JPH01254656A - Production of 4-acetoxy-3-hydroxyethylazetidin-2-one - Google Patents
Production of 4-acetoxy-3-hydroxyethylazetidin-2-oneInfo
- Publication number
- JPH01254656A JPH01254656A JP63083633A JP8363388A JPH01254656A JP H01254656 A JPH01254656 A JP H01254656A JP 63083633 A JP63083633 A JP 63083633A JP 8363388 A JP8363388 A JP 8363388A JP H01254656 A JPH01254656 A JP H01254656A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- acetoxy
- acetonitrile
- compound
- organic solvent
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- CQXFYUIOYBEJOS-UHFFFAOYSA-N [3-(2-hydroxyethyl)-4-oxoazetidin-2-yl] acetate Chemical compound CC(=O)OC1NC(=O)C1CCO CQXFYUIOYBEJOS-UHFFFAOYSA-N 0.000 title claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 54
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 9
- 239000011707 mineral Substances 0.000 claims abstract description 9
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 5
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims abstract description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 150000007524 organic acids Chemical class 0.000 claims description 4
- -1 betalactam compound Chemical class 0.000 abstract description 7
- 239000003782 beta lactam antibiotic agent Substances 0.000 abstract description 4
- 239000002132 β-lactam antibiotic Substances 0.000 abstract description 4
- 229940124586 β-lactam antibiotics Drugs 0.000 abstract description 4
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 abstract description 3
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 abstract description 2
- 238000006884 silylation reaction Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000001816 cooling Methods 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 7
- 230000000704 physical effect Effects 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 238000005828 desilylation reaction Methods 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 150000003952 β-lactams Chemical class 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 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
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- GWHDKFODLYVMQG-UBHAPETDSA-N [(2r,3r)-3-[(1r)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C)[C@@H]1[C@@H](OC(C)=O)NC1=O GWHDKFODLYVMQG-UBHAPETDSA-N 0.000 description 1
- AUOZWPIJJHFQMQ-UHFFFAOYSA-N [3-(2-hydroxyethyl)azetidin-2-yl] acetate Chemical compound C(C)(=O)OC1C(CN1)CCO AUOZWPIJJHFQMQ-UHFFFAOYSA-N 0.000 description 1
- JSWAHRJBQMEUQL-UHFFFAOYSA-N [3-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl] acetate Chemical compound CC(=O)OC1NC(=O)C1CCO[Si](C)(C)C(C)(C)C JSWAHRJBQMEUQL-UHFFFAOYSA-N 0.000 description 1
- QPEZJSLLRIHFEE-UHFFFAOYSA-N acetonitrile 4-methylbenzenesulfonic acid hydrate Chemical compound C(C)#N.O.C1(=CC=C(C=C1)S(=O)(=O)O)C QPEZJSLLRIHFEE-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- WRYNUJYAXVDTCB-UHFFFAOYSA-M acetyloxymercury Chemical compound CC(=O)O[Hg] WRYNUJYAXVDTCB-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 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
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 150000002731 mercury compounds Chemical class 0.000 description 1
- 229910000370 mercury sulfate Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、３−位にヒドロキシエチル基を何し、４−位
にアセトキシ基を有する４−アセトキシ−３−ヒドロキ
シエチルアゼチジン−２−オンの新規な製造法に関する
。Detailed Description of the Invention (Industrial Application Field) The present invention provides 4-acetoxy-3-hydroxyethylazetidine-2- Concerning a new manufacturing method for on.
（従来の技術と問題点）
４−アセトキシ−３−ヒドロキシエチルアゼチジン−２
−オン誘導体は、チェナマイシン等に代表すれるカルバ
ペネム系β−ラクタム抗生物質やペネム系β−ラクタム
抗生物質の合成中間体として有用であることが知られて
いる〔たとえば、レイダー等、テトラヘドロン・レター
ズ、２３巻、２２９３頁（１９８２年）、およびヨシタ
等、ケミカル・アンド・ファーマシュテイ力ルーブチレ
ン（Ｃｈｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ、 ）、２９
巻、２８９９頁（１９８１年）〕。(Prior art and problems) 4-acetoxy-3-hydroxyethylazetidine-2
-one derivatives are known to be useful as synthetic intermediates for carbapenem β-lactam antibiotics such as chenamycin and penem β-lactam antibiotics [for example, tetrahedrons such as Raider, etc. Letters, Vol. 23, p. 2293 (1982), and Yoshita et al., Chem, Pharm, Bull, 29.
