JPH01294661A - Production of 4-acetoxyazetidinone derivative - Google Patents
Production of 4-acetoxyazetidinone derivativeInfo
- Publication number
- JPH01294661A JPH01294661A JP63120732A JP12073288A JPH01294661A JP H01294661 A JPH01294661 A JP H01294661A JP 63120732 A JP63120732 A JP 63120732A JP 12073288 A JP12073288 A JP 12073288A JP H01294661 A JPH01294661 A JP H01294661A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- group
- compound expressed
- reaction
- transfer catalyst
- 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
- OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical class CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000005843 halogen group Chemical group 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 18
- -1 t-butyldimethylsilyl group Chemical group 0.000 claims description 17
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 21
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000002904 solvent Substances 0.000 abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 150000003839 salts Chemical class 0.000 abstract description 4
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 abstract description 3
- HJJGOOONOIFDRH-UHFFFAOYSA-N (4-oxoazetidin-2-yl) benzoate Chemical class C=1C=CC=CC=1C(=O)OC1CC(=O)N1 HJJGOOONOIFDRH-UHFFFAOYSA-N 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract 2
- 239000004599 antimicrobial Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002961 penems Chemical class 0.000 abstract 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 abstract 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 235000011056 potassium acetate Nutrition 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VJGNLOIQCWLBJR-UHFFFAOYSA-M benzyl(tributyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 VJGNLOIQCWLBJR-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- DOBUSJIVSSJEDA-UHFFFAOYSA-L 1,3-dioxa-2$l^{6}-thia-4-mercuracyclobutane 2,2-dioxide Chemical compound [Hg+2].[O-]S([O-])(=O)=O DOBUSJIVSSJEDA-UHFFFAOYSA-L 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- WRYNUJYAXVDTCB-UHFFFAOYSA-M acetyloxymercury Chemical compound CC(=O)O[Hg] WRYNUJYAXVDTCB-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- CODNYICXDISAEA-UHFFFAOYSA-N bromine monochloride Chemical compound BrCl CODNYICXDISAEA-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 150000002731 mercury compounds Chemical class 0.000 description 1
- 229910000370 mercury sulfate Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
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
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、−数式（Ｉ［）
（式中、Ｒ１は水酸基の保護基を表わす、）で表わされ
る４−アセトキシアゼチジノン誘導体を製造する新規な
方法に関する。Detailed Description of the Invention [Industrial Application Field] The present invention provides a method for producing a 4-acetoxyazetidinone derivative represented by the formula (I[) (wherein R1 represents a hydroxyl protecting group). Concerning a novel method.
一般式（ｎ）で表わされる４−アセトキシアゼチジノン
誘導体は、強力な抗苗性を有するベネム類及ヒカルバペ
ネム類の合成中間体として重要な化合物であり、これら
に関しては、Ｐ、 Ｊ、 Ｒｅ１ｄｅｒ等の報告（Ｔｅ
ｔｒａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ ２３２２９３
（１９８２年）〕、ヨシダ等の報告（Ｃｈｅｗ、 Ｐｈ
ａｒｗ、 Ｂｕｌｌ、２９２Ｂ９９ （１９８１年）〕
、〕特開昭６０−１９７６および特開昭６１−２０７３
８７などに記載がある。The 4-acetoxyazetidinone derivative represented by the general formula (n) is an important compound as a synthetic intermediate for venems and hycarbapenems, which have strong anti-seedling properties. Report (Te
trahedron Letters 232293
(1982)], Yoshida et al.'s report (Chew, Ph.
arw, Bull, 292B99 (1981)]
, ] JP-A-60-1976 and JP-A-61-2073
It is described in 87 etc.
従来、４−アセトキシアゼチジノン誘導体（ｎ）の合成
法として、アスパラギン酸から合成する方法ＣＰ、 Ｊ
、 Ｒｅ１ｄｅｒ ＄Ｔａｔｒａｈｅｄｒａｎ Ｌｅｔ
ｔｅｒｓ ２３２２９３ （１９８２年）〕、６−アミ
ツベニシラン酸から合成する方法〔ヨシダ等Ｃｈｅｗ、
Ｐｈａｒｍ、 Ｂｕｌｌ、 ２９゜２Ｂ９９ （１９
８１年）〕、スレオニンから合成する方法〔シオザキ等
、Ｔｅｔｒａｈｅｄｒｏｎ ３９２３９９（１９８３年
）〕、〕β−ヒドロキシ酪酸エステから合成する方法〔
特開昭６２−１９５３５９）等が知られている。Conventionally, methods for synthesizing 4-acetoxyazetidinone derivatives (n) from aspartic acid CP, J
, Re1der $Tatrahedran Let
ters 232293 (1982)], a method of synthesis from 6-amitubenicilanic acid [Yoshida et al. Chew,
Pharm, Bull, 29°2B99 (19
1981)], method of synthesis from threonine [Shiozaki et al., Tetrahedron 392399 (1983)], method of synthesis from β-hydroxybutyric acid ester [
JP-A-62-195359) is known.
