JPH0479333B2 - - Google Patents
Info
- Publication number
- JPH0479333B2 JPH0479333B2 JP60004724A JP472485A JPH0479333B2 JP H0479333 B2 JPH0479333 B2 JP H0479333B2 JP 60004724 A JP60004724 A JP 60004724A JP 472485 A JP472485 A JP 472485A JP H0479333 B2 JPH0479333 B2 JP H0479333B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- general formula
- formula
- protecting group
- acetoxy
- 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.)
- Expired - Lifetime
Links
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- -1 t-butyldimethylsilyl group Chemical group 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 14
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical group CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 9
- CQXFYUIOYBEJOS-UHFFFAOYSA-N [3-(2-hydroxyethyl)-4-oxoazetidin-2-yl] acetate Chemical class CC(=O)OC1NC(=O)C1CCO CQXFYUIOYBEJOS-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 150000008282 halocarbons Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 239000007788 liquid Substances 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 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 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- PRPRZHRTVOEUQM-SOLBZPMBSA-N (3r,4r)-1-[tert-butyl(dimethyl)silyl]-3-[(1r)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-trimethylsilyloxyazetidin-2-one Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C)[C@@H]1[C@@H](O[Si](C)(C)C)N([Si](C)(C)C(C)(C)C)C1=O PRPRZHRTVOEUQM-SOLBZPMBSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- NJKXOGAJJYVLQQ-XSRFYTQQSA-N 3-[(2R)-1-dimethylsilyloxy-3-methylbutan-2-yl]-4-trimethylsilyloxyazetidin-2-one Chemical compound C(C)(C)[C@@H](CO[SiH](C)C)C1C(NC1O[Si](C)(C)C)=O NJKXOGAJJYVLQQ-XSRFYTQQSA-N 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
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- WKDDRNSBRWANNC-ATRFCDNQSA-N Thienamycin Chemical compound C1C(SCCN)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 WKDDRNSBRWANNC-ATRFCDNQSA-N 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-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
- 238000006137 acetoxylation reaction Methods 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
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- SFSURLOVKBVPAD-UHFFFAOYSA-N chloro-dimethyl-(2-methylpropyl)silane Chemical compound CC(C)C[Si](C)(C)Cl SFSURLOVKBVPAD-UHFFFAOYSA-N 0.000 description 1
- YCXVDEMHEKQQCI-UHFFFAOYSA-N chloro-dimethyl-propan-2-ylsilane Chemical compound CC(C)[Si](C)(C)Cl YCXVDEMHEKQQCI-UHFFFAOYSA-N 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007033 dehydrochlorination reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 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
- 150000002736 metal compounds Chemical class 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 1
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 1
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- HNOLIWBAJVIBOU-UHFFFAOYSA-N prop-2-enyl 2-chloro-2-oxoacetate Chemical compound ClC(=O)C(=O)OCC=C HNOLIWBAJVIBOU-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 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
Description
（産業上の利用分野）
本発明は、３−位に水酸基が保護されたヒドロ
キシエチル基を有し、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−オン誘導体の新規な製造法に関す
る。４−アセトキシ−３−ヒドロキシエチルアゼ
チジン−２−オン誘導体は、チエナマイシン等に
代表さ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
P.2293（1982）、およびヨシダ等，Chem.Pharm.
Bull.29巻，P.2899（1991）〕。
（従来の技術と問題点）
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〔ヨシダ
等，Chem Pharm Bull.29巻P.2899（1981）〕、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，P.2399（1983）〕、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P.2293（1982）〕等が知られてい
る。しかし、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、酢酸水銀や四酢酸鉛等の工業的には好ましく
ない重金属化合物を使用する難点を有していた。
本発明者らは、エノールシリルエーテル類とクロ
ルスルホニルイソシアネートの反応によつて、３
−位に０−保護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
物の製法を見出し既に出願した。さらに本発明者
等はこのβ−ラクタム化合物を用いて、４−アセ
トキシ−３−ヒドロキシエチルアゼチジン−２−
オンを簡便に合成できることを見出して、本発明
に至つた。以下に詳細に説明する。
（問題点を解決するための手段および作用効果）
本発明は、一般式（）
（式中、R1は水酸基の保護基、R2，R3，R4は
C1〜C4の低級アルキル基、フエニル基、又はア
ラルキル基、ＲはＮの保護基を示す。）で表わさ
れるβ−ラクタム化合物に、有機溶媒中で塩基存
在下に無水酢酸を作用させ、ついでＮの保護基を
脱離させることを特徴とする、一般式（）
（式中、R1は水酸基の保護基を示す。）で表わ
される４−アセトキシ−３−ヒドロキシエチルア
ゼチジン−２−オン誘導体の製造法に関する。
一般式（）で示されるβ−ラクタム化合物
は、一般（′）
（式中、R1は水酸基の保護基、R2，R3，R4は
C1〜C4の低級アルキル基，フエニル基又はアラ
ルキル基を示す。）で示されるβ−ラクタム化合
物のＮに置換基Ｒを導入することによつて得られ
る。一般式（′）で示される４−位にシリルエ
ーテル基を有するβ−ラクタム化合物は、本発明
者らが既に出願（昭和59年特許願第139797号）し
たように、反応式の方法によつて簡便に取得で
きる。
このβ−ラクタム化合物（′）とＲ−Ｘ（Ｘは
ハロゲン）で示される試薬を反応させることによ
り、一般式（）で示されるＮに保護基を有する
β−ラクタム化合物（）を取得することができ
る。Ｒ−Ｘの試薬としては、ｔ−ブチルジメチル
シリルクロリド，イソプロピルジメチルシリルク
ロリド，イソブチルジメチルシリルクロリド、ト
リメチルシリルクロリドなどのトリアルキル−シ
リルハライドや、
(Industrial Application Field) The present invention relates to a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having a hydroxyethyl group with a protected hydroxyl group at the 3-position and an acetoxy group at the 4-position. Concerning a new manufacturing method. 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives are known to be useful as synthetic intermediates for carbapenem β-lactam antibiotics such as thienamycin and penem β-lactam antibiotics. [For example, Rader et al., Tetrahedron Letters, vol. 23]
P.2293 (1982), and Yoshida et al., Chem.Pharm.
