し、Xはカルボニル基、チオカルボニル基、置換されていてもよいイミノ基(C=NR6;R6は低級アルキル基、フェニル基を示す。)またはスルホニル基を示し、また、R3−N−X−R4は一緒になって環を形成してもよい。(以後R3 −N−X−R4で形成する基を補助基と呼称する。))で表される化合物と式〔III〕
Ti(OR7)Cl3 〔III〕
(式中、R7は低級アルキル基を示す。)で表される化合物および塩基より調整したエノラート化合物とを芳香族系有機溶媒中で反応させることを特徴とする式〔IV〕
【化14】
(式中、R1、R2、R3、R4、Xは前記と同じ意味を示す。)で表される化合物の製造方法である。
【0006】
【発明の実施の形態】
本発明において、低級アルキル基としては炭素原子数1〜7で直鎖状または分岐鎖状いずれでもよく、例えばメチル、エチル、プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、n−ヘキシル、n−ヘプチル等が挙げられる。シクロアルキル基としてはシクロプロピル、シクロペンチル、シクロヘキシル等の炭素数3〜8個のシクロアルキル基が挙げられる。アラルキル基としてはベンジル基、フェネチル基等が挙げられる。アルケニル基としては炭素数2〜8の直鎖状または分岐鎖状または環状いずれでもよく、例えば、ビニル基、アリル基、ブテニル基、ヘキセニル基、シクロヘキセニル基等が挙げられ、二重結合の位置、個数は任意である。これらの基の置換基としては低級アルキル基、低級アルコキシ基、低級アルキルチオ基、ニトロ基、ハロゲン原子等が挙げられる。芳香族基としては、フェニル基、ナフチル基、アントラセニル基等が、またその置換基としては、低級アルキル基、低級アルコキシ基、低級アルキルチオ基、低級アルキルアミノ基、アニリノ基、ニトロ基、ハロゲン原子等が挙げられる。
【0007】
R1における水酸基の保護基としては一般に水酸基を保護するのに用いられている保護基が使用できる。その具体例としては、トリメチルシリル、トリエチルシリル、t−ブチルジメチルシリル、トリイソプロピルシリル、ジメチルヘキシルシリル、t−ブチルジフェニルシリル等のトリ置換シリル基、置換されていてもよいベンジル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる。)、低級アルコキシカルボニル基、ハロゲノ低級アルコキシカルボニル基、置換されていてもよいベンジルオキシカルボニル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる。)、アセチル基、ベンゾイル基等のアシル基、トリフェニルメチル基、テトラヒドロピラニル基等が挙げられる。
【0008】
Zで表される脱離基としては、アセチルオキシ、プロピオニルオキシ等のアルカノイルオキシ基、低級アルキル基、低級アルコキシ基、ハロゲン原子、ニトロ基等で置換されていてもよいベンゾイルオキシ基、アルコキシカルボキシ基、アルキルスルフィニル基、アリールスルフィニル基、アルキルスルホニル基、アリールスルホニル基、塩素、臭素、フッ素等のハロゲン原子等が挙げられる。
【0009】
塩基としては第2級、3級アミン類、アニリン類が挙げられ、例えば、ジシクヘキシルアミン、ジイソプロピルアミン、ジエチルアミン等のアルキルアミン、N−メチルアニリン、N−エチルアニリン等のアルキルアニリン、ピペリジン、ピロリジン、2、2、6、6−テトラメチルピペリジン、モルホリン、ピペラジン等の複素環状アミン等の第2級アミン、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン等のアルキルアミン、N,N−ジメチルアニリン等のジアルキルアニリン、1−エチルピペリジン、4−メチルモルホリン、1−メチルピロリジン、1、4−ジアザビシクロ〔2.2.2〕オクタン、1、8−ジアザビシクロ〔5.4.0〕−7−ウンデセン等の複素環状アミンもしくはN,N,N',N'−テトラメチルエチレンジアミン等のジアミン等の3級アミンが挙げられる。
【0010】
芳香族系溶媒としては反応に関与しなければ特に限定されないが、ベンゼン、トルエン、キシレン、トリフロロメチルベンゼンあるいはクロルベンゼン等が挙げられる。
【0011】
式〔III〕の化合物は一般に知られている方法、例えば4塩化チタンとアルコキシチタンTi(OR7)4を3:1の比で混合することで調整することもでき、また4塩化チタンにアルコールを反応させて調整することもできる。この化合物は単離したものでも、調整した溶液をそのまま用いてもよい。
【0012】
反応は、式〔II〕の化合物(式〔I〕の化合物に対し1〜5倍モル)を溶媒に溶解し、−20℃〜50℃にて式〔III〕で表されるチタン化合物(式〔I〕の化合物に対し1〜5倍モル)を加え、或いは逆にチタン化合物〔III〕を溶媒に溶解しておき、式〔II〕の化合物を同温度で加えてもよい。次いでこの反応液に塩基1〜5倍モルを同温度で滴下することにより調整されるエノラート化合物に、0〜80℃にて、式〔I〕の化合物を加える事により行われる。反応終了後は反応液を冷却し、もしくはそのまま水にあけ、有機層を水洗し、通常の処理をすることにより目的物を得ることが出来る。この化合物の生成の確認はHPLC,NMRにより行った。
【0013】
【実施例】
次に実施例を挙げ本発明をさらに詳細に説明する。
実施例1
(3−〔(R)−2−〔(3S,4R)−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕−2−オキソアゼチジン−4−イル〕プロピオニル〕−4,4−ジメチルチアゾリジン−2−チオン)
【化15】
テトライソプロポキシチタン35.5gのトルエン500mlの溶液に四塩化チタン71.1gを0〜5℃前後で加え、トリクロロイソプロポキシチタンを調整した。ついでこの調整液に4,4−ジメチル−3−プロピオニルチアゾリジン−2−チオン61.9gを同温度で滴下し,次にトリエチルアミン48.6gを同温度で滴下した。滴下終了後、温度を15℃に上げ(3R,4R)−4−アセトキシ−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕アゼチジン−2−オン 57.5gのトルエン220mlの溶液を加えた。28〜31℃で10分攪拌したのち冷却し、反応液を冷水にあけ、有機層をHPLCにて分析したところ、目的物を75.1g含有していた。収率 87%
【0014】
実施例2
(3−〔(R)−2−〔(3S,4R)−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕−2−オキソアゼチジン−4−イル〕プロピオニル〕−4,4−ジメチルチアゾリジン−2−チオン)