しかしながら、これらの方法に於いては、β−ラクタム
環の４位にアセトキシ基を導入するために、酢酸水銀、
硫酸水銀等の水銀化合物や四酢酸鉛等の工業的には好ま
しくない試薬を使用していたり、収率が低く操作が繁雑
である等の難点を有していた。However, in these methods, mercury acetate,
It has disadvantages such as the use of mercury compounds such as mercury sulfate and industrially unfavorable reagents such as lead tetraacetate, low yields, and complicated operations.
本発明者等は、Ｓ、 Ｈａｎｅｓｓｉａｎ等ＣＪ、 Ａ
ｓ、 Ｃｈｅｓ。The inventors, S., Hannessian et al., C.J., A.
s, Ches.
Ｓｏｃ、ユ０７１４３８ （１９８５年）〕の方法に
従い、スレオニンから容易に合成できる４−ベンゾイル
オキシアゼチジノン誘導体の４位ベンゾイルオキシ基を
容易かつ好収率でアセトキシ基に変換できる方法を見出
して、本発明に至った。Soc, U071438 (1985)], we discovered a method for converting the benzoyloxy group at the 4-position of a 4-benzoyloxyazetidinone derivative, which can be easily synthesized from threonine, into an acetoxy group easily and in good yield, and the present invention This led to the invention.
本発明は、−数式（１）
（式中、Ｒ１は水酸基の保護基、Ｒ２はハロゲン原子、
低級アルキル基、又は低級アルコキシ基、ｎは０．１，
２又は３を表わす、）
で表わされるアゼチジノン誘導体と酢酸のアルカリ金属
塩とを反応させる事を特徴とする、−数式（１１）
（式中、Ｒ１は水酸基の保護基を表わす、）で表わされ
る４−アセトキシアゼチジノン誘導体の製造法である。The present invention provides - formula (1) (wherein, R1 is a hydroxyl protecting group, R2 is a halogen atom,
Lower alkyl group or lower alkoxy group, n is 0.1,
2 or 3) is characterized by reacting an azetidinone derivative represented by the formula (2 or 3) with an alkali metal salt of acetic acid, represented by the formula (11) (wherein R1 represents a hydroxyl protecting group) This is a method for producing a 4-acetoxyazetidinone derivative.
−ｍ式（１）で示されるアゼチジノン誘導体は例えば、
Ｓ、 Ｈａｎｅｓｓｉａｎ等（Ｊ、 Ａｓ、 Ｃｈｅｗ
、 Ｓｏｃ。-m The azetidinone derivative represented by formula (1) is, for example,
S, Hanessian et al. (J, As, Chew
, Soc.
１０７１４３８ （１９８５年）〕の方法に従い、反応
式Ｉの方法によって簡便に取得できる。1071438 (1985)], and can be easily obtained by the method of Reaction Scheme I.
反応式Ｉ
Ｈ
ＮＨ□
アゼチジノン誘導体（１）の３位ヒドロキシエチル基の
〇−保護基としては、トリアルキルシリル基、たとえば
ｔ−ブチルジメチルシリル基、クミルジメチルシリル基
、トリイソプロとルシリル基、イソプロピルジメチルシ
リル基、インブチルジメチルシリル基、ジメチル−１，
１，２−）リメチルプロビルシリル基や、その他ベンジ
ル基、トリクロロエトキシカルボニル基、ｔ−ブトキシ
カルボニル基、アリ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等があげられるが、好まし
くは、反応中に安定であり、さらに酸処理により選択的
に脱保護されうるｔ−ブチルジメチルシリル基が好まし
い。Reaction formula I dimethylsilyl group, inbutyldimethylsilyl group, dimethyl-1,
1,2-)limethylprobylsilyl group, and other groups such as benzyl group, trichloroethoxycarbonyl group, t-butoxycarbonyl group, allyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, etc., but preferably, reaction Preferred is a t-butyldimethylsilyl group which is stable in the compound and can be selectively deprotected by acid treatment.
