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Ep 0247378 A1 Europaisches Patentamt 0 247 378 J European Patent Office © Publication number: A1 Office europeen des brevets EUROPEAN PATENT APPLICATION © Application number: 87106234.5 © int. Ci.<: C07D 205/08 , C07F 7/18 , C07F7/10 © Date of filing: 29.04.87 © Priority: 30.04.86 JP 101856/86 © Applicant: KANEGAFUCM KAGAKU KOGYO 13.11.86 JP 270622/86 KABUSHIKI KAISHA 09.02.87 JP 28942/87 2-4 Nakanoshima 3-chome Kita-ku Osaka-shi Osaka-fu(JP) @ Date of publication of application: 02.12.87 Bulletin 87/49 © Inventor: Kan, Kazunori 9-30-616, Maikodai 2-chome Tarumi-ku © Designated Contracting States: Kobe-shi Hyogo-ken(JP) BE CH DE ES FR GB IT LI NL Inventor: Ueyama, Noboru 61-8, Mizonokuchi Kakogawa-cho Kakogawa-shi Hyogo-ken(JP) Inventor: Sada, Isao Mutsumi-so 1459-1, Fujie Akashi-shi Hyogo-ken(JP) Inventor: Ohashi, Takehisa ■ 9-14, Shinoharaobanoyama-cho 3-ch. Nada-ku Kobe-shi Hyogo-ken(JP) Inventor: Watanabe, Kiyoshi 15-41, Matsugaoka 5-chome Akashi-shi Hyogo-ken(JP) 0 Representative: Turk, Gille, Hrabal Bruckner Strasse 20 D-4000 Dusseldorf 13(DE) © Process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-qne derivatives. © A process for preparing a 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II): 00 o OCOCH3 CH.-C^ (II) 3 H -N CM J- O H a. wherein R1 is a protective group for the hydroxyl group, which comprises reacting a B-lactam compound LU having the formula (I): Xerox Copy Centre 0 247 378 H2 0 1 4 I ,OSi-E. GH-5 -*C ■ (I) 3 H -N V H wherein R1 is as defined above, and R2, R3 and R4 are a lower alkyl group having I to 6 carbon atoms, phenyl group or an aralkyl group, with acetic anhydride in an organic solvent in the presence of a low concentration of a substituted pyridine. According to the present invention, there can be obtained 4-acetoxy- 3-hydroxyethylazetidin-2-one derivatives, which are useful intermediates for preparing carbapenem B-lactam antibiotics. 0 247 378 PROCESS FOR PREPARING 4-ACETOXY-3-HYDROXYETHYLAZETIDIN-2-ONE DERIVATIVES The present invention relates to a process for preparing 4-acetoxy-3-hydroxyethylazetidin-2-one deriva- tives which have a hydroxyethyl group, wherein the hydroxyl group is protected, at the C3-position and has an acetoxy group at the exposition. It is known that 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives are useful intermediates for preparing carbapenem fi-lactam antibiotics such as thienamycin and penem B- 5 lactam antibiotics (cf., for example, Tetrahedron Letters by Reider et al., vol. 23, page 2293, 1982 and CheTn. Pharm. Bull, by Yoshida et al., vol. 29, page 2899, 1981). There hitherto have been known processes for synthesizing 4-acetoxy-3-hydroxyethylazetidin-2-one derivatives, for instance, synthesis from 6-amino-penicillanic acid (cf. Chem. Pharm. Bull, by Yoshida et al., vol. 29, page 2899, 1981), synthesis from threonine (cf. Tetrahedron by Shiozaki et al, vol. 39, page 2399, w I983) synthesis from aspartic acid (cf. Tetrahedron Letters by Reider et al., vol. 23, page 2293, I982) and synthesis from a metal enolate of !3-hydroxy butyric acid (cf. Chemistry Letters by Nakai et al., page I927, I984). However, these processes have a problem that industrially unfavourable reagents such as mercury compound, e.g., mercury acetate or mercury sulfate and lead tetraacetate are employed in order to introduce an acetoxy group at the C4-position of the flrlactam ring. 75 The inventors found a process for introducing an acetoxy group at the C4-position by using an N- protected B-lactam compound having an O-protected hydroxyethyl group at the C3-position and a silylether No. group at the C4-postion, and filed a patent application (cf. Japanese Unexamined Patent Publication I8758/I986). However, this process needs two steps, one is to introduce previously a protective group for N of the B- 20 lactam, and the other is to remove the protective group after acetoxy group is introduced at the C4-position. The inventors have found a process for introducing acetoxy group at the C4-position directly without protecting N of the /3-lactam, and thus the present invention has been accomplished. According to the present invention, there is provided a process for preparing a 4-acetoxy-3- hydroxyethylazetidin-2-one derivative having the formula (II): 25 R1 0 CH,-CN / 3 (ID 30 3 h^t r '/> N cr H 35 wherein R1 is a protective group for the hydroxy group, which comprises reacting a 0-lactam compound having the formula (I): 40 0 ' I A I OSi-R CH,-C\ / ' 3 CD l3 H R A N * 45 0^ H wherein R1 is as defined above, and R2, R3 and R" are a lower alkyl group having I to 6 carbon atoms, phenyl group or an aralkyl group, with acetic anhydride in an organic solvent in the presence of a low concentration of a substituted pyridine. 