Volume, 2899 pages (1981)].
従来、４−アセトキシ−３−ヒドロキシエチルアゼチジ
ン−２−オン誘導体の合成法として、６−アミノペニシ
ラン酸から合成する方法〔ヨシグ等、Ｃｈｅｍ、 Ｐｈ
ａｒｍ、 Ｂｕｌｌ、 ２９巻、２８９９頁（１９８１
年）〕、スレオニンから合成する方法〔シオザキ等、テ
トラヘドロン％３９巻、２３９９頁（１９８３年）〕、
アスパラギン酸から合成する方法〔レイダー等、テトラ
ヘドロン・レターズ、２３巻、２２９３頁（１９８２年
〕〕、β−ヒドロキシ酪酸の金属エルレートから合成す
る方法〔ナカイ等、ケミストリー・レターズ、１９２７
頁（１９８４年）〕等が知られている。しかし、これ等
いずれの方法においても、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
を使用する難点を有していた。Conventionally, a method for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives from 6-aminopenicillanic acid [Yosig et al., Chem, Ph.
arm, Bull, vol. 29, p. 2899 (1981
)], method of synthesis from threonine [Shiozaki et al., Tetrahedron% vol. 39, p. 2399 (1983)],
A method for synthesizing from aspartic acid [Raider et al., Tetrahedron Letters, Vol. 23, p. 2293 (1982]), a method for synthesizing from metal erulate of β-hydroxybutyric acid [Nakai et al., Chemistry Letters, 1927]
Page (1984)] are known. However, in all of these methods, industrially unfavorable reagents such as mercury compounds such as mercury acetate and mercury sulfate, and lead tetraacetate are used to introduce an acetoxy group into the 4-position of the β-lactam ring. There were some difficulties in using it.
そこで本発明者らは、３−位にシリル基で保護したヒド
ロキシエチル基、４−位にシリルエーテル基を有する新
規なβ−ラクタム化合物を用いて、４−位にアセトキシ
基を導入する製法を見出し、既に特許を出願した（特開
昭６１−１８７９１、特開昭６１−１８７５８、特開昭
６ｌ−２５８５８）。Therefore, the present inventors developed a method for introducing an acetoxy group into the 4-position using a new β-lactam compound having a silyl-protected hydroxyethyl group at the 3-position and a silyl ether group at the 4-position. A patent application has already been filed for the heading (JP-A-61-18791, JP-A-61-18758, JP-A-61-25858).
４−アセトキシ−３−ヒドロキシエチルアゼチジン−２
−オン誘導体のなかでも、特に４−アセトキシ−３−ヒ
ドロキシエチルアゼチジン−２−オンは、３−位に好み
の基を導入することができ、汎用性が更に増す利点があ
る。しかしながら、４−アセトキシ−３−ヒドロキシエ
チルアゼチジン−２−オンの簡便な合成方法は報告され
ていない。4-acetoxy-3-hydroxyethylazetidine-2
Among the -one derivatives, 4-acetoxy-3-hydroxyethylazetidin-2-one in particular has the advantage that a desired group can be introduced at the 3-position, further increasing its versatility. However, a simple method for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one has not been reported.
そこで本発明者らは簡便に合成できる、３−位にｔｅｒ
ｔ−ブチルジメチルシリロキシエチル基、４−位にアセ
トキシ基を有するβ−ラクタムから合成する方法を種々
検討した。Therefore, the present inventors added ter at the 3-position, which can be easily synthesized.
Various methods were investigated for synthesis from β-lactam having a t-butyldimethylsilyloxyethyl group and an acetoxy group at the 4-position.
３−位にｔｅｒｔ−ブチルジメチルシリロキシエチル基
、４−位にアセトキシ基を有するβ−ラクタム化合物の
脱シリル化に関しては、特開昭６１−５０９６４におい
て、酢酸−水による方法が報告されているが、収率２４
％と低収率である。また、一般にテトラブチルアンモニ
ウムフルオライド等による脱シリル化が知られているが
、上記の４−アセトキシ−３−ｔｅｒｔ−ブチルジメチ
ルシリロキシエチルアゼチジン−２−オンに適用した場
合、単純な抽出、濃縮、純品化操作では４−アセトキシ
−３−ヒドロキシエチルアゼチジン−２−オンが単離精
製しに＜＜、収率的に低くなる結果が得られる。Regarding the desilylation of a β-lactam compound having a tert-butyldimethylsilyloxyethyl group at the 3-position and an acetoxy group at the 4-position, a method using acetic acid and water is reported in JP-A-61-50964. However, the yield was 24
%, which is a low yield. In addition, desilylation using tetrabutylammonium fluoride is generally known, but when applied to the above-mentioned 4-acetoxy-3-tert-butyldimethylsilyloxyethylazetidin-2-one, simple extraction, In the concentration and purification operations, 4-acetoxy-3-hydroxyethylazetidin-2-one is isolated and purified, resulting in a low yield.
