The current interest in new azetidinone antibiotics and their preparation has stimulated an intensive search for the synthesis of appropriately substituted monocyclic azetidinones.2- 5 Our initial efforts in this field resulted in the chlorinolysis of the carbon-sulfur bond in penicillin

S. Kukolja

S. R. Lammert

English

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CROATICA CHEMICA ACTA CCACAA 45 (4) 581-583 (1973) YU ISSN 0011-1643 CCA-804 547.718 P rel.iminary Communica ti.on Synthesis of 2-Chloro-3-phthalimido-4-azetidinone and Related Derivatives from Penicillins1 S. R. Lammert and S. Kukolja The LiHy Research L aboratori es, Eli L illy and Company I ndianapolis, I ndiana 43296, USA Received June 18, 1973 The current interest in new azetidinone antibiotics and their preparation has stimulated an intensive search for the synthesis of appropriately substituted monocyclic azetidinones.2- 5 Our initial efforts in this field resulted in the chlorinolysis of the carbon-sulfur bond in penicillins.7 A parallel reaction with anhydropenicillin has been described by Wolfe and coworkers.8 Consequently, compounds ·Of type 1 can be prepared by a simple synthetic route with high yields. As an extension of our work the removal of the five-carbon olefinic mo.iety from the azetidinone nitrogen in 1 was undertaken. This effort resulted in the synthesis of azetidinones 3 which are ver.satile intermediates for the preparation of new azetidinone antibi•otics. Closely related removals of the five-carbon unit by a pyrazoline route6d a:o.d by an oxidative method3•9 have been recently published. We have developed two methods for the synthesis of 3a which are, together with related chemistry, described in this com-munication. a : Ri = Cl, R2 = H b: R i = H, R2 =Cl 3 c: Ri = OMe, R2 = H 1 COOMe O""" N~ T-r o 2,4-0NP H~R1 Ft R2 2 4 Ft = phthalimido 5: Rs= CHPh2 6: R3 = H 582 S. R. LAMMERT AND S. KUKOLJA Ozonoly;sis of 2-chloro-3-ph thalimido-1-(1 '-methyloxycarbony1-2' -methyl--prop-1 '-enyl)-4-azetidinone (1) with ozone in methylene chlor.ide at - 20 °C' gives 2-chloro-1-methoxyoxalyl-3-phthalimido-4-azetidinone (2) in 970/o yield* The glyoxalate 2 is isolated as a colorless foam : IR (CHC13) 1850 (oxalyl C = O), 1799 'and 1743 (phthalimido C = O) and 1778 cm-1 (azetidinone C = O) ; NMR** 240 (s, 3, OMe), 341 (d, 1, J = 2.5 Hz), 374.5 (d, 1, J = 2.5 Hz) , and 474 (m, 4, Ar H) . An attempt to remove the glyoxalate subst~tuent in 2 by methanolysis according to the method of Cooper and .Jose9 resulted in isolation of 3c: m . p. 188-190 °c, IR (KBr) 1800 cm-1 (azetidinone C = O), NMR (DMSO-d6) 200 (s, 3, OMe), 295 (d, 1, J = 1.5 Hz) , 315.5 (d, 1, J = 1.5 Hz), 476 (m, 4, Ar H) and 560 (s, NH, exchangeable/D 20) ; mass spectrum m /e 246, M+. Apparently 3c is formed from 2 by methanolysis of the oxamide group and concomitant solvo-lytic displacement of chloride by methoxy group. Since we were interested in synthesizing 3a and 3b from 2, other possibi-lities for the removal of the glyoxalate functionality from the azetidinone nitro-gen were investigated. Thus, when 2 is relfuxed with an equivalent amount of 2,4-dinitrophenylhydrazine in tetrahy drofuran for 35 min, a mixture of cis- and trans-isomers 3a and 3b · is obtained. This mixture · is separated by chromatoqraphy over silica gel yielding 38'0/o of 2S-ch1oro-3R-phthalimido-4--azetidinone (3a) as prisms, mp 154-155 °C; IR (CHC13) 1810 cm-1 (azetidinone C- 0); NMR (acetm:ie (d6) 326 (d, 1, J = 1.8 Hz), 368 (d, 1, J = 1.8 Hz), and 473 (m, 4, Ar H); mass spectrum m /e 214 (M+, HCl) . The cis-is omer (3b) is obtained in 40/o yield. The cis arrangement of the hydrogens on the four membered ring is .established on the ba2is of the coupling constant (J = 4.5 Hz).10 An alternate method for the preparation of 3a and 3b starting from 4 has also been found. When a methylene chloride solution of 411 is treated w ith 2 equiv. of chlorine for 30 min, a mixture of 3a and 3b is obtained in the ratio of ca. 9 : 1. The major component 3a is easily separated in a crystalline form b y fractional crystallization from methylene chloride and petroleum ether.12 Methanolysi1s of 3a gives 3c in 730/o yield. In order to explore the feasibility of the chloride displacement in com-pounds 3 the reaction of 3a w iith sulfur containing nucleophiles was also investi-gated. When 3a is reacted with diphenylmethyl 2-mercaptoisobutyrate