【化16】
イソプロパノール1.50g、トリエチルアミン2.53gのトルエン30mlの溶液に四塩化チタン4.74gを5〜10℃にて滴下した。ついで4,4−ジメチル−3−プロピオニルチアゾリジン−2−チオン 3.09gを滴下した。次に同温度でトリエチルアミン2.43gを3〜4℃にて滴下した.温度を20℃に上げ(3R,4R)−−アセトキシ−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕アゼチジン−2−オン 2.87gを加えた。28-30℃で30分攪拌したのち冷却し、冷水にあけた。トルエン層を、HPLCで分析したところ目的物を3.2g含有していた。
【0015】
実施例3
(N-〔(R)−2−〔(3S,4R)−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕−2−オキソアゼチジン−4−イル〕プロピオニル〕−N-イソプロピル-(2クロロベンズアミド)
【化17】
テトライソプロポキシチタン58.6gのトルエン1320mlの溶液に四塩化チタン117.4gを-2〜0℃で加え,トリクロロイソプロポキシチタンを調整した。ついでこの調整液にN-イソプロピル-N-プロピオニル-(2-クロロベンズアミド)127.4gを同温度で滴下し,次にトリエチルアミン80.1gを同温度で滴下した。滴下終了後、温度を15℃に上げ(3R,4R)−4−アセトキシ−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕アゼチジン−2−オン 94.9gを加えた。28〜31℃で30分攪拌したのち冷却し、反応液を冷水にあけて分液し、有機層を水洗し、HPLCにて分析したところ、目的物を130.2g含有していた。
収率 82%
【0016】
実施例4
(N-〔(R)−2−〔(3S,4R)−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕−2−オキソアゼチジン−4−イル〕プロピオニル〕−N-イソプロピル-(2,6-ジクロロベンズアミド)
【化18】
テトライソプロポキシチタン17.8gのトルエン300mlの溶液に四塩化チタン35.6gを5℃で加え,トリクロロイソプロポキシチタンを調整した。ついでこの調整液にN-イソプロピル-N-プロピオニル-(2,6-ジクロロベンズアミド)42.1gのトルエン55mlの溶液を同温度で滴下し、次にトリエチルアミン24.3gを同温度で滴下した。滴下終了後、温度を20℃に上げ(3R,4R)−4−アセトキシ−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕アゼチジン−2−オン 28.7gのトルエン100mlの溶液を加えた。28-34℃で30分攪拌したのち冷却し、反応液を冷水にあけて分液し、有機層を水洗し、HPLCにて分析したところ,目的物を45.7g含有していた。
収率 89%
有機層の一部を濃縮し。n−ヘキサンにて晶析して白色結晶を得た。このものの1H−NMRから目的物であることを確認した。
【0017】
参考例
(3−〔(R)−2−〔(3S,4R)−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕−2−オキソアゼチジン−4−イル〕プロピオニル〕−4,4−ジメチルチアゾリジン−2−チオン)
【化19】
4,4−ジメチル−3−プロピオニルチアゾリジン−2−チオン 3.51gのトルエン40mlの溶液に四塩化チタン2.85gを0〜5℃前後で加え,次にジイソプロピルエチルアミン1.81gを同温度で滴下した.反応液はオイル状物質が析出していた。滴下終了後、温度を30℃に上げ(3R,4R)−4−アセトキシ−3−〔(R)−1−t−ブチルジメチルシリロキシエチル〕アゼチジン−2−オン 2.87gを加えた。器壁に粘性の高いオイル状物質が付着し攪拌しずらい状況であった。そのまま28〜31℃で30分攪拌したのち冷却し、器壁の付着物質を塩化メチレンで溶解しながら反応液を冷水にあけ,有機層をHPLCにて分析したところ、目的物を0.9g含有していた。
収率 21%
【0018】
【発明の効果】
本発明は優れた抗菌作用を有するカルバペネム系抗生物質の中間体として有用なアゼチジノン誘導体を高収率、高選択率で安価に製造する方法である。[0001]
[Industrial application fields]
The present invention relates to a method for producing an azetidinone derivative useful as an intermediate of a carbapenem antibiotic having an excellent antibacterial action.
[0002]
[Prior art]
Formula [VIII] as an intermediate to produce carbapenem antibiotics, which are excellent antibacterial agents
[Chemical 7]
In the formula, r 1 and r 2 are the same or different and each represents hydrogen or a lower alkyl group, and T 1 and T 2 are the same or different and each represents an oxygen atom or a sulfur atom. Various compounds have been proposed and synthesized (Japanese Patent Laid-Open No. 63-284176, Tetrahedron Letters, vol 27 (47), 5687-5690 (1986), PTC / J92 / 01698, etc.). These compounds can be hydrolyzed and converted into carboxylic acid derivatives and the like, and are extremely useful intermediates for the synthesis of carbapenem antibiotics. As a more practical production method of these compounds, for example, the formula [IX]
[Chemical 8]