そこで、本発明者らは詳細な検討を行なった結果、簡便
に脱シリル化が行なえ、しかも単離精製が容易な方法を
見出し、本発明に至った。以下に詳細を説明する。As a result of detailed studies, the present inventors discovered a method that allows simple desilylation and easy isolation and purification, leading to the present invention. Details will be explained below.
（課題を解決するための手段および作用効果）本発明は
、化合物（１）
に脱シリル化剤を作用させることを特徴とする、式印
で表される４−アセトキシ−３−ヒドロキシエチルアゼ
チジン−２−オンの製造法を内容とする。(Means for Solving the Problems and Effects) The present invention provides 4-acetoxy-3-hydroxyethylazetidine represented by the formula symbol, characterized in that a desilylating agent is allowed to act on the compound (1). The content is a method for producing -2-one.
化合物（１）で表されるβ−ラクタム化合物は、本発明
者等が既に特許出願した（特開昭６１−１８７９１、特
開昭６１−１８７５８、特開昭６２−２５８５８）下記
の反応式ＧＩＤに示すような簡便な方法で合成できる。The β-lactam compound represented by compound (1) has the following reaction formula GID for which the present inventors have already applied for a patent (JP-A-61-18791, JP-A-61-18758, JP-A-62-25858). It can be synthesized by a simple method as shown below.
反応式口
上記の反応によって合成した化合物（１）に脱シリル化
剤を作用させて、目的の４−アセトキシ−３−ヒドロキ
シエチルアゼチジン−２−オンに変換する。この際の脱
シリル化剤としては、鉱酸および有機の強酸であり、そ
の中でも塩酸、フッ化水素酸、臭化水素酸、硫酸、トリ
フルオロ酢酸、トリクロロ酢酸、パラトルエンスルホン
酸などが好ましい。溶媒としてはテトラヒドロフラン、
ジオキサン、アセトニトリル、メタノール、エタノール
及び上記の含水溶媒が使用できるが、その中でもアセト
ニトリル、含水アセトニトリルが最適である。反応は一
２０°Ｃから室温付近の範囲で選択することができる。Reaction formula Compound (1) synthesized by the above reaction is treated with a desilylating agent to convert it to the desired 4-acetoxy-3-hydroxyethylazetidin-2-one. Desilylating agents in this case include mineral acids and strong organic acids, and among these, hydrochloric acid, hydrofluoric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid, p-toluenesulfonic acid, and the like are preferred. Tetrahydrofuran as a solvent,
Dioxane, acetonitrile, methanol, ethanol and the above-mentioned water-containing solvents can be used, among which acetonitrile and water-containing acetonitrile are most suitable. The reaction can be selected in the range from -20°C to around room temperature.
鉱酸あるいは有機の強酸は、化合物（Ｉ）に対して０．
３〜１０モル当量用いればよく、好ましくは２〜７モル
当量用いるのがよい。The mineral acid or organic strong acid has a 0.0.
It is sufficient to use 3 to 10 molar equivalents, preferably 2 to 7 molar equivalents.
また（基質（Ｉ）／溶媒）が１〜６０ （ｗ／ｖ％）の
濃度で行なうことができ、場合によっては反応開始時に
（１）が溶媒に懸濁状態になっていてもよいが、好まし
くは（基質（Ｉ）／溶媒）が３〜８０ （ｗ／ｖ％）で
行なうのがよい。溶媒中の含水率としては、１〜４０
（ｖ／ｖ％）で行なうのがよいが、好ましくは１０〜３
０ （ｖ／ｖ％）で行なうのがよい。Furthermore, the reaction can be carried out at a concentration of (substrate (I)/solvent) of 1 to 60 (w/v%), and in some cases, (1) may be suspended in the solvent at the start of the reaction. Preferably, the ratio (substrate (I)/solvent) is 3 to 80 (w/v%). The water content in the solvent is 1 to 40
(v/v%), preferably 10 to 3
It is preferable to carry out at 0 (v/v%).