Bull.29, P.2899 (1991)]. (Prior art and problems) Conventionally, as a method for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives, 6
- Synthesis from aminopenicillanic acid [Yoshida et al., Chem Pharm Bull. Vol. 29, P. 2899 (1981)], Synthesis from threonine [Shiozaki et al., Tetrahedron Vol. 39, P. 2399 (1983)], Asparagine A method of synthesizing it from an acid [Raider et al., Tetrahedron Letters, Vol. 23, P. 2293 (1982)] is known. However, both methods have the disadvantage of using industrially undesirable heavy metal compounds such as mercury acetate and lead tetraacetate to introduce an acetoxy group into the 4-position of the β-lactam ring. .
The present inventors have discovered that 3
We have already discovered a method for producing a new β-lactam compound having a 0-protected hydroxyethyl group at the -position and a silyl ether group at the 4-position, and have already filed an application. Furthermore, the present inventors used this β-lactam compound to obtain 4-acetoxy-3-hydroxyethylazetidine-2-
The present invention was achieved by discovering that ion can be easily synthesized. This will be explained in detail below. (Means and effects for solving the problems) The present invention is based on the general formula () (In the formula, R 1 is a hydroxyl protecting group, R 2 , R 3 , R 4 are
C1 to C4 lower alkyl group, phenyl group, or aralkyl group; R represents a protecting group for N; ) is treated with acetic anhydride in the presence of a base in an organic solvent, and then the N protecting group is removed, the general formula () The present invention relates to a method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by the formula (wherein, R 1 represents a hydroxyl-protecting group). The β-lactam compound represented by the general formula () is the general formula (′) (In the formula, R 1 is a hydroxyl protecting group, R 2 , R 3 , R 4 are
Indicates a C1 to C4 lower alkyl group, phenyl group, or aralkyl group. ) can be obtained by introducing a substituent R to N of the β-lactam compound shown in (). The β-lactam compound having a silyl ether group at the 4-position represented by the general formula (') can be obtained by the reaction method as previously filed by the present inventors (Patent Application No. 139797 of 1982). It can be easily obtained. By reacting this β-lactam compound (') with a reagent represented by R-X (X is a halogen), a β-lactam compound () having a protecting group at N represented by the general formula () is obtained. I can do it. As the reagent for R-X, trialkyl-silyl halides such as t-butyldimethylsilyl chloride, isopropyldimethylsilyl chloride, isobutyldimethylsilyl chloride, trimethylsilyl chloride,
【式】【formula】
【式】【formula】
【式】【formula】
【式】【formula】
【式】などのアルキルオ
キシオキザリルクロリド、アラルキルオキシ−オ
キザリルクロリドやアリルオキシオキザリルクロ
リドなどを利用することができる。これらの中
で、好ましいのはｔ−ブチルジメチルシリルクロ
リドであり、Ｎにｔ−ブチルジメチルシリル基を
保護基をして導入できる。
導入法としては、化合物（′）をトリエチル
アミンやイミダゾール等の塩基の存在下、DMF
や塩化メチレン溶媒中で脱塩化水素反応を実施
し、溶媒を留去後、抽出し、抽出溶媒を留去して
化合物（）を取得できる。
β−ラクタム化合物（）の３−位のヒドロキ
シエチル基の０−保護基R1としては、R1が一般
式（）Alkyloxyoxalyl chloride, aralkyloxy-oxalyl chloride, allyloxyoxalyl chloride, and the like can be used. Among these, preferred is t-butyldimethylsilyl chloride, in which a t-butyldimethylsilyl group can be introduced into N by using a protective group. For introduction, compound (') is added to DMF in the presence of a base such as triethylamine or imidazole.