又、アゼチジノン誘導体（１）のＲ□で表わされるベン
ゾイル基の置換基としてはハロゲン原子（クロル、ブロ
ム）、低級アルキル基（メチル基、エチル基、プロピル
基等）、低級アルコキシ基（メトキシ基、エトキシ基、
プロポキシ基等）があげられるが、合成上安価なｎが０
、即ち無置換又はｐ−クロルが好ましい。In addition, substituents for the benzoyl group represented by R□ of the azetidinone derivative (1) include halogen atoms (chloro, bromine), lower alkyl groups (methyl group, ethyl group, propyl group, etc.), lower alkoxy groups (methoxy group, ethoxy group,
(propoxy group, etc.), but n is 0 because it is cheap in terms of synthesis.
, that is, unsubstituted or p-chlor is preferred.
上記のようにして調整した一般式（１）で示されるアゼ
チジノン誘導体と、酢酸のアルカリ金属塩とを反応させ
る事により、−数式（ＩＩ）で示される４−アセトキシ
アゼチジノン誘導体に好収率で変換できる。By reacting the azetidinone derivative represented by the general formula (1) prepared as described above with an alkali metal salt of acetic acid, the 4-acetoxyazetidinone derivative represented by the formula (II) is produced in a good yield. Can be converted.
反応は、通常、非プロトン性有機溶媒中、相間移動触媒
の存在下で行なわれる。The reaction is usually carried out in an aprotic organic solvent in the presence of a phase transfer catalyst.
反応溶媒としては、ハロゲン化炭化水素類、ケトン類、
エステル類等の非プロトン性有機溶媒の使用が好ましく
、例えば塩化メチレン、クロロホルム、アセトン、メチ
ルイソブチルケトン、酢酸エチル等があげられるが、反
応後の後処理を容易なものとするため塩化メチレン、ク
ロロホルム、メチルイソブチルケトン、酢酸エチル等の
水難溶性の溶媒を使用する事がより好ましい。As reaction solvents, halogenated hydrocarbons, ketones,
It is preferable to use aprotic organic solvents such as esters, such as methylene chloride, chloroform, acetone, methyl isobutyl ketone, ethyl acetate, etc. However, in order to facilitate post-treatment after the reaction, methylene chloride, chloroform It is more preferable to use a poorly water-soluble solvent such as , methyl isobutyl ketone, or ethyl acetate.
上記の溶媒を使用する際には、相関移動触媒を存在させ
る事で反応が円滑に進行するが、例えばメタノール、エ
タノール等のアルコール類やＤＭＦ、ＤＭＳＯ等の極性
溶媒を使用する場合には、相間移動触媒が存在しなくて
も反応は進行する。When using the above solvents, the presence of a phase transfer catalyst facilitates the reaction, but when using alcohols such as methanol and ethanol, or polar solvents such as DMF and DMSO, the phase transfer catalyst The reaction proceeds even in the absence of a mobile catalyst.
しかしながら、こうした溶媒を使用した場合、副反応に
より収率が低下したり、反応後の後処理が繁雑になる等
、工業的には好ましくない場合がある。However, when such a solvent is used, it may be industrially undesirable, such as the yield being lowered due to side reactions or the post-reaction treatment becoming complicated.
相間移動触媒としては、四級アンモニウム塩がすぐれて
おり、例えばテトラエチルアンモニウムクロリド、テト
ラブチルアンモニウムクロリド、トリエチルベンジルア
ンモニウムクロリド、トリブチルベンジルアンモニウム
クロリド、又は以上の四級アンモニウムプロミド等、通
常重版されている脂肪族系の四級アンモニウム塩が使用
でき、アゼチジノン誘導体（１）に対して、０．５〜５
モル％の使用で充分目的を達せられる。Quaternary ammonium salts are excellent as phase transfer catalysts, such as tetraethylammonium chloride, tetrabutylammonium chloride, triethylbenzylammonium chloride, tributylbenzylammonium chloride, or the above quaternary ammonium bromides, which are usually reprinted. Aliphatic quaternary ammonium salts can be used, and 0.5 to 5
The use of mol% is sufficient to achieve the purpose.