処理は、反応終了後、炭酸水素ナトリウム等の塩基で中
和し、また必要に応じて無水硫酸ナトリウム等で脱水を
行ない、次に不溶物を濾過、除去した後、反応液を減圧
上濃縮し、再結晶化を行なうことにより収率よく４−ア
セトキシ−３−ヒドロキシエチルアゼチジン−２−オン
を取得することができる。After completion of the reaction, the reaction solution is neutralized with a base such as sodium hydrogen carbonate, and if necessary, dehydrated with anhydrous sodium sulfate, etc. After filtering and removing insoluble materials, the reaction solution is concentrated under reduced pressure. By performing recrystallization, 4-acetoxy-3-hydroxyethylazetidin-2-one can be obtained in good yield.
本発明方法によると、鉱酸あるいは有機の強酸存在下、
有機溶媒又は含水有機溶媒中で温和な条件で処理するこ
とにより、簡便に目的とする４−アセトキシ−３−ヒド
ロキシエチルアゼチジン−２−オンが取得できる。また
、目的の４−アセトキシ−３−ヒドロキシエチルアゼチ
ジン−２−オンは光学活性体であることが、カルバペネ
ムやペネム系β−ラクタム合成中間体として重要である
が、出発物質の（ＳＲ，４Ｒ）−４−アセトキシ−３−
〔（几） −ｉ −ｔｅｒｔ−ブチルジメチルシリロキ
シエチル〕−アゼチジン−２−オンの光学活性を保持す
ることが本方法では可能であり、化学純度に加え、光学
純度の秀れた（３Ｒ１４Ｒ）−４−アセトキシ−８−（
（Ｒ）−１−ヒドロキシエチルクーアゼチジン−２−オ
ンが容易に取得できる。According to the method of the present invention, in the presence of a strong mineral acid or organic acid,
The desired 4-acetoxy-3-hydroxyethylazetidin-2-one can be easily obtained by treatment under mild conditions in an organic solvent or a water-containing organic solvent. Furthermore, it is important that the target 4-acetoxy-3-hydroxyethylazetidin-2-one is an optically active form as an intermediate for the synthesis of carbapenems and penem-based β-lactams. )-4-acetoxy-3-
This method makes it possible to maintain the optical activity of [(几)-i-tert-butyldimethylsilyloxyethyl]-azetidin-2-one, which has excellent optical purity (3R14R) in addition to chemical purity. -4-acetoxy-8-(
(R)-1-Hydroxyethylcouazetidin-2-one can be easily obtained.
（実施例）
次に実施例をあげて本発明を更に詳細に説明するが、本
発明はこれらの実施例のみで限定されるものではない。(Examples) Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.
実施例１
（３Ｒ，４Ｒ）−４−アセトキシ−３−〔（几）−１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
（３Ｒ１４几）−４−アセトキシ−３−〔（几ン一１−
ｔｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチ
ジン−２−オン５．２Ｏｆをアセトニトリル２０ｙｔｔ
ｌに溶解し、０“Ｃに冷却した後、フッ化水素酸水溶液
（４６％）８．４ｒｔｔｌを加え、２０時間撹拌した。Example 1 (3R,4R)-4-acetoxy-3-[(几)-1-
Production of hydroxyethyl]azetidin-2-one (3R14)-4-acetoxy-3-[(R14)
tert-Butyldimethylsilyloxyethyl]azetidin-2-one 5.2Of in acetonitrile 20ytt
After cooling to 0"C, 8.4 rttl of an aqueous solution of hydrofluoric acid (46%) was added, and the mixture was stirred for 20 hours.
ＮａＨＣＯａ １５ ｆを加えて生じる懸濁液を、塩
化メチレンを用いて戸別し、溶媒を減圧留去することに
より、白色の結晶を得た。これを、塩化メチレン−ヘキ
サンから再結晶して、（３Ｒ，４Ｒ）−４−アセトキシ
−８−（（Ｒ）−１−ヒドロキシエチル〕アゼチジン−
２−オンの無色針状結晶を２．６５！ｆ（８５％〕得た
。物性値は以下の通りであった。A suspension formed by adding 15 f of NaHCOa was separated using methylene chloride, and the solvent was distilled off under reduced pressure to obtain white crystals. This was recrystallized from methylene chloride-hexane and (3R,4R)-4-acetoxy-8-((R)-1-hydroxyethyl]azetidine-
2.65 colorless needle crystals of 2-one! f (85%) was obtained.The physical properties were as follows.