50 As shown in the application of the inventors (Japanese Unexamined Patent Publication No. I979I/I986), the fl-lactam compound (I) having a siiylether group at the C4-position can be easily obtained by the process of the following reaction scheme: 0 247 378 OR R CHo-C-CH=CH-OSi-R4 + C£SO2NCO H k3 R R R 70 0 1 . i reduction 0 OSi-R I ,OSi-R" ' 3 k3 3 H H I R ■N. 4? J 75 SO2C£ H . (I) 20 Examples of the O-protective group of R1 for the hydroxyethyl group at the C3-position of the B-lactam compound (I) are, for instance, trialkyisilyl group having the formula (III): R5 25 k-R6 (III) R7 30 wherein R5, R6 and R7 are a lower alkyl group having I to 6 carbon atoms such as tert-butyldimethylsilyl group, triisopropylsilyl group, isopropyldimethylsilyl group, isobutyldimethylsilyl group, 1,2-dimethyIpropyl- dimethylsilyi group, dimethyl-l,l,2-trimethyl-propytsilyl group, t-butyl group, benzyl group, trichloroethoxycar- bonyl group, tert-butoxycarbonyl group, p-nitrobenzyloxycarbonyi group or the like. Among them, tert- butyldimethylsilyl group, isopropyldimethylsilyl group and dimethyl-!,l,2-trimethylpropylsilyl group are most 35 preferable since they are stable during the reaction and can be selectively removed by acid treatment. Groups R2, R3 and R* of the B-iactam compound having the formula (I) may be the same or different with each other, and selected from a lower alkyl group having I to 6 carbon atoms such as methyl, ethyl, isopropyl, isobutyl, tert-butyl or 1,1,2-trimethyipropyl group, phenyl group, or an aralkyl group such as benzyl group, p-nitrobenzyl group. It is preferred all of R2, R3 and R4 are methyl group. 40 The B-lactam compound, prepared as mentioned above, having the formula (I): R R2 0 .OSi-R4 45 CH-.-O (I) 3 H r r3 S -N H 50 wherein R1, R2, R3 and R4 are as defined above, is reacted with acetic anhydride in an organic solvent in the presence of a low concentration of substituted pyridine to convert the B-lactam compound (I) into the desired 4-acetoxy-3-hydroxyethylazetidin-2-one derivative having the formula (II): 55 0 247 378 R1 0 I OCOCH, 3 HI 1 A N J & H 70 wherein R1 is as defined above. In the above reaction, the concentration of substituted pyridine in the reaction system is an important factor to be considered in order to obtain the desired compound in a sufficient yield, and the most suitable concentration can be decided. As the substituted pyridine used in the present invention, a dialkylaminopyridine such as 4- dimethyiaminopyridine or 4-diethylaminopyridine, and a substituted pyridine, which has a heterocyclic 75 group containing nitrogen atom as substituent, e.g. 4-pyrrolidinopyridine or 4-piperidinopyridine are prefer- able. The concentration of the substituted pyridine in the reaction system is preferably in a range of from 0.2 to 3 % by weight. When it is lower than 0.2 % by weight, the reaction velocity is lowered and the side reaction of substrate decomposition occurs largely. When the concentration is higher than 3 % by weight, the yield of by-product having the formula (IV): 20 R1 0 I .OCOCH. 25 CH,-C^. / 3 (IV) 3 H I I -N 0^ COCH- 30 wherein R1 is as defined above, becomes high, and the desired compound cannot be obtained in a sufficient yield. 35 In the present invention, acetic anhydride is used in a larger amount than that of substituted pyridine, since the reaction velocity is lowered when the amount of acetic anhydride is smaller than that of substituted pyridine. Preferably, acetic anhydride is used in an amount ranging from 10 to 50 % by weight in the reaction system. A haiogenated hydrocarbon such as methyiene chloride or carbon tetrachloride, a hydrocarbon such as n-hexane, an aromatic hydrocarbon such as toluene, ethyl acetate, tetrahydrofuran 40 and tetrahydropyran are preferably employed as a reaction solvent. Pyridine, picoline, lutidine, diethyl ether, diglyme, dimethylformamide, acetone and the like can be also employed as a reaction solvent. The reaction is carried out at a low temperature in the range from 0 to -70°C to obtain the desired compound (II) in a sufficient yield. Preferably, the reaction is carried out at a temperature in the range from -10 to -60 °C. C4- 45 The reaction is carried out by dissolving a (3-lactam compound (I) having a silyl ether group at the position in an organic solvent such as methyiene chloride or toluene, cooling the mixture and then adding acetic anhydride and a substituted pyridine such as 4-dimethylaminopyridine thereto at one time or at several times.
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