A dehydrochlorination reaction is carried out in a dichloromethane or methylene chloride solvent, the solvent is distilled off, extraction is performed, and the extraction solvent is distilled off to obtain the compound (). As the 0-protecting group R 1 of the hydroxyethyl group at the 3-position of the β-lactam compound (), R 1 has the general formula ()
【式】（式中、R5，R6，R7
はC1〜C4の低級アルキル基を示す。）で表わされ
るトリアルキルシリル基、たとえばtert−ブチル
ジメチルシリル基、トリイソプロピルシリル基、
イソプロピルジメチルシリル基、イソブチルジメ
チルシリル基や、その他ｔ−ブチル基、ベンジル
基、トリクロロエトキシカルボニル基、tert−ブ
トキシカルボニル基、ｐ−ニトロベンジルオキシ
カルボニル基等が挙げられるが、好ましくは、反
応中により安定であり、さらに酸処理により選択
的に脱保護されうるtert−ブチルジメチルシリル
基やイソプロピルジメチルシリル基がよい。又、
β−ラクタム化合物（）のR2，R3，R4は、メ
チル，エチル，イソプロピル，イソブチル，tert
−ブチル等のC1〜C4の低級アルキル基，フエニ
ル基、又はベンジル基、ｐ−ニトロベンジル基等
のアラルキル基から同一または異なつた基を選択
できるが、好ましくはR2＝R3＝R4＝メチルが最
適である。
上記のように調製した一般式（）
（式中、R1，R2，R3，R4，Ｒは前記と同じ）
で示されるβ−ラクタム化合物に、有機溶媒中、
塩基の存在下で無水酢酸を作用させて、目的の４
−アセトキシ−３−ヒドロキシエチルアゼチジン
−２−オン誘導体（′）
（式中、R1，Ｒは前記と同じ）に変換するの
であるが、この際の塩基と溶媒および反応温度が
収率に影響を与える因子である。反応溶媒として
は、ハロゲン系炭化水素や芳香族系炭化水素が使
用でき、好ましくは塩化メチレンなどのハロゲン
系炭化水素である。塩基としては、ジメチルアミ
ノピリジンが最適であり、又、ジメチルアミノピ
リジンと、他の塩基を組合せて使用することもで
きる。他の塩基として使用できるのはピリジン、
ルチジン、ピコリン等である。一般式（）で示
されるβ−ラクタム化合物に対し、塩基を１〜５
倍モル、好ましくは１〜３倍モル使用し、アセト
キシ化試薬として使用する無水酢酸は１〜20倍モ
ル、好ましくは３〜15倍モル使用すればよい。反
応操作としては、塩化メチレン等の有機溶媒中
で、一般式（）で示される４−位にシリルエー
テル基を有するβ−ラクタム化合物に、ジメチル
アミノピリジンと無水酢酸を添加し、攪拌下−50
℃〜室温、好ましくは−30℃〜５℃の温度条件下
で、出発物質の化合物（）が消失する迄反応を
つづける。ジメチルアミノピリジンに加えて、他
の塩基のピリジンやルチジンやピコリンを添加し
た場合には、収率の向上が認められる。反応後は
抽出溶媒として塩化メチレン又はヘキサン等を添
加し、炭酸水素ナトリウム水溶液を加え、分液
し、有機層を水洗後、脱水し有機溶媒を留去して
一般式（′）で示される４−位がアセトキシ化
されたＮ−保護β−ラクタム化合物を取得でき
る。この化合物（′）はそのまま次のＮ−保護
基の脱離反応に供することができるが、所望によ
つてはシリカゲルカラムクロマトグラフイーで精
製できる。
Ｎ−保護基の脱離に際しては、３−位に置換し
ているヒドロキシエチル基の０−保護基を脱離す
ることなく、Ｎ−保護基だけを選択的に脱離させ
る必要がある。具体的には、Ｎ−保護基がアルキ
ルシリル基、たとえばtert−ブチルジメチルシリ
ル基の際には、テトラブチルアンモニウムフロリ
ドを用いるのが好適である。テトラブチルアンモ
ニウムフロリドのかわりにテトラブチルアンモニ
ウムクロリドとフツ化カリの組合わせ試薬を用い
ても同等の効果を得ることができる。
Ｎ−保護基の脱離反応の際の溶媒はテトラヒド
ロフランやアセトニトリルが好ましく、反応は室
温で攪拌することにより円滑に進行する。脱保護
反応の際、酢酸を共存させることは、脱保護反応
の収率向上に寄与する。反応後、酢酸エチル等の
抽出溶媒を加え、炭酸水素ナトリウム水溶液等の
稀アルカリ水を添加し、有機層を抽出、水洗し、
有機層を脱水乾燥後、有機溶媒を留去することに
より目的の４−アセトキシ−３−ヒドロキシエチ
ルアゼチジン−２−オン誘導体を得ることができ
る。４−アセトキシ−３−ヒドロキシエチルアゼ
チジン−２−オン誘導体の精製は、ｎ−ヘキサン
や石油エーテルからの結晶化や、シリカゲルクロ
マトフラフイーにより純品を得ることができる。
（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。
実施例 １
（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−オンの合成。
（3R，5R）−３−（１−tert−ブチルジメチル
シリロキシエチル）−４−トリメチルシリロキシ
アゼチジン−２−オン1.0ｇをDMF10mlに溶解
し、これにトリエチルアミン0.89ｇとtert−ブチ
ルジメチルシリルクロライド0.61ｇを加え、室温
下で９時間攪拌する。反応後、DMFを減圧留去
し、ヘキサン80mlを加えた。この溶液を2.5％
NaHCO3水溶液、ついでPH３の塩酸水溶液、お
よび飽和食塩水で洗浄後、硫酸マグネシウムで乾
燥後、溶媒を留去すると、粗生成物の液体1.24ｇ
を得る。この液体1.0ｇを塩化メチレン５mlに加
え、さらにジメチルアミノピリジン0.85ｇと無水