（／＋）２０＝＋６５．４° （０＝０．４６、ＣＢ（
０１３）ｍｐ １１４〜１１４．５”Ｃ
’Ｈ−ＮＭＲ（９０ＭＨｚ、ＣＤＣｌ３ ） δ（ｐ
ｐｍＣ１，３０（３Ｈ，ａ）、２．１０（ＩＨ，ｓ）、
３．１８（ＩＨ。(/+)20=+65.4° (0=0.46, CB(
013) mp 114-114.5"C'H-NMR (90MHz, CDCl3) δ(p
pmC1,30 (3H, a), 2.10 (IH, s),
3.18 (IH.
ａｄ ）、３．９０ （Ｈ（、ｂｒｏａｄ ｓ ）、４
．１６ （ＨＩ、 ｍ）、５．８４（ＩＨｌｄ）、７．
７８ （１ｆＬ ｂｒｏａｄ ｓ ）実施例２
（３Ｒ，４几）−４−アセトキシ−３−（（Ｒ）−１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
（３Ｌ４几ン−４−アセトキシ−８−（（Ｒ）−１−ｔ
ｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチジン
−２−オン２８７ Ｍ（／をアセトニトリル６ｔｓｌに
溶解し、トリフルオロ酢酸の水溶液２ｍ１（濃度１モル
／ｌ）を、水冷下、１時間かかつて滴下した後、０°Ｃ
で３日間撹拌した。反応後、水冷下に、５％ＮａＨＯＯ
３でｐＨ５，５とした後、塩化メチレン５０ｍ１を加え
、無水硫酸ソーダで乾燥した。硫酸ソーダを戸別し、溶
液を減圧濃縮すると、無色のワックス状固体が得られた
。これを塩化メチレン−ヘキサンから再結晶すると、（
３几、４几）−４−アセトキシ−８−（（Ｒ）−１−ヒ
ドロキシエチル〕アゼチジン−２−オン １４３ｆｆＳ
’（８８％）を、白色結晶として得た。物性値は、実施
例１に示した値に一致した。ad ), 3.90 (H(, broad s ), 4
．． 16 (HI, m), 5.84 (IHld), 7.
78 (1fL broads) Example 2 (3R,4L)-4-acetoxy-3-((R)-1-
Production of hydroxyethyl]azetidin-2-one (3L4-4-acetoxy-8-((R)-1-t
After dissolving 287 M of ert-butyldimethylsilyloxyethyl]azetidin-2-one (/ in 6 tsl of acetonitrile, adding 2 ml of an aqueous solution of trifluoroacetic acid (concentration 1 mol/l) dropwise for 1 hour under water cooling, 0°C
The mixture was stirred for 3 days. After the reaction, 5% NaHOO was added under water cooling.
3 to adjust the pH to 5.5, 50 ml of methylene chloride was added, and the mixture was dried over anhydrous sodium sulfate. Sodium sulfate was added separately and the solution was concentrated under reduced pressure to yield a colorless waxy solid. When this is recrystallized from methylene chloride-hexane, (
3 liters, 4 liters) -4-acetoxy-8-((R)-1-hydroxyethyl]azetidin-2-one 143ffS
' (88%) was obtained as white crystals. The physical property values matched those shown in Example 1.
実施例３
（３几、４Ｒ）−４−アセトキシ−８−（（Ｒ）−１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
Ｍ３ｒｔ、４Ｒ）−４−アセトキシ−３−（（Ｒ）−１
−ｔｅｒｔ−ブチルジメチルシリロキシ二チル〕アゼチ
ジン−２−オン２８７■をアセトニトリル３ｍｌに浴解
し、氷冷下、１規定塩酸２ｍｌを３０分かけて滴下した
。アセトニトリル２ｍｌを追加し、０°Ｃで１日撹拌し
た。反応後、水冷下、強（撹拌しながらＮａＨＯＯａ
１７０ ’９を加え、中和した。Example 3 (3 liters, 4R)-4-acetoxy-8-((R)-1-
Production of hydroxyethyl]azetidin-2-one M3rt, 4R)-4-acetoxy-3-((R)-1
-tert-Butyldimethylsilyloxydityl]azetidin-2-one (287 ml) was dissolved in 3 ml of acetonitrile, and 2 ml of 1N hydrochloric acid was added dropwise over 30 minutes under ice cooling. 2 ml of acetonitrile was added and stirred at 0°C for 1 day. After the reaction, add NaHOOa under water cooling (with stirring).