酢酸のアルカリ金属塩としては、例えば酢酸カリウムや
酢酸ナトリウムがあげられるが、酢酸カリウムの使用が
反応速度を上げるうえで好ましく、アゼチジノン誘導体
（１）に対し、重量比で１〜３倍量用いればよい。Examples of alkali metal salts of acetic acid include potassium acetate and sodium acetate, but it is preferable to use potassium acetate in order to increase the reaction rate. good.
反応温度は、０６〜６０℃の範囲から選択できるが、室
温程度で充分目的を達せられる。The reaction temperature can be selected from the range of 06 to 60°C, but the purpose can be sufficiently achieved at about room temperature.
反応操作としては、酢酸エチル等の有機溶媒に、アゼチ
ジノン誘導体（りを溶解し、次に酢酸のアルカリ金属塩
及び四級アンモニウム塩等の相間移動触媒を加えて反応
を行なう０反応経過を薄層クロマトグラフィー等でチエ
ツクしながら実施し、反応終了後水を加えて酢酸のアル
カリ金属塩を溶解させる０次に有機層を水で洗浄した後
、硫酸マグネシウム等で乾燥し、溶媒を留去して得られ
た粗結晶をヘキサン等の溶媒で再結晶する事により、目
的の４−アセトキシアゼチジノン誘導体（ｎ）を得る。The reaction process involves dissolving an azetidinone derivative in an organic solvent such as ethyl acetate, and then adding a phase transfer catalyst such as an alkali metal salt of acetic acid or a quaternary ammonium salt to carry out the reaction. The reaction is carried out while checking with chromatography, etc., and after the reaction is completed, water is added to dissolve the alkali metal salt of acetic acid.Next, the organic layer is washed with water, dried over magnesium sulfate, etc., and the solvent is distilled off. The desired 4-acetoxyazetidinone derivative (n) is obtained by recrystallizing the obtained crude crystals with a solvent such as hexane.
以下実施例で本発明を説明するが、これら実施例によっ
て本発明が限定されるものではない。The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples.
実 施 例 １
（３Ｒ，４Ｒ，１’Ｒ）−４−アセトキシ−３−（１’
−ｔｓｒｔ−ブチルジメチルシリルオキシエチル）アゼ
チジン−２−オンの合成：（３Ｒ，４Ｒ，１’Ｒ）−４
−ベンゾイルオキシ−３−（１’−Ｌｅｒｔ−ブチルジ
メチルシリルオキシエチル）アゼチジン−２−オン４．
０ｇを酢酸エチル４０■ｌに溶解し、酢酸カリウム８．
０ｇ及びトリブチルベンジルアンモニウムクロリド０．
０８ｇを加えて、室温にて４時間攪拌した。ついで水２
０ｓ ｊを加えて析出している塩を溶解させた後分液し
、得られた有機層を水２０−１で３回洗浄後、無水硫酸
マグネシウムで乾燥した。濾別後、溶媒を減圧濃縮して
無色結晶３．３６ｇを得た。得られた粗結晶をｎ−ヘキ
サン４０−ｌに温めて溶かし、−１５℃に冷却する事に
より、目的物２．８１ ｇを無色針状晶として得た。収
率８５．５％。Example 1 (3R,4R,1'R)-4-acetoxy-3-(1'
Synthesis of -tsrt-butyldimethylsilyloxyethyl)azetidin-2-one: (3R,4R,1'R)-4
-Benzoyloxy-3-(1'-Lert-butyldimethylsilyloxyethyl)azetidin-2-one4.
0 g was dissolved in 40 μl of ethyl acetate, and 8.0 g of potassium acetate was dissolved in 40 μl of ethyl acetate.
0g and tributylbenzylammonium chloride 0.
08 g was added thereto, and the mixture was stirred at room temperature for 4 hours. Then water 2
After adding 0sj to dissolve the precipitated salt, the layers were separated, and the resulting organic layer was washed three times with water 20-1 and then dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to obtain 3.36 g of colorless crystals. The obtained crude crystals were warmed and dissolved in 40 l of n-hexane, and cooled to -15°C to obtain 2.81 g of the target product as colorless needle crystals. Yield 85.5%.
〔α〕。−十５０° （Ｃ＝０．５ 、ｌｊｌｃＩｓ）
ｍ、 ｐ １０７〜１０８℃
’ Ｈ−Ｎ Ｍ Ｒ（ＣＤ Ｃｌ ｓ ） δｐ ｐ
ｍ ；０．０７ （６Ｈ，Ｓ）、０．８７ （９Ｈ，Ｓ
）、１．２６ （３Ｈ，ｄ。[α]. -150° (C=0.5, ljlcIs)
m, p 107-108°C' H-NMR(CDCls) δp p
m; 0.07 (6H,S), 0.87 (9H,S
), 1.26 (3H, d.