酢酸1.1mlを加え、室温で６時間反応させる。次
に、反応液を５％NaHCO3水溶液、PH３の塩酸
水および飽和食塩水で洗浄後、硫酸マグネシウム
で乾燥させ、溶媒を留去すると、粗生成物の液体
0.8ｇを得る。この液体をシリカゲルカラム（ベ
ンゼン：ヘキサン＝２：１）で精製すると（3R，
4R，5R）−４−アセトキシ−１−（tert−ブチル
ジメチルシリル）−３−（１−tert−ブチルジメチ
ルシロキシエチル）−アゼチジン−２−オン0.5ｇ
を液体として得た。上記の液体0.5ｇTHF2mlに
加え、この溶液にテトラブチルアンモニウムフロ
ライド0.4ｇと酢酸0.17ｇを溶解したTHF溶液２
mlを添加し、室温で30分攪拌する。次に、この反
応液に酢酸エチル20mlを加え、つづいて５％
NaHCO3水溶液、および飽和食塩水で洗浄後、
硫酸マグネシウムで乾燥する。溶媒を留去すると
目的物の結晶0.30ｇを得た。これをシリカゲルカ
ラム（ベンゼン：酢酸エチル＝６：１）で精製す
ると目的のβ−ラクタムを固体として0.27ｇ得
た。
mp107℃〜108℃
〔α〕25 D＝＋50° （ｃ＝0.5 CHCl3）
1HNMR（90MHz，CDCl3） δ，（ppm）
0.88（6H，ｓ），0.84（9H，ｓ），1.20（3H，
ｄ），2.01（3H，ｓ），3.04（1H，dd），4.12（1H，
ｍ），5.76（1H，ｄ），6.73（NH）
実施例 ２
（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−オンの合成。
（3R，4R）−１−tert−ブチルジメチルシリル
−３−〔（Ｒ）−１−tert−ブチルジメチルシリロ
キシエチル〕−４−トリメチルシリロキシアゼチ
ジン−２−オン1.0ｇを塩化メチレン10mlに溶か
し、さらにジメチルアミノピリジン0.85ｇと無水
酢酸0.71ｇを加え、０℃で１日間反応させた。次
に反応液をヘキサンで希釈し、５％NaHCO3水
溶液、PH４の塩酸水および飽和食塩水で洗浄後、
硫酸マグネシウムで乾燥させ、溶媒を留去すると
粗生成物の液体0.85ｇを得た。この液体をシリカ
ゲルカラム（ヘキサン：エーテル＝30：１）で精
製すると、（3R，4R）−４−アセトキシ−１−
tert−ブチルジメチルシリル−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0.40ｇを無色の液体として得
た。この液体にTHF2mlを加え、この溶液にテト
ラブチルアンモニウムフロライド0.26ｇと酢酸
0.12ｇを溶解したTHF溶液２mlを添加し、室温
で30分間攪拌した。反応液に酢酸エチル20mlを加
え、つづいて５％NaHCO3水溶液、および飽和
食塩水で洗浄後、硫酸マグネシウムで乾燥した。
溶媒を留去して0.29ｇの固体を得た。ヘキサンよ
り再結晶して、0.20ｇの無色針状晶として目的の
β−ラクタムを得た。各々の性状は実施例１に示
した値と同一であつた。
実施例 ３
（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−オンの合成。
（3R，4R）−１−tert−ブチルジメチルシリル
−３−〔（Ｒ）−１−tert−ブチルジメチルシリロ
キシエチル〕−４−トリメチルシリロキシアゼチ
ジン−２−オン1.0ｇを塩化メチレン10mlに溶か
し、さらに、ジメチルアミノピリジン0.85ｇと、
２，６−ルチジン0.75ｇおよび無水酢酸1.42ｇを
加え、−15℃で44時間反応させた。次に反応液を
エーテルで希釈し５％NaHCO3水溶液、PH４の
塩酸水および飽和食塩水で洗浄後、硫酸マグネシ
ウムで乾燥させ、溶媒を留去すると粗生成物の液
体0.88ｇを得た。この液体をシリカゲルカラム
（ヘキサン：酢酸エチル＝100：１）で精製する
と、（3R，4R）−４−アセトキシ−１−tert−ブ
チルジメチルシリル−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0.58ｇを液体として得た。この液体を
THF2mlに溶かし、これにテトラブチルアンモニ
ウムフロライド0.38ｇと酢酸0.17ｇを溶解した
THF溶液２mlを添加し、室温で30分間攪拌した。
反応液に、酢酸エチル20mlを加え、つづいて５％
NaHCO3水溶液および飽和食塩水で洗浄後、硫
酸マグネシウムで乾燥した。溶媒を留去して0.42
ｇの固体を得た。これをシリカゲルカラム（ヘキ
サン：エーテル＝10：３）で精製すると、目的の
β−ラクタムを無色の針状晶として0.39ｇ得た。
各々の性状は実施例１に示した値と同一であつ
た。
実施例 ４
（3R，4R）−４−アセトキシ−３−〔（Ｒ）−１
−イソプロピルジメチルシリロキシエチル〕−ア
ゼチジン−２−オンの合成。
３−〔（Ｒ）−１−イソプロピルジメチルシリロ
キシエチル〕−４−トリメチルシリロキシアゼチ
ジン−２−オン1.2ｇ〔（3R，4R，5R）体：（3S，
4S，5R）体＝５：１〕をDMF12mlに溶解し、こ
れにトリエチルアミン0.52ｇとtert−ブチルジメ
チルシリルクロライド0.79ｇを加え、室温下で９
時間攪拌した。反応後、DMFを減圧留去し、ヘ
キサン30mlを加えた。この溶液を2.5％NaHCO3
水溶液、ついでpH5の塩酸水溶液および飽和食塩
水で洗浄後、硫酸マグネシウムで乾燥し、溶媒を
留去すると粗生成物の液体1.13ｇを得る。次に、
この液体0.90ｇを塩化メチレン10mlに加え、さら
にジメチルアミノピリジン0.79ｇと無水酢酸0.61
mlを加え、４℃で16時間反応させた。次に、この
反応液を５％NaHCO3水溶液、pH5の塩酸水お
よび飽和食塩水で洗浄後、硫酸マグネシウムで乾
燥させ、溶媒を留去すると粗生成物の液体0.70ｇ
を得る。この液体をシリカゲルカラム（ヘキサ
ン：エーテル＝100：３）で精製し、４−アセト
キシ−１−（tert−ブチルジメチルシリル）−３−
（１−イソプロピルジメチルシリロキシエチル）−