An azetidinone compound represented by the formula [X]
[Chemical 9]
(Wherein r 1 , r 2 , T 1 and T 2 have the same meanings as described above). A so-called aldol, in which a compound represented by Lewis triacid such as tin triflate and titanium tetrachloride and an amine are reacted. A method that applies type reaction or formula [XI]
[Chemical Formula 10]
(Wherein r 1 , r 2 , T 1 and T 2 have the same meaning as described above) and the formula [IX]
Embedded image
A method using a so-called Reformatsky reaction in which a compound represented by the formula is reacted has been reported.
[0003]
[Problems to be solved by the invention]
However, aldol-type reactions have been described that various solvents are possible as reaction solvents. However, due to the superiority in solubility and yield of metal complexes formed in the middle of the reaction, regulations have recently been regulated due to environmental problems. Chlorinated solvents, especially methylene chloride, are being used favorably, and methylene chloride is the most reported example. In the Reformatsky reaction, THF is mainly used as a solvent. However, it is not practically preferable because THF recovery in anhydrous water is not easy.
[0004]
[Means for Solving the Problems]
Under these circumstances, the present inventors have intensively studied a method for producing a high yield, a high selectivity and a low cost, and as a result, the present invention has been completed.
[0005]
That is, the present invention relates to the formula [I]
Embedded image
Wherein R 1 is a hydroxyl-protecting group and Z is a leaving group; and the formula [II]
Embedded image
(Wherein R 2 represents a hydrogen atom or a lower alkyl group, R 3 represents a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, an aralkyl group which may be substituted, or a substituted group; R 4 represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, and an optionally substituted alkenyl group. , An optionally substituted aromatic group, or —YR 5 (Y represents an oxygen atom, a sulfur atom, an optionally substituted alkylamino group, an optionally substituted anilino group, and R 5 represents a substituted An optionally substituted lower alkyl group, an optionally substituted aralkyl group, an optionally substituted alkenyl group, and an optionally substituted aromatic group.), X is a carbonyl group, O carbonyl group, an optionally substituted imino group (C = NR 6;. R 6 is a lower alkyl group, a phenyl group) or indicates a sulfonyl group, also, R 3 -N-X-R 4 Together To form a ring (hereinafter, the group formed by R 3 —N—X—R 4 is referred to as an auxiliary group) and the formula [III]
Ti (OR 7 ) Cl 3 [III]
(Wherein R 7 represents a lower alkyl group) and an enolate compound prepared from a base are reacted in an aromatic organic solvent [IV]
Embedded image
(Wherein R 1 , R 2 , R 3 , R 4 , and X have the same meaning as described above).