170'9 was added to neutralize.
この液に塩化メチレン５０ｘｌを加え、無水硫酸ソーダ
を加え、乾燥後、硫酸ソーダを戸別し、溶液を減圧濃縮
すると、ワックス状の白色固体１９０■が得られた。こ
れを塩化メチレン−ヘキサンから再結晶すると、（ａｎ
、４Ｒ）−４−アセトキシ−３−（（Ｒ）−１−ヒドロ
キシエチル〕アゼチジン−２−オン １５０ｑ（８７％
）を白色結晶として得た。物性値は実施例１に示した値
に一致した。50xl of methylene chloride was added to this liquid, anhydrous sodium sulfate was added, and after drying, the sodium sulfate was poured out separately, and the solution was concentrated under reduced pressure to obtain 190cm of a waxy white solid. When this is recrystallized from methylene chloride-hexane, (an
, 4R)-4-acetoxy-3-((R)-1-hydroxyethyl]azetidin-2-one 150q (87%
) was obtained as white crystals. The physical property values matched those shown in Example 1.
実施例４
（３几、４Ｒ）−４−アセトキシ−３−（（Ｒ）−１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
（３几、４Ｒ）−４−アセトキシ−３−（（Ｒ）−１−
ｔｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチジ
ン−２−オン２８７１１ｇをアセトニトリル３ｍｌに溶
解し、水冷下で１規定の硫酸水溶液２Ｎｔを滴下した。Example 4 (3 liters, 4R)-4-acetoxy-3-((R)-1-
Production of hydroxyethyl]azetidin-2-one (3 bottles, 4R)-4-acetoxy-3-((R)-1-
28,711 g of tert-butyldimethylsilyloxyethyl]azetidin-2-one was dissolved in 3 ml of acetonitrile, and 2Nt of a 1N aqueous sulfuric acid solution was added dropwise under water cooling.
滴下終了後、アセトニトリル２ｙｔｌを加え、激しく撹
拌しなからＯ″Ｃで２日間反応後、ＮａＨＣＯ３を１７
０ｑ加え、中和した。無水硫酸ソーダ１０ｙと塩化メチ
レン５０ｒｔｔｌを加え、乾燥した。乾燥剤を戸別し、
減圧濃縮して、ワックス状の白色固体を得た。これを塩
化メチレン−ヘキサンから再結晶して、（３几、４几）
−４−アセトキシ−３−（ＯＬ）−１−ヒドロキシエチ
ル〕アゼチジン−２−オン １４Ｃ１１８２％）を白色
結晶として得た。物性値は、実施例１に示した値に一致
した。After dropping, add 2 ytl of acetonitrile, stir vigorously and react at O''C for 2 days, then add 17 ml of NaHCO3.
0q was added to neutralize. 10 y of anhydrous sodium sulfate and 50 rttl of methylene chloride were added and dried. Distribute the desiccant from door to door.
Concentration under reduced pressure gave a waxy white solid. This was recrystallized from methylene chloride-hexane (3 liters, 4 liters).
-4-acetoxy-3-(OL)-1-hydroxyethyl]azetidin-2-one 14C1182%) was obtained as white crystals. The physical property values matched those shown in Example 1.