アゼチジン−２−オン0.20ｇを液体として得た。
この液体0.20ｇをTHF2mlに加え、この溶液にテ
トラブチルアンモニウムフロライド0.13ｇと酢酸
0.03ｇを溶解したTHF溶液２mlを添加し、室温
で30分攪拌した。次に、この反応液に酢酸エチル
60mlを加え、つづいて５％NaHCO3水溶液およ
び飽和食塩水で洗浄後、硫酸マグネシウムで乾燥
し、溶媒を留去すると目的物の粗生成物（3R，
4R，5R，：3S，4S，5R＝５：１）を0.14ｇ得る。
これをヘキサンで再結晶を行なうことにより
（3R，4R，5R）体を0.58ｇの白色結晶として得
た。1HNMR（90MHz，CDCl3）（3R，4R，5R）
体δ，（ppm）0.04（6H，ｓ），0.90（7H），1.23
（3H，ｄ），2.06（3H，ｓ），3.13（1H，dd），4.13
（1H，ｍ），5.76（1H，ｄ），6.40（NH）
〔α〕25 D＝＋54.2° （Ｃ＝0.5，CHCl3）
mp＝92℃〜94℃。A trialkylsilyl group represented by [Formula] (wherein R 5 , R 6 , and R 7 represent a C 1 to C 4 lower alkyl group), such as a tert-butyldimethylsilyl group, a triisopropylsilyl group,
Examples include isopropyldimethylsilyl group, isobutyldimethylsilyl group, and other groups such as t-butyl group, benzyl group, trichloroethoxycarbonyl group, tert-butoxycarbonyl group, and p-nitrobenzyloxycarbonyl group. Preferred are tert-butyldimethylsilyl and isopropyldimethylsilyl groups, which are stable and can be selectively deprotected by acid treatment. or,
R 2 , R 3 , R 4 of the β-lactam compound () are methyl, ethyl, isopropyl, isobutyl, tert
The same or different groups can be selected from C 1 -C 4 lower alkyl groups such as -butyl, phenyl groups, or aralkyl groups such as benzyl group and p-nitrobenzyl group, but preferably R 2 =R 3 =R 4 = methyl is optimal. General formula () prepared as above (In the formula, R 1 , R 2 , R 3 , R 4 , and R are the same as above)
In an organic solvent, a β-lactam compound represented by
By reacting acetic anhydride in the presence of a base, the desired 4
-acetoxy-3-hydroxyethylazetidin-2-one derivative (') (wherein R 1 and R are the same as above), and the base, solvent and reaction temperature are factors that affect the yield. As the reaction solvent, halogenated hydrocarbons and aromatic hydrocarbons can be used, preferably halogenated hydrocarbons such as methylene chloride. Dimethylaminopyridine is most suitable as the base, and dimethylaminopyridine and other bases can also be used in combination. Other bases that can be used are pyridine,
These include lutidine and picoline. 1 to 5 bases are added to the β-lactam compound represented by the general formula ().
The amount of acetic anhydride used as an acetoxylation reagent is 1 to 20 times the mole, preferably 3 to 15 times the mole. For the reaction operation, dimethylaminopyridine and acetic anhydride were added to a β-lactam compound having a silyl ether group at the 4-position represented by the general formula () in an organic solvent such as methylene chloride, and the mixture was heated at -50° C. with stirring.