Ｊ ”６．４１１ｚ） 、 ２．１１ （３Ｈ，Ｓ）
、 ３．１８ （Ｉ Ｈ。J”6.411z), 2.11 (3H,S)
, 3.18 (IH.
ｄｄ、 Ｊ＝１．３ 、３．５ Ｈｚ） 、 ４．２
３ （ＬＨ，ｄｑ。dd, J=1.3, 3.5 Hz), 4.2
3 (LH, dq.
Ｊ＝３．５ 、６．４ ｂ） 、 ５．８４ （Ｉ Ｈ
，ｂ ｓ） 。J=3.5, 6.4 b), 5.84 (I H
,b s).
６．５１ （Ｌ Ｈ，ｂ ｓ ）
実 施 例 ２
（３Ｒ，４Ｒ，１’Ｒ）−４−アセトキシ−３（１’−
ｔａｒｔ−ブチルジメチルシリルオキシエチル）アゼチ
ジン−２−オンの合成：（３Ｒ，４Ｒ，１’Ｒ）−４−
ベンゾイルオキシ−３−（１’−ｔｅｒｔ−ブチルジメ
チルシリルオキシエチル）アゼチジン−２−オン４．０
ｇを酢酸エチル４Ｑｓｌに溶解し、酢酸カリウム１０．
０ ｇ及びトリブチルベンジルアンモニウムクロリドの
５０％水溶液０．１６ｇを加えて、室温にて５時間反応
させた０反応後の後処理を実施例１と同様に行ない、目
的物２．８９ ｇを無色針状晶として得た。6.51 (L H, b s ) Example 2 (3R,4R,1'R)-4-acetoxy-3(1'-
Synthesis of tart-butyldimethylsilyloxyethyl)azetidin-2-one: (3R,4R,1'R)-4-
Benzoyloxy-3-(1'-tert-butyldimethylsilyloxyethyl)azetidin-2-one 4.0
Dissolve 10.g of potassium acetate in 4Qsl of ethyl acetate.
0 g and 0.16 g of a 50% aqueous solution of tributylbenzylammonium chloride were added and reacted for 5 hours at room temperature.The post-treatment after the 0 reaction was carried out in the same manner as in Example 1, and 2.89 g of the target product was transferred to a colorless needle. Obtained as crystals.
収率８７，９％
実 施 例 ３
（３Ｒ，４Ｒ，１’Ｒ）−４−アセトキシ−３−（１′
ｔａｒｔ−ブチルジメチルシリルオキシエチル）アゼ
チジン−２−オンの合成：（３Ｒ，４Ｒ，１’Ｒ）
３−（１′−ｔｅｒｔ−ブチルジメチルシリルオキシ
エチル）−４＝（ｐ−クロロベンゾイルオキシ）アゼチ
ジン−２−オン４６４ｇを酢酸エチル４０ｍ １２に溶
解し、酢酸カリウム８．０ｇ及びテトラエチルアンモニ
ウムクロリド０．０５ ｇを加えて、室温にて４時間反
応させた０反応後の後処理を実施例１と同様に行ない、
目的物２．９１ ｇを無色針状晶として得た。Yield 87.9% Example 3 (3R,4R,1'R)-4-acetoxy-3-(1'
Synthesis of tart-butyldimethylsilyloxyethyl)azetidin-2-one: (3R,4R,1'R)
464 g of 3-(1'-tert-butyldimethylsilyloxyethyl)-4=(p-chlorobenzoyloxy)azetidin-2-one was dissolved in 40 ml of ethyl acetate, 8.0 g of potassium acetate and 0.0 g of tetraethylammonium chloride. 05 g was added and reacted for 4 hours at room temperature. Post-treatment was carried out in the same manner as in Example 1.
2.91 g of the target product was obtained as colorless needle crystals.
収率８８．５％。Yield 88.5%.
種々の反応試剤を用いた場合の（３Ｒ，４Ｒ。(3R, 4R) when using various reaction reagents.