[0006]
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, the lower alkyl group may be linear or branched with 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl and the like can be mentioned. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclopentyl, and cyclohexyl. Examples of the aralkyl group include a benzyl group and a phenethyl group. The alkenyl group may be linear, branched or cyclic having 2 to 8 carbon atoms, and examples thereof include a vinyl group, an allyl group, a butenyl group, a hexenyl group, a cyclohexenyl group, and the like. The number is arbitrary. Substituents for these groups include lower alkyl groups, lower alkoxy groups, lower alkylthio groups, nitro groups, halogen atoms and the like. As the aromatic group, a phenyl group, a naphthyl group, an anthracenyl group, etc., and the substituents thereof include a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylamino group, an anilino group, a nitro group, a halogen atom, Is mentioned.
[0007]
As the hydroxyl-protecting group for R 1 , a protecting group generally used for protecting a hydroxyl group can be used. Specific examples thereof include tri-substituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl, and optionally substituted benzyl groups (as substituents Nitro group, lower alkoxy group, etc.), lower alkoxycarbonyl group, halogeno lower alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group (substituents include nitro group, lower alkoxy group, etc.). ), Acyl groups such as acetyl group and benzoyl group, triphenylmethyl group, tetrahydropyranyl group and the like.
[0008]
The leaving group represented by Z includes an alkanoyloxy group such as acetyloxy and propionyloxy, a lower alkyl group, a lower alkoxy group, a halogen atom, a benzoyloxy group which may be substituted with a nitro group, and an alkoxycarboxy group. Alkylsulfinyl group, arylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, halogen atoms such as chlorine, bromine and fluorine.
[0009]
Examples of the base include secondary, tertiary amines, and anilines. For example, alkylamines such as dicyclohexylamine, diisopropylamine and diethylamine, alkylanilines such as N-methylaniline and N-ethylaniline, piperidine, Secondary amines such as heterocyclic amines such as pyrrolidine, 2,2,6,6-tetramethylpiperidine, morpholine and piperazine, alkylamines such as triethylamine, tributylamine and diisopropylethylamine, dialkyls such as N, N-dimethylaniline Complexes such as aniline, 1-ethylpiperidine, 4-methylmorpholine, 1-methylpyrrolidine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene Cyclic amine or N, N, N ′, N′-teto They include tertiary amines such as diamines and methyl ethylenediamine.
[0010]
The aromatic solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include benzene, toluene, xylene, trifluoromethylbenzene and chlorobenzene.
[0011]
The compound of the formula [III] can also be prepared by a generally known method, for example, mixing titanium tetrachloride and alkoxytitanium Ti (OR 7 ) 4 at a ratio of 3: 1. It can also be adjusted by reacting. This compound may be isolated or the prepared solution may be used as it is.
[0012]
In the reaction, a compound of formula [II] (1 to 5 moles compared to the compound of formula [I]) is dissolved in a solvent, and the titanium compound represented by formula [III] (formula) at −20 ° C. to 50 ° C. The compound of formula [II] may be added at the same temperature by adding 1 to 5 times mol) of the compound of [I] or conversely dissolving the titanium compound [III] in a solvent. Subsequently, the compound of the formula [I] is added at 0 to 80 ° C. to an enolate compound prepared by adding 1 to 5 times mole of a base dropwise to the reaction solution at the same temperature. After completion of the reaction, the reaction solution is cooled or poured into water as it is, and the organic layer is washed with water and subjected to normal treatment to obtain the desired product. The production of this compound was confirmed by HPLC and NMR.
[0013]
【Example】
EXAMPLES Next, an Example is given and this invention is demonstrated further in detail.