The reaction is continued under a temperature condition of .degree. C. to room temperature, preferably -30.degree. C. to 5.degree. C. until the starting compound () disappears. When other bases such as pyridine, lutidine, and picoline are added in addition to dimethylaminopyridine, the yield is improved. After the reaction, methylene chloride or hexane, etc. is added as an extraction solvent, an aqueous sodium hydrogen carbonate solution is added, the layers are separated, the organic layer is washed with water, dehydrated, and the organic solvent is distilled off to obtain a compound represented by general formula (') 4 An N-protected β-lactam compound acetoxylated at the -position can be obtained. This compound (') can be directly subjected to the next N-protecting group elimination reaction, but if desired, it can be purified by silica gel column chromatography. When removing the N-protecting group, it is necessary to selectively remove only the N-protecting group without removing the 0-protecting group of the hydroxyethyl group substituted at the 3-position. Specifically, when the N-protecting group is an alkylsilyl group, such as a tert-butyldimethylsilyl group, it is preferable to use tetrabutylammonium fluoride. Similar effects can be obtained by using a combination reagent of tetrabutylammonium chloride and potassium fluoride instead of tetrabutylammonium fluoride. The solvent used in the N-protecting group elimination reaction is preferably tetrahydrofuran or acetonitrile, and the reaction proceeds smoothly by stirring at room temperature. The presence of acetic acid during the deprotection reaction contributes to improving the yield of the deprotection reaction. After the reaction, add an extraction solvent such as ethyl acetate, add dilute alkaline water such as aqueous sodium bicarbonate solution, extract the organic layer, wash with water,
After dehydrating and drying the organic layer, the desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can be obtained by distilling off the organic solvent. The 4-acetoxy-3-hydroxyethylazetidin-2-one derivative can be purified into a pure product by crystallization from n-hexane or petroleum ether, or by silica gel chromatography. (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. Example 1 (3R,4R)-4-acetoxy-3-[(R)-1
Synthesis of -tert-butyldimethylsilyloxyethyl]-azetidin-2-one. Dissolve 1.0 g of (3R,5R)-3-(1-tert-butyldimethylsilyloxyethyl)-4-trimethylsilyloxyazetidin-2-one in 10 ml of DMF, and add 0.89 g of triethylamine and tert-butyldimethylsilyl Add 0.61 g of chloride and stir at room temperature for 9 hours. After the reaction, DMF was distilled off under reduced pressure, and 80 ml of hexane was added. Add this solution to 2.5%
After washing with NaHCO 3 aqueous solution, then hydrochloric acid aqueous solution of PH 3, and saturated saline solution, drying with magnesium sulfate and distilling off the solvent, 1.24 g of crude product liquid was obtained.
get. Add 1.0 g of this liquid to 5 ml of methylene chloride, then add 0.85 g of dimethylaminopyridine and 1.1 ml of acetic anhydride, and react at room temperature for 6 hours. Next, the reaction solution was washed with 5% NaHCO 3 aqueous solution, hydrochloric acid solution of PH 3, and saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off.
Obtain 0.8g. When this liquid is purified with a silica gel column (benzene:hexane = 2:1) (3R,
4R,5R)-4-acetoxy-1-(tert-butyldimethylsilyl)-3-(1-tert-butyldimethylsiloxyethyl)-azetidin-2-one 0.5 g
was obtained as a liquid. In addition to 0.5 g of the above liquid and 2 ml of THF, 0.4 g of tetrabutylammonium fluoride and 0.17 g of acetic acid were dissolved in this solution.
ml and stir for 30 minutes at room temperature. Next, 20 ml of ethyl acetate was added to this reaction solution, and then 5%
After washing with NaHCO 3 aqueous solution and saturated saline solution,
Dry with magnesium sulfate. When the solvent was distilled off, 0.30 g of crystals of the target product were obtained. This was purified using a silica gel column (benzene: ethyl acetate = 6:1) to obtain 0.27 g of the target β-lactam as a solid. mp107℃～108℃ [α] 25 D = +50° (c=0.5 CHCl 3 ) 1HNMR (90MHz, CDCl 3 ) δ, (ppm) 0.88 (6H, s), 0.84 (9H, s), 1.20 (3H,
d), 2.01 (3H, s), 3.04 (1H, dd), 4.12 (1H,
m), 5.76 (1H, d), 6.73 (NH) Example 2 (3R, 4R)-4-acetoxy-3-[(R)-1
Synthesis of -tert-butyldimethylsilyloxyethyl]-azetidin-2-one. (3R,4R)-1-tert-butyldimethylsilyl-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one (1.0 g) in 10 ml of methylene chloride After dissolving, 0.85 g of dimethylaminopyridine and 0.71 g of acetic anhydride were added, and the mixture was reacted at 0° C. for 1 day. Next, the reaction solution was diluted with hexane, washed with 5% NaHCO 3 aqueous solution, PH4 hydrochloric acid water and saturated saline,
After drying with magnesium sulfate and distilling off the solvent, 0.85 g of a liquid crude product was obtained. When this liquid was purified using a silica gel column (hexane:ether = 30:1), (3R,4R)-4-acetoxy-1-
tert-butyldimethylsilyl-3-[(R)-1-
0.40 g of tert-butyldimethylsilyloxyethyl]-azetidin-2-one was obtained as a colorless liquid. Add 2ml of THF to this liquid, add 0.26g of tetrabutylammonium fluoride and acetic acid to this solution.
2 ml of THF solution containing 0.12 g was added and stirred at room temperature for 30 minutes. 20 ml of ethyl acetate was added to the reaction solution, followed by washing with a 5% aqueous NaHCO 3 solution and saturated brine, and drying over magnesium sulfate.
The solvent was distilled off to obtain 0.29 g of solid. Recrystallization from hexane gave the desired β-lactam as colorless needles of 0.20 g. The properties of each were the same as those shown in Example 1. Example 3 (3R,4R)-4-acetoxy-3-[(R)-1
Synthesis of -tert-butyldimethylsilyloxyethyl]-azetidin-2-one. (3R,4R)-1-tert-butyldimethylsilyl-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one (1.0 g) in 10 ml of methylene chloride Dissolve and add 0.85g of dimethylaminopyridine,
0.75 g of 2,6-lutidine and 1.42 g of acetic anhydride were added, and the mixture was reacted at -15°C for 44 hours. Next, the reaction solution was diluted with ether, washed with a 5% aqueous NaHCO 3 solution, aqueous hydrochloric acid at pH 4, and saturated brine, dried over magnesium sulfate, and the solvent was distilled off to obtain 0.88 g of a liquid crude product. When this liquid was purified using a silica gel column (hexane:ethyl acetate = 100:1), (3R,4R)-4-acetoxy-1-tert-butyldimethylsilyl-3-[(R)-1-tert-butyldimethyl silyloxyethyl]-azetidine-
0.58 g of 2-one was obtained as a liquid. this liquid
Dissolved in 2 ml of THF, and dissolved in it 0.38 g of tetrabutylammonium fluoride and 0.17 g of acetic acid.