実施例５
（３Ｌ ４Ｒ）−４−アセトキシ−３−（（Ｒ，）−１
−ヒドロキシエチル〕アゼチジン−２−オンの製造
（３几、４几）−４−アセトキシ−８−（（Ｒ）−１−
ｔｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチジ
ン−２−オン２８７１１１ｆｊをアセトニトリル８ｍｌ
にだ解し、ｐ−トルエンスルホン酸−水和物１９１７ｆ
ｆｙの水（２ｔｔｔｌ）溶液を滴下した。滴下終了後、
アセトニトリル２ｔｘｌを加え、０°Ｃで２９時間撹拌
した。反応後、ＮａＨＣＯａを８４ダ加え、塩化メチレ
ン５０ｔｘｌで希釈後、無水硫酸ソーダで乾燥した。乾
燥剤を戸別後、減圧濃縮して、無色の固体（ワックス状
ンを得た（１８８＃）。これを塩化メチレン−ヘキサン
から再結晶して、（ＳＲ，４Ｒ）−４−アセトキシ−３
−〔（几）−１−ヒドロキシエチル〕アゼチジン−２−
オン １３９ｑ（８０％）を白色結晶として得た。物性
値は、実施例１に示した値に一致した。Example 5 (3L 4R)-4-acetoxy-3-((R,)-1
-Hydroxyethyl]Azetidin-2-one production (3 and 4 bottles) -4-acetoxy-8-((R)-1-
tert-butyldimethylsilyloxyethyl]azetidin-2-one 287111fj in 8 ml of acetonitrile
p-toluenesulfonic acid hydrate 1917f
A solution of fy in water (2tttl) was added dropwise. After finishing dropping,
2 txl of acetonitrile was added, and the mixture was stirred at 0°C for 29 hours. After the reaction, 84 Da of NaHCOa was added, diluted with 50 txl of methylene chloride, and dried over anhydrous sodium sulfate. After removing the desiccant from each house, it was concentrated under reduced pressure to obtain a colorless solid (waxy substance (188#)). This was recrystallized from methylene chloride-hexane to give (SR,4R)-4-acetoxy-3
-[(几)-1-hydroxyethyl]azetidine-2-
On 139q (80%) was obtained as white crystals. The physical property values matched those shown in Example 1.
実施例６
（３Ｌ ４Ｒ）−４−アセトキシ−３−〔（凡）−１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
（８Ｌ ４Ｒ）−４−アセトキシ−３−（（Ｒ）−１−
ｔｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチジ
ン−２−オン２８７ ＩＩ！をアセトニトリル３１１１
ｔに溶解し、水冷下で１規定の臭化水累水浴液２ｔｔｔ
ｌを３０分かけて滴下し、これにアセトニトリル２ｙｔ
ｔを追加し、０°Ｃで２４時間撹拌した。反応後、固体
Ｎａｌ−ＩＣ０ｑ １７０ ’！９を加え、塩化メチ
レン（５０ｓｔ／Ｘ２）で抽出、無水硫酸ソーダで乾燥
した。乾燥剤をＰ別後、減圧濃縮して、無色ワックス状
の固体１８８ｍｇを得た。これを、塩化メチレン−ヘキ
サンから再結晶して、（３Ｒ１４几）−４−アセトキシ
−３−（（Ｒ）−１−ヒドロキシエチル〕アゼチジン−
２−オンの白色結晶１４８Ｎ９（８３％）を得た。物性
値は実施例１に示した値に一致した。Example 6 (3L 4R)-4-acetoxy-3-[(ordinary)-1-
Production of hydroxyethyl]azetidin-2-one (8L 4R)-4-acetoxy-3-((R)-1-
tert-butyldimethylsilyloxyethyl]azetidin-2-one 287 II! acetonitrile 3111
Dissolved in 1N bromide water bath solution 2ttt under water cooling.
1 was added dropwise over 30 minutes, and 2 yt of acetonitrile was added to this.
t was added and stirred at 0°C for 24 hours. After the reaction, solid Nal-IC0q 170'! 9 was added, extracted with methylene chloride (50st/X2), and dried over anhydrous sodium sulfate. After removing the desiccant from P, the mixture was concentrated under reduced pressure to obtain 188 mg of a colorless waxy solid. This was recrystallized from methylene chloride-hexane and (3R14)-4-acetoxy-3-((R)-1-hydroxyethyl]azetidine-
White crystals of 2-one 148N9 (83%) were obtained. The physical property values matched those shown in Example 1.
