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Thienamycin (Imipenem) 1520 THE JOURNAL OF ANTIBIOTICS OCT. 1989 CONVERSION OF OA-6129 B2 INTO OA-6129 B2, a fermentation carbapenem product, (5i?,6^)-6-[(i?)- l -FLUOROETHYL]-7- into optically active 88617, an 8-fluorinated OXO- 3 -[(7V,Ar,Ar-TRIM ETHYL- carbapenem derivative which improved antimicro- CARBAMIMIDOYL)METHYL]THIO- bial activity and dehydropeptidase-I stability. l -AZABICYCLO[3.2.0]HEPT-2-ENE- Treatment of OA-6129B2 sodium salt 1 with 2-CARBOXYLIC ACID (88617)t /7-nitrobenzyl (PNB) bromide or pivaloyloxymethyl chloride in DMFgave /?NB ester 2 or pivaloyl- Takeo Yoshioka, AzumaWatanabe, oxymethyl (POM) ester 3 of OA-6129 B2 (Fig. 1). Noritaka Chida and Yasuo Fukagawa The two hydroxyl groups in the pantoyl moiety of OA-6129B2 were protected by isopropylidena- Central Research Laboratories, tion for differentiation from the C-8 hydroxyl Sanraku Incorporated, 4-9-1 Johnan, Fujisawa 251, Japan group. The protected compound4 or 5 was allowed to (Received for publication May 25, 1989) react with 1.2 equiv of diethylaminosulfur trifluoride (DAST)11} at -68°C in methylene chloride for 10 minutes. After the reaction mixture was diluted with Since the epoch-making discovery of thienamy- methylene chloride and washed with a saturated cin2), a numberof extensive studies have been carried aqueous sodium bicarbonate solution, silica gel out on the development of clinically useful car- column chromatography of the organic layer pro- bapenem compounds. As a result, formimidoyl- vided the desired fluorinated compound 6 or 7 thienamycin (imipenem) has recently been put on having a fluorine atom in the R configuration at C-8 the market as a combination drug (Primaxin)3) in 43 or 49% yield, respectively. No epimer at C-8 with cilastatin, a renal dehydropeptidase-I inhib- was observed at all in these reaction conditions. itor40. It has, however, a shortcoming in that On the other hand, Ishikawa reagent (a mixture its poor solubility in water5), limits its clinical use of diethylaminohexafluoropropane and diethylami- to infusion. nopentafluoropropene)1^ with which it has been Mak and Fliri have succeeded in the total confirmed that fluorination proceeds by perfect synthesis of novel 8-fluorinated carbapenem deriva- inversion in the case of non-fused azetidinones tives as racemates1) via the Melillo lactone6). Among (Watanabe, A. et al.\ unpublished results), was also them, 88617 is most promising by virtue of excellent tested for stereospecific fluorination. However, antimicrobial activity, improved resistance to treatment of 4 with 1.0mol equiv of Ishikawa dehydropeptidase-I and high physico-chemical reagent afforded fluorinated compounds in 30% stability. Subsequent biological evaluation studies, yield as a 1:1 mixture of the %R and SS however, indicated that the optical activity of 48.5Hz,epimers; 78>9=6.4Hz(coupling constantsfor SR, /6>8=6.5Hz,/6 8=7.3 Hz, 78'F=/8>F= 8-fluoro carbapenem derivatives was critically important for expression of the desirable anti- 46.2Hz, /89=6.5Hz, for 8S); the ethylidene microbial and enzymological profiles7). compound at C-6 was also produced in 10% yield. In the meanwhile, a series of OA-6129 car- From these findings, it is concluded that DASTis bapenems which are characterized by the C-3 better than Ishikawa reagent for the stereospecific pantetheinyl side chain are produced by a strep- fluorination of 8-hydroxycarbapenem compounds. tomycete8); and a selective fermentation method The fluorinated derivative 6 or 7 was oxidized of OA-6129 B2 which has a 1-hydroxyethyl side with ra-chloroperbenzoic acid in methylene chloride chain at C-6 became available by mutagenesis of at -20~0°C to give the corresponding S-oxide 8 specifically-blocked strains9). As the absolute con- or 9 in 76 or 73% yield. 