2 ml of THF solution was added and stirred at room temperature for 30 minutes.
Add 20 ml of ethyl acetate to the reaction solution, then add 5%
After washing with NaHCO 3 aqueous solution and saturated brine, it was dried over magnesium sulfate. Distill the solvent to 0.42
g of solid was obtained. When this was purified using a silica gel column (hexane:ether=10:3), 0.39 g of the target β-lactam was obtained as colorless needle-like crystals.
The properties of each were the same as those shown in Example 1. Example 4 (3R,4R)-4-acetoxy-3-[(R)-1
Synthesis of -isopropyldimethylsilyloxyethyl]-azetidin-2-one. 3-[(R)-1-isopropyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one 1.2 g [(3R,4R,5R) form: (3S,
4S, 5R) body = 5:1] was dissolved in 12 ml of DMF, 0.52 g of triethylamine and 0.79 g of tert-butyldimethylsilyl chloride were added, and the solution was dissolved at room temperature.
Stir for hours. After the reaction, DMF was distilled off under reduced pressure, and 30 ml of hexane was added. Add this solution to 2.5% NaHCO3
After washing with an aqueous solution, then with an aqueous hydrochloric acid solution of pH 5 and a saturated saline solution, it is dried over magnesium sulfate, and the solvent is distilled off to obtain 1.13 g of a liquid crude product. next,
Add 0.90g of this liquid to 10ml of methylene chloride, then add 0.79g of dimethylaminopyridine and 0.61g of acetic anhydride.
ml was added and reacted at 4°C for 16 hours. Next, this reaction solution was washed with a 5% NaHCO 3 aqueous solution, a pH 5 hydrochloric acid solution, and a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off, yielding 0.70 g of crude product liquid.
get. This liquid was purified with a silica gel column (hexane:ether = 100:3) and 4-acetoxy-1-(tert-butyldimethylsilyl)-3-
(1-isopropyldimethylsilyloxyethyl)-
0.20 g of azetidin-2-one was obtained as a liquid.
Add 0.20g of this liquid to 2ml of THF, add 0.13g of tetrabutylammonium fluoride and acetic acid to this solution.
2 ml of THF solution containing 0.03 g was added and stirred at room temperature for 30 minutes. Next, add ethyl acetate to this reaction solution.
After washing with 5% NaHCO 3 aqueous solution and saturated saline, drying with magnesium sulfate and distilling off the solvent yielded the desired crude product (3R,
Obtain 0.14g of 4R, 5R, :3S, 4S, 5R=5:1).
By recrystallizing this with hexane, 0.58 g of the (3R, 4R, 5R) form was obtained as white crystals. 1HNMR (90MHz, CDCl 3 ) (3R, 4R, 5R)
Body δ, (ppm) 0.04 (6H, s), 0.90 (7H), 1.23
(3H, d), 2.06 (3H, s), 3.13 (1H, dd), 4.13
(1H, m), 5.76 (1H, d), 6.40 (NH) [α] 25 D = +54.2° (C = 0.5, CHCl 3 ) mp = 92°C to 94°C.
Claims (1)
C1〜C4の低級アルキル基、フエニル基またはア
ラルキル基、ＲはＮの保護基を示す。）で表わさ
れるβ−ラクタム化合物に、有機溶媒中、塩基の
存在下で無水酢酸を作用させ、ついでＮの保護基
を脱離させることを特徴とする一般式（） （式中、R1は水酸基の保護基を示す。）で表わ
される４−アセトキシ−３−ヒドロキシエチルア
ゼチジン−２−オン誘導体の製造法。 ２ R1が一般式（）【式】 （式中、R5，R6，R7はC1〜C4の低級アルキル
基を示す。）である特許請求の範囲第１項記載の
製造法。 ３ R1がｔ−ブチルジメチルシリル基である特
許請求の範囲第１項記載の製造法。 ４ R1がイソプロピルジメチルシリル基である
特許請求の範囲第１項記載の製造法。 ５ Ｒがｔ−ブチルジメチルシリル基である特許
請求の範囲第１項記載の製造法。 ６ R2，R3，R4がメチル基である特許請求の範
囲第１項記載の製造法。 ７ 塩基がジメチルアミノピリジンである特許請
求の範囲第１項記載の製造法。 ８ 塩基がジメチルアミノピリジンと他の塩基か
らなる特許請求の範囲第１項記載の製造法。 ９ 他の塩基がピリジン、ピコリンまたはルチジ
ンである特許請求の範囲第８項記載の製造法。 １０ 有機溶媒が、ハロゲン系炭化水素である特
許請求の範囲第１項記載の製造法。 １１ 一般式（′） （式中、R1は水酸基の保護基、R2，R3，R4は
C1〜C4の低級アルキル基、フエニル基、又はア
ラルキル基を示す） で示される化合物をＲ−Ｘ（ＲはＮの保護基、Ｘ
はハロゲンを示す）で示される試薬を反応させる
ことにより、一般式（） （式中、Ｒ，R1，R2，R3，R4はいずれも前記
に同じ）で表わされる化合物を生成せしめ、次い
で該化合物（）に、有機溶媒中、塩基の存在下
で無水酢酸を作用させ、ついでＮの保護基を脱離
せしめて、一般式（） （式中、R1は前記に同じ） で表わされる４−アセトキシ−３−ヒドロキシエ
チルアゼチジン−２−オン誘導体を製造する方
法。[Claims] 1 General formula () (In the formula, R 1 is a hydroxyl protecting group, R 2 , R 3 , R 4 are
