N N N OMe O NPri OH N N HN S(O)Me OMe N N HN OMe OMe X N N HN OMe OMe O PriN 1 2 OH 9 H H 5 X = H 6 X = OCH2CH(OH)CH2OH 7 X = OCH2CH(OH)CH2N(H)Pri N NH2 NO2 Cl O NPri HO O N NH2 NO2 O O NPri O N NH2 HN O O NPri O O OMe OMe N NH2 NH2 O O NPri O N N HN OMe OMe O N O O N N N OMe OMe + i O PriN N N N OMe OMe 10 11 ii 14 12 PriN 13 iii RO Pri H H 3 5 O H RO– 5 N N HN OMe OMe 6 17 R = H 18 R = CH2CH2OH iv H O 19 PriN v,vi or vii 15 16 + 6¢ H + 7 N NH2 NO2 NMe2 N NH2 NO2 OR Cl HN O N HN OMe OMe – 20 21 22 196 J.CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 196–197 J. Chem. Research (M), 1997, 1359–1376 Synthesis of ‘A’ Ring Isomazole Oxypropanolamines via Hydrolysis of 1H-Imidazo[4,5-c]pyridine Oxazolidin-2-ones Paul Barraclough,*a Janet Gillam,b W. Richard King,a Malcolm S. Nobbs*a,† and Susan J. Vinea aDepartment of Medicinal Chemistry, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BR3 3BS, UK bDepartment of Physical Sciences, Wellcome Research Laboratories, Langley Court, Beckenham, Kent BE3 3BS, UK The base-catalysed hydrolysis of oxazolidin-2-one 15 gives an oxypropanolamine 7 and 4,5-dihydro-1H-imidazo[4,5-c]- pyridin-4-ones (17–19) and may occur by a BAL mechanism.BW567C, (�)-1,1 is a combined inotrope–b-adrenoceptor antagonist. In connection with our studies of the structure– activity relationships of 1, isomazole (2) and its analogue (5),2 we wished to synthesise and evaluate the pharmacological properties of the oxypropanolamines (�)-7 and (�)-9.Attempts to convert (�)-63 into (�)-7 via monomethanesulfonate or epoxide intermediates were unsuccessful. An alternative route (Scheme 1) utilising the racemic oxazolidinone precursor 15 was therefore employed. The first and last stages in this synthesis, however, proved problematical. Reaction of 104–6 and racemic 117–9 in N,N-dimethylformamide, containing an equivalent of NaOMe at 50 °C, gave the diamine 20 (55%) and 12 (5%).The poor conversion into 12, and the distinctive deep-red colour of the reaction mixture, was attributed to the formation of either the sodium salt of 10 or a Meisenheimer complex 21. To suppress these side reactions we reacted 10 and 11 in ButOH at 80 °C in the presence of ButOK and obtained a 60% yield of 12. Attempted deprotection10 of the oxazolidinone 15 by reaction with 10 M NaOH in ethane-1,2-diol (1:10) at 120 °C gave the 4,5-dihydro-1H-imidazo[4,5-c]pyridin-4-ones 17 and 18 as the major products.When the above reaction was carried out using Ba(OH)2 as the base, 17 and 18 were again formed along with a third product, assigned structure 19. *To receive any correspondence. †Current address: Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Scheme 1 Reagents and conditions: i, KOBut, ButOH, 80 °C (64%); ii, H2, 10% Pd–C, MeOH (84%); iii, 2,4-dimethoxybenzoyl chloride, pyridine (58%); iv, POCl3, pyridine (63%); v, 10 M NaOH–ethane-1,2-diol (1:10), 120 °C, 15h17 (20%), 18 (26%); vi, Ba(OH)2, ethane- 1,2-diol, 120 °C, 15h17 (26%), 18 (24%), 19 (16%); vii, 10 M NaOH–ethane-1,2-diol (1:1), 120 °C, 15h7 (24%), 17 (14%), 22 (5%)N O N N OMe NPri OMe HN O N N OMe NPri OMe H 15 OR H 23 24 R = H 25 R = CH2CH2OH N O2N NH2 Cl N O2N NH2 O O NPri O N N HN OMe OMe O PriN O O N N HN OMe OMe + 11 i PriN O OH ii,iii iv 26 27 H v 31 O 32 +9 N N NH OMe OMe O NPri O O N N N OMe OMe O NPri 33 34 H i J.CHEM. RESEARCH (S), 1997 197 The formation of 17–19 may be explained by deprotonation of 15 to give the anion which reacts at the pyridyl rather than the imidazo nitrogen. Intramolecular nucleophilic attack at C-5 of the oxazolidinone with concomitant oxygen– alkyl ring cleavage would give a carbamate anion which would readily lose carbon dioxide to produce 16. Reaction of 16 with µOH or HO[CH2]2Oµ may then proceed by a similar, although intermolecular, mechanism (BAL2, Ingold notation15) but with two possible regiochemical outcomes.Intermolecular nucleophilic attack at C-5 and oxygen–alkyl ring cleavage would give 17 and 18, while 7 would be the product arising from C-6 attack. The azetidine 19 would result from 16 by intramolecular attack at C-5 by the side-chain amine. Products such as 23–25 (Scheme 2), arising from intramolecular nucleophilic attack by imidazo nitrogen on the oxazolidinone group of 15, were not