in tetra-hydrofuran in the presence of triethylamine at room temperature for 45 min, the compound 5 is obtained: NMR 96 (s, 6) , 301 (d, 1, J = 2.5 Hz), 368 (s, 1, NH) , 403 (s, 1, CH), 436 (s, 10), and 461 Hz (m, 4) . Cleavage of ester 5 with a mixturE of anisole, trifluoroacetic and formic acid at -5 °c for 15 min y•ields a viscous oil. After a work-up procedure and crystallizat ion from ethyl acetate, colorless crystals of 6, mp 219-222 °c are obtained: NMR (D20) 90 (s, 6) 311 (d, 1, J = 2 Hz), 317 (d, 1, J = 2 Hz) ,- and 468 (4, m) ; IR (KBr) 1765 (azetidinone CO), 1741 and 1775 (phthalimido CO), and 1720 cm-1 (carboxy CO) ; mass .spectrum m/e 334, M+. The coupling constant (J = 2.5 Hz) for the azetidinone doublets indicates the trans stereochemistry of the corresponding •protons in 6. A closely related compound having the cis stereochemistry has been described by * The reaction was discontinued when a TLC plate showed none of the olefinic starting material (ca. 2 h). ** The NMR spectra (60 MHz, TMS internal standard, CDC13) are recorded in hertz. 2-CHLOR0-3-PHTHALIMID0-4-AZETIDINONE 583 Sheehan and Brandt.11 Evidently the chloride in compound 3a can be easily displaced by thio substituent. Further examples of a similar displacement will be described in a full paper. Acknowledgements. The authors wish to thank J. L. Occolowitz for mass spectral analyses and to A. I. Ellis for technical assistance. We also wish to acknow-ledge many helpful discussions with M. Gorman and R .D. G. Cooper . REFERENCES 1. Azetidinone antibiotics IX. Part VIII : S. Kuk o 1 j a, P. V. Demarco, N. D. Jones, M. 0. Ch an e y, and J . W. Pasch a 1, J. Amer. Chem. Soc. 94 (1972) 7592. 2. (a) K. Heu s 1 er, Helv. Chim. Acta 55 (1972) 388; (b) R. Scar ta z z in i, H . Peter, H. Bick e 1, K. Heu s 1 er, and R. B. W o o d w a rd, ibid. 55 (1972) 408; (c) R. Scartazzini and H . Bickel, ibid. 55 (1972) 423. 3. E. G. Brain, A. J. Eglington, J . H. C. Nayler, M. J. Pearson, and R. S out h gate, Chem. Commun. (1972) 229. 4. J. H . Nay 1 er, M. J. Pe arson, and R. Southgate, ibid. (1973) 58. 5. M. D. B a chi and 0 . Go 1 db erg, ibid. (1972) 319. 6. (a) I. Ager, D. H . R. B art on, G. Lu cent e, and P . G. S a mm es, ibid. (1972) 601; (b) D. H. R. Barton, D. G. T. Greig, G. Luce .nte, P. G. Sam mes, and M. V. Tay 1 or, ibid. (1970) 1683; (c) D. H. R. Barton, P. G. Sammes, and M. V. Taylor, ibid. (1971) 1137; (d) D. H. R. Barton, D. G. T. Greig, P . G. S am me s, and M. V. T a y 1 or, ibid. (1971) 845. 7. S. Kuk o 1 j a, J. Amer. Chem. Soc. 94 (1972) 7590; see ref. 2. 8. S. W o 1 f e, W. S. Lee, G. Kanne n g i es s er, and J. Duce p, Can. J. Chem. 50 (1972) 2894. 9. R. D. G. Cooper and F. L. Jose, J . Amer. Chem. Soc. 94 (1972) 1021. 10. G. V. Kais er and S. Ku k o 1 j a, in CCphalosporins and Penicillins - Che-mistry and Biology, E. H . F 1 y n n, ed., Academic Press, New York 1972, p . 97. 11. J . C. Sheehan and K . G. Br and t, J. Amer. Chem. Soc. 87 (1965) 5468. 12. J . C. Sheehan, D. Ben - Is ha i, and J. U. Piper, ibid. 95 (1973i 3064. IZVOD Sinteza 2-kloro-3-ftalimido-4-azetidinona i srodnih derivata penicilina S. R. Lammert i S. Kukolja Ozonoliza 2-kloro-3-ftalimido-1-(1' -metiloksikarbonil-2' -metil-prop-1' -enil)-4-aze-tidinona ozonom u CH2Ch kod - 20 °c daje 2-klor-1-metiloksioksalil-3-ftalimido-4--azetidinon (2) u 970/o-tnom iskoriStenju. Taj glioksalat metanolizom daje 2-metoksi--3-ftalimido-4-azetidinon, t. t . 188-190 °c. Kada se gHoksalat (2) refluksira s ekvi-valentnom kolicinom 2,4-dinitrofenilhidrazina u THF tijekom 30 min, dobiva se smjesa cis- i trans-izomera 2-kloro-3-ftalimido-4-azetidinona koja kromatografskom separacijom daje 38% trans-izomera 3a, t . t. 154-155 °c, i 40/o cis-izomera (3b). Kloro-izomeri 3a i 3b takoder su pripravljeni klorolizom 2-(l'-formil-l ' -metiletiltio)--3-ftalimido-4-azetidinona. Djelovanjem difenil 2-merkaptoizobutirata na 3a u THF uz prisustvo Et3N tijekom 45 minuta, dobiva se odgovarajuci ester 5. Odstranjenje esterske grupe u 5 pomocu smjese anisola, trifluoroctene i mravlje kiseline kod - 5 °c tijekom 15 min daje slobodnu kiselinu 6, t. t. 219-222 °c. '!'HE LILLY RESEARCH LABORATORIES, ELI LILLY AND COMPANY, INDIANAPOLIS, INDIANA 46206 U . S . A. Primljeno 18. lipnja 1973 

Synthesis of 2-Chloro-3-phthalimido-4-azetidinone and Related Derivatives from Penicillins

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