C 1 -C 4 lower alkyl group, phenyl group or aralkyl group; R represents a protecting group for N; ) is treated with acetic anhydride in an organic solvent in the presence of a base, and then the N protecting group is removed. A method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by the formula (wherein R 1 represents a hydroxyl protecting group). 2. The manufacturing method according to claim 1, wherein R 1 is the general formula () [formula] (wherein R 5 , R 6 , and R 7 represent a C 1 to C 4 lower alkyl group) . 3. The manufacturing method according to claim 1, wherein R1 is a t-butyldimethylsilyl group. 4. The manufacturing method according to claim 1, wherein R 1 is an isopropyldimethylsilyl group. 5. The manufacturing method according to claim 1, wherein R is a t-butyldimethylsilyl group. 6. The manufacturing method according to claim 1, wherein R 2 , R 3 and R 4 are methyl groups. 7. The manufacturing method according to claim 1, wherein the base is dimethylaminopyridine. 8. The production method according to claim 1, wherein the base consists of dimethylaminopyridine and another base. 9. The production method according to claim 8, wherein the other base is pyridine, picoline or lutidine. 10. The production method according to claim 1, wherein the organic solvent is a halogenated hydrocarbon. 11 General formula (') (In the formula, R 1 is a hydroxyl protecting group, R 2 , R 3 , R 4 are
C 1 to C 4 lower alkyl group, phenyl group, or aralkyl group)
represents a halogen), the general formula () is obtained. (wherein R, R 1 , R 2 , R 3 , and R 4 are all the same as above), and then the compound () was added to acetic anhydride in an organic solvent in the presence of a base. and then remove the protecting group of N to form the general formula () (wherein R 1 is the same as above) A method for producing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative represented by the following.
Priority Applications (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60004724A JPS6118758A (en) | 1985-01-14 | 1985-01-14 | Preparation of 4-acetoxy-hydroxyethylacetidin-2-one derivative |
| CA000485100A CA1256443A (en) | 1984-07-05 | 1985-06-25 | Process for preparing 4-acetoxy-3- hydroxyethylazetidin-2-one derivatives |
| SU853923699A SU1442071A3 (en) | 1984-07-05 | 1985-07-03 | Versions of method of producing derivatives of 4-acetoxy-3-oxyethyl-azetidi-2-non |
| EP85108208A EP0167154B1 (en) | 1984-07-05 | 1985-07-03 | Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives |
| DE8585108208T DE3575128D1 (en) | 1984-07-05 | 1985-07-03 | METHOD FOR PRODUCING 4-ACETOXY-3-HYDROXYETHYLAZETIZIN-2-ON DERIVATIVES. |
| CN85105098.0A CN1003514B (en) | 1985-01-14 | 1985-07-04 | Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives |
| ES544864A ES8609238A1 (en) | 1984-07-05 | 1985-07-04 | Process for preparing 4-acetoxy-3-hydroxyethylazetizin-2-one derivatives. |
| KR1019850004830A KR900001170B1 (en) | 1984-07-05 | 1985-07-05 | A preparation process for 4-acetoxy-3-hydroxyl ethyl-azetizin-2-one derivatives |
| US07/000,809 US4861877A (en) | 1984-07-05 | 1987-01-06 | Process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60004724A JPS6118758A (en) | 1985-01-14 | 1985-01-14 | Preparation of 4-acetoxy-hydroxyethylacetidin-2-one derivative |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP59139797A Division JPS6118791A (en) | 1984-07-05 | 1984-07-05 | Novel beta-lactam compound and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6118758A JPS6118758A (en) | 1986-01-27 |
| JPH0479333B2 true JPH0479333B2 (en) | 1992-12-15 |
Family
ID=11591837
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60004724A Granted JPS6118758A (en) | 1984-07-05 | 1985-01-14 | Preparation of 4-acetoxy-hydroxyethylacetidin-2-one derivative |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS6118758A (en) |
| CN (1) | CN1003514B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0830057B2 (en) * | 1986-04-30 | 1996-03-27 | 鐘淵化学工業株式会社 | Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| JPH0655717B2 (en) * | 1986-11-13 | 1994-07-27 | 鐘淵化学工業株式会社 | Process for producing 4-acetoxy-3-hydroxyethylazetidin-2-one derivative |
| CN101029056B (en) * | 2006-02-28 | 2011-06-08 | 天津国韵生物材料有限公司 | Use of poly-3-ester oxybate in preparation of beta-lactam compound |
| CN102491912A (en) * | 2011-12-28 | 2012-06-13 | 上海新先锋药业有限公司 | Synthesizing method of N-methoxyphenyl-N-(acetyl)methylamine |
-
1985
- 1985-01-14 JP JP60004724A patent/JPS6118758A/en active Granted
- 1985-07-04 CN CN85105098.0A patent/CN1003514B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN85105098A (en) | 1986-07-09 |
| JPS6118758A (en) | 1986-01-27 |
| CN1003514B (en) | 1989-03-08 |
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