Example 1
(3-[(R) -2-[(3S, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl] -4,4- Dimethylthiazolidine-2-thione)
Embedded image
Trichloroisopropoxytitanium was prepared by adding 71.1 g of titanium tetrachloride at around 0 to 5 ° C. to a solution of 35.5 g of tetraisopropoxytitanium in 500 ml of toluene. Subsequently, 61.9 g of 4,4-dimethyl-3-propionylthiazolidine-2-thione was added dropwise at the same temperature, and then 48.6 g of triethylamine was added dropwise at the same temperature. After completion of the dropwise addition, the temperature was raised to 15 ° C. and a solution of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one 57.5 g in 220 ml toluene was added. added. The mixture was stirred at 28 to 31 ° C. for 10 minutes and then cooled. The reaction solution was poured into cold water, and the organic layer was analyzed by HPLC. As a result, it contained 75.1 g of the desired product. Yield 87%
[0014]
Example 2
(3-[(R) -2-[(3S, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl] -4,4- Dimethylthiazolidine-2-thione)
Embedded image
To a solution of 1.50 g of isopropanol and 2.53 g of triethylamine in 30 ml of toluene, 4.74 g of titanium tetrachloride was added dropwise at 5 to 10 ° C. Then, 3.09 g of 4,4-dimethyl-3-propionylthiazolidine-2-thione was added dropwise. Next, 2.43 g of triethylamine was added dropwise at 3 to 4 ° C. at the same temperature. The temperature was raised to 20 ° C. and 2.87 g of (3R, 4R) -acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one was added. The mixture was stirred at 28-30 ° C. for 30 minutes, cooled, and poured into cold water. The toluene layer was analyzed by HPLC and contained 3.2 g of the desired product.
[0015]
Example 3
(N-[(R) -2-[(3S, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl] -N-isopropyl- (2 chlorobenzamide)
Embedded image
Trichloroisopropoxy titanium was prepared by adding 117.4 g of titanium tetrachloride at -2 to 0 ° C to a solution of 58.6 g of tetraisopropoxy titanium in 1320 ml of toluene. Next, 127.4 g of N-isopropyl-N-propionyl- (2-chlorobenzamide) was added dropwise at the same temperature, and then 80.1 g of triethylamine was added dropwise at the same temperature. After completion of the dropwise addition, the temperature was raised to 15 ° C., and 94.9 g of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one was added. The mixture was stirred at 28 to 31 ° C. for 30 minutes and then cooled. The reaction solution was poured into cold water and separated, and the organic layer was washed with water and analyzed by HPLC. As a result, 130.2 g of the desired product was contained.
Yield 82%
[0016]
Example 4
(N-[(R) -2-[(3S, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl] -N-isopropyl- (2,6-dichlorobenzamide)
Embedded image
Trichloroisopropoxy titanium was prepared by adding 35.6 g of titanium tetrachloride to a solution of 17.8 g of tetraisopropoxy titanium in 300 ml of toluene at 5 ° C. Then, a solution of 42.1 g of N-isopropyl-N-propionyl- (2,6-dichlorobenzamide) in 55 ml of toluene was added dropwise at the same temperature, and then 24.3 g of triethylamine was added dropwise at the same temperature. After completion of the dropping, the temperature was raised to 20 ° C. and a solution of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one 28.7 g in 100 ml toluene was added. added. The mixture was stirred at 28-34 ° C for 30 minutes and then cooled. The reaction solution was poured into cold water for liquid separation, and the organic layer was washed with water and analyzed by HPLC. As a result, 45.7 g of the desired product was contained.
Yield 89%
Concentrate part of the organic layer. Crystallization with n-hexane gave white crystals. This product was confirmed to be the target product by 1 H-NMR.
[0017]
Reference Example (3-[(R) -2-[(3S, 4R) -3-[(R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl] -4, 4-dimethylthiazolidine-2-thione)
Embedded image
To a solution of 4,4-dimethyl-3-propionylthiazolidine-2-thione in 3.51 g of toluene in 40 ml of toluene, 2.85 g of titanium tetrachloride was added at around 0-5 ° C., and then 1.81 g of diisopropylethylamine was added dropwise at the same temperature. An oily substance was precipitated in the reaction solution. After completion of the addition, the temperature was raised to 30 ° C., and 2.87 g of (3R, 4R) -4-acetoxy-3-[(R) -1-t-butyldimethylsilyloxyethyl] azetidin-2-one was added. A viscous oily substance adhered to the vessel wall, making stirring difficult. The mixture was stirred at 28-31 ° C for 30 minutes and then cooled. The reaction solution was poured into cold water while dissolving the deposits on the vessel wall with methylene chloride, and the organic layer was analyzed by HPLC. It was.
Yield 21%
[0018]
【The invention's effect】
The present invention is a method for producing an azetidinone derivative useful as an intermediate of a carbapenem antibiotic having an excellent antibacterial action at high yield and high selectivity at low cost.
Claims (4)
Ti(OR7)Cl3 〔III〕
(式中、R7は低級アルキル基を示す。)で表される化合物および塩基より調整したエノラート化合物とを芳香族系有機溶媒中で反応させることを特徴とする式〔IV〕
Ti (OR 7 ) Cl 3 [III]
(Wherein R 7 represents a lower alkyl group) and an enolate compound prepared from a base are reacted in an aromatic organic solvent [IV]
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