実施例７
（３Ｌ４Ｒン−４−アセトキシ−８−（（Ｒ） −１−
ヒドロキシエチル〕アゼチジン−２−オンの製造
（３Ｒ，４Ｒ）−４−アセトキシ−３−（（Ｒ）−１−
ｔｅｒｔ−ブチルジメチルシリロキシエチル〕アゼチジ
ン−２−オン２８７〜を含水アセトニトリル（水−アセ
トニトリル：２ｍ１−’１ｍ１）に溶解し、水冷下、ト
リクロロ酢酸３２６Ｍ！を加え、０°Ｃで３日間撹拌し
た。反応後、ＮａＨＣＯ３（固体）を０．１７９加え、
５分間撹拌後、塩化メチレン５０ｍ１と無水硫酸ソーダ
ｌＯダを加えた。硫酸ソーダを炉別し、溶液を減圧濃縮
すると、ワックス状の無色固体が得られた。これを、塩
化メチレン−ヘキサンから結晶化すると、（３Ｒ１４Ｒ
）−４−アセトキシー：１ｌ−（（Ｒ）−１−ヒドロキ
シエチル〕アゼチジン−２−オン １３８Ｍｇ（８０％
ンが白色結晶として得られた。物性値は実施例１に示し
た値に一致した。Example 7 (3L4R-4-acetoxy-8-((R)-1-
Production of hydroxyethyl]azetidin-2-one (3R,4R)-4-acetoxy-3-((R)-1-
tert-butyldimethylsilyloxyethyl]azetidin-2-one (287~) was dissolved in aqueous acetonitrile (water-acetonitrile: 2ml-'1ml), and under water cooling, trichloroacetic acid (326M) was dissolved! was added and stirred at 0°C for 3 days. After the reaction, 0.179% of NaHCO3 (solid) was added,
After stirring for 5 minutes, 50 ml of methylene chloride and 10 ml of anhydrous sodium sulfate were added. The sodium sulfate was removed in a furnace and the solution was concentrated under reduced pressure to obtain a waxy colorless solid. When this is crystallized from methylene chloride-hexane, (3R14R
)-4-acetoxy: 1l-((R)-1-hydroxyethyl]azetidin-2-one 138Mg (80%
was obtained as white crystals. The physical property values matched those shown in Example 1.
Claims (4)
水有機溶媒中で処理することを特徴とする、式（II）で
表される４−アセトキシ−３−ヒドロキシエチルアゼチ
ジン−２−オンの製造法。 ▲数式、化学式、表等があります▼（II）(1) Compound (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Formula (II) is characterized by treating (I) in an organic solvent or a water-containing organic solvent in the presence of a mineral acid or a strong organic acid. ) A method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II)
硫酸である請求項１記載の製造法。(2) The method according to claim 1, wherein the mineral acid is hydrofluoric acid, hydrochloric acid, hydrobromic acid or sulfuric acid.
ルホン酸もしくはトリクロロ酢酸である請求項１記載の
化合物（II）の製造法。(3) The method for producing compound (II) according to claim 1, wherein the strong organic acid is trifluoroacetic acid, p-toluenesulfonic acid or trichloroacetic acid.
含水アセトニトリルである請求項１記載の製造法。(4) The organic solvent or water-containing organic solvent is acetonitrile,
The method according to claim 1, wherein the acetonitrile is hydrous acetonitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63083633A JP2604794B2 (en) | 1988-04-04 | 1988-04-04 | Method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63083633A JP2604794B2 (en) | 1988-04-04 | 1988-04-04 | Method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01254656A true JPH01254656A (en) | 1989-10-11 |
| JP2604794B2 JP2604794B2 (en) | 1997-04-30 |
Family
ID=13807872
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63083633A Expired - Lifetime JP2604794B2 (en) | 1988-04-04 | 1988-04-04 | Method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one |
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| Country | Link |
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| 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 |
| JPS6284057A (en) * | 1985-10-07 | 1987-04-17 | Kanegafuchi Chem Ind Co Ltd | Production of 4-acetoxy-3-hydroxyethylazetidine-2-one derivative |
| JPS62195359A (en) * | 1986-02-22 | 1987-08-28 | Kanegafuchi Chem Ind Co Ltd | Production of 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| JPS6345251A (en) * | 1987-03-05 | 1988-02-26 | Sankyo Co Ltd | Production of 4-acyloxyazetidinone derivative |
-
1988
- 1988-04-04 JP JP63083633A patent/JP2604794B2/en not_active Expired - Lifetime
Patent Citations (5)
| 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 |
| JPS6284057A (en) * | 1985-10-07 | 1987-04-17 | Kanegafuchi Chem Ind Co Ltd | Production of 4-acetoxy-3-hydroxyethylazetidine-2-one derivative |
| JPS62195359A (en) * | 1986-02-22 | 1987-08-28 | Kanegafuchi Chem Ind Co Ltd | Production of 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| JPS6345251A (en) * | 1987-03-05 | 1988-02-26 | Sankyo Co Ltd | Production of 4-acyloxyazetidinone derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2604794B2 (en) | 1997-04-30 |
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