8 or 9 was treated with figuration of the hydroxyl group is S in the C-6 a-mercapto-iV,A^,7V'-trimethylacetoamidine nonaflu- side chain of OA-6129 B2, it was thought that orobutanesulfonate or its hydrochloride, providing optically active 88617 could be prepared efficiently the /?NB ester nonafluorobutanesulfonate 10 in 40% from OA-6129 B2 by an S-oxide replacement yield or the POMester hydrochloride ll in 56% reaction10), if fluorination at C-8 proceeded under yield after CM-Sephadex C-25 column chroma- perfect inversion. tography. The physico-chemical properties of the This paper describes the efficient conversion of t1" Ishikawa reagent was purchased from Tokyo Kasei t Seeref1. Kogyo Co., Ltd. I Fig. 1. Conversion ofOA-6129 B2 into 88617. o o f o 1 1522 THE JOURNAL OF ANTIBIOTICS OCT. 1989 sulfonate 10: MP 140~142.5°C; [a]£3 +25.3° (c Thienamycin, a new /Mactam antibiotic. I. Discovery, 0.975, CH2C12); UV Xá"fl2nm (e) 269.5 (14,000), taxonomy, isolation and physical properties. J. 312.5 (14,600); IR vSl cm"1 1775 (j&-lactam); *H Antibiotics 32: 1 - 12, 1979 NMR(CDCl3+a few drops of DMSO-J6) 6 1.43 Imipenem-Sodium Cilastatin (Primaxin). Medical (3H, dd, /=6.3 and 24.0Hz, 9-H), 3.19 (3H, s, Lett. (Japanese) 2: 29-31, 1986 NCH3 or =NCH3), 3.30 (6H, s, =NCH3 and NCH3 Graham, D. W.; W. T. Ashton, L. Brash, J. E. or N(CH3)2), 3.3-3.8 (3H, m, 4-H and 6-H), 4.18 Brown, R. D. Brown, L. F. Canning, A. Chen, J. P. Springer & E. F. Rogers: Inhibition of the (2H, s, SCH2), 4.33 (1H, m, 5-H), 4.6-5.4 (1H, m, mammalian/Mactamase renal dipeptidase (dehydro- 8-H), 5.20 (1H, d, /=14.1 Hz, C//H-Ar), 5.47 (1H, peptidase-I) by (Z)-2-(acylamino)-3-substituted-pro- d, /=14.1Hz, CHi/-Ar), 7.62 (2H, d, J=9.0Hz, penoic acids. J. Med. Chem. 30: 1074- 1090, 1987 Ar), 8.17 (2H, d, /=9.0Hz, Ar), 8.3-8.9 (1H, br, Shih, D. H.; F. Baker, L. Cama & B. G. Christensen: SO3H)were in good accordance with those of the Synthetic carbapenem antibiotics I. 1-jS-Methylcar- authentic sample1" synthesized by resolution of the bapenem. Heterocycles 21: 29-40, 1984 Melillo lactone. Compound10 was hydrogenated Melillo, D. G.; I. Shinkai, T. Liu, K. Ryan & M. over 10%Pd-C in a mixture of ethyl acetate and Sletzinger: A practical synthesis of ( + )-thienamy- 0.15 m MOPSbuffer, pH 7.5, and purified by column cin. Tetrahedron Lett. 21: 2783-2786, 1980 chromatography on QAE-Sephadex A-25 and Watanabe, A.; M. Sakamoto, Y. Fukagawa & T. Yoshioka: Syntheses and biological activities of new Diaion CHP-20 P to give 88617 in 43% yield as 8-fluorocarbapenem derivatives. Chem. Pharm. Bull., colorless crystals from ethan'ol. in preparation Using a similar procedure, 8-fluorinated car- Yoshioka, T.; I. Kojima, K. Isshiki, A. Watanabe, bapenem derivatives having a variety of C-3 side Y. Shimauchi, M. Okabe, Y. Fukagawa & T. chains were prepared. Their structure-activity rela- Ishikura: Structures of OA-6129A, Bl5 B2 and C, new carbapenem antibiotics produced by Streptmyces tionships will be discussed in a separate paper. sp. OA-6129. J. Antibiotics 36: 1473- 1482, 1983 Acknowledgment Kojima, I.; Y. Fukagawa, M. Okabe, T. Ishikura & N. Shibamoto: Mutagenesis of OA-6129 carbape- Weare indebted to Prof. Y. Yamada, Tokyo College nem-producing blocked mutants and the biosynthesis of Pharmacy, for his helpful advice and discussions on this work. of carbapenems. J. Antibiotics 41: 899-907, 1988 Yamamoto, K.; T. Yoshioka, Y. Kato, K. Isshiki, M. Nishino, F. Nakamura, Y. Shimauchi & T. Re ferences Ishikura: Chemical modification of carbapenem 1) Mak, C. P. & H. Fliri (Sandoz): Fluoralkyl- antibiotics. Versatile methods for displacement of the atedcarbapenem Derivatives. U.S. 4,720,490, Jan. C-3 sulfur side chain of carbapenems with other thiol 19, 1988 groups. J. Antibiotics 36: 407-415, 1983 2) Kahan, J.S.; F. M. Kahan, R. Goegelman, S. A. Mak, C. P. & K. Wagner: Synthesis of fluorinated Currie, M. Jackson, E. O. Stapley, T. W. Miller, carbapenems. Reaction of monocyclic and bicyclic A. K. Miller, D. Hendlin, S. Mochales, S. /Mactams with diethylaminosulfur trifluoride. In Hernandez, H. B. Woodruff & J. Birnbaum: Recent Advances in the Chemistry of /?-Lactam Antibiotics. Third International Symposium 1984. * The authentic sample of 10 was kindly supplied by Eds., A. G. Brown & S. M. Roberts, pp. 366-370, Sandoz Company. The Royal Society of Chemistry, 1984.
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