１’Ｒ）−４−ベンゾイルオキシ−３−（１’−ｔａｒ
ｔ−ブチルジメチルシリルオキシエチル）アゼチジン−
２−オンから（３Ｒ，４Ｒ，１’Ｒ）−４−アセトキシ
−３−（１’−ｔａｒｔ−ブチルジメチルシリルオキシ
エチル）アゼチジン−２−オンの収率を表１に示す０反
応方法および反応液の処理は実施例１と同様に行なった
。1'R)-4-benzoyloxy-3-(1'-tar
t-Butyldimethylsilyloxyethyl)azetidine-
The yield of (3R,4R,1'R)-4-acetoxy-3-(1'-tart-butyldimethylsilyloxyethyl)azetidin-2-one from 2-one is shown in Table 1.0 Reaction method and reaction The liquid was treated in the same manner as in Example 1.
Claims (3)
子、低級アルキル基、又は低級アルコキシ基、ｎは０、
１、２又は３を表わす。） で表わされるアゼチジノン誘導体と酢酸のアルカリ金属
塩とを反応させることを特徴とする一般式（II） ▲数式、化学式、表等があります▼（II） （式中、Ｒ＿１は水酸基の保護基を表わす。）で表わさ
れる４−アセトキシアゼチジノン誘導体の製造法。(1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a hydroxyl protecting group, R_2 is a halogen atom, lower alkyl group, or lower alkoxy group, n is 0,
Represents 1, 2 or 3. General formula (II) characterized by reacting an azetidinone derivative represented by A method for producing a 4-acetoxyazetidinone derivative represented by:
に反応させる特許請求の範囲第１項記載の製造法。(2) The production method according to claim 1, wherein the reaction is carried out in an aprotic organic solvent in the presence of a phase transfer catalyst.
が０である特許請求の範囲第１項又は第２項記載の製造
法。(3) R_1 is a t-butyldimethylsilyl group, and n
The manufacturing method according to claim 1 or 2, wherein is 0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63120732A JP2608458B2 (en) | 1988-05-19 | 1988-05-19 | Method for producing 4-acetoxyazetidinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63120732A JP2608458B2 (en) | 1988-05-19 | 1988-05-19 | Method for producing 4-acetoxyazetidinone derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01294661A true JPH01294661A (en) | 1989-11-28 |
| JP2608458B2 JP2608458B2 (en) | 1997-05-07 |
Family
ID=14793617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63120732A Expired - Lifetime JP2608458B2 (en) | 1988-05-19 | 1988-05-19 | Method for producing 4-acetoxyazetidinone derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2608458B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010107078A (en) * | 2000-05-25 | 2001-12-07 | 윤재승 | Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008007836A1 (en) * | 2006-07-13 | 2008-01-17 | Choongwae Pharma Corporation | Method for preparing 4-acetoxyazetidinone and derivatives thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6054358A (en) * | 1983-08-04 | 1985-03-28 | フア−ミタリア・カルロ・エルバ・ソシエタ・ペル・アツイオ−ニ | Azetidinones |
| JPS6187661A (en) * | 1984-10-01 | 1986-05-06 | チバ‐ガイギー アクチエンゲゼルシヤフト | Optically active acyloxyazetidinone and manufacture |
| JPS6345251A (en) * | 1987-03-05 | 1988-02-26 | Sankyo Co Ltd | Production of 4-acyloxyazetidinone derivative |
| JPS63112559A (en) * | 1986-10-15 | 1988-05-17 | フアームイタリア カルロ エルバ エス．ピー．エー． | Manufacture of azetidinone |
-
1988
- 1988-05-19 JP JP63120732A patent/JP2608458B2/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6054358A (en) * | 1983-08-04 | 1985-03-28 | フア−ミタリア・カルロ・エルバ・ソシエタ・ペル・アツイオ−ニ | Azetidinones |
| JPS6187661A (en) * | 1984-10-01 | 1986-05-06 | チバ‐ガイギー アクチエンゲゼルシヤフト | Optically active acyloxyazetidinone and manufacture |
| JPS63112559A (en) * | 1986-10-15 | 1988-05-17 | フアームイタリア カルロ エルバ エス．ピー．エー． | Manufacture of azetidinone |
| JPS6345251A (en) * | 1987-03-05 | 1988-02-26 | Sankyo Co Ltd | Production of 4-acyloxyazetidinone derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010107078A (en) * | 2000-05-25 | 2001-12-07 | 윤재승 | Method of preparing 4-alkoxy-2-azetidinone derivative and its optical isomer |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2608458B2 (en) | 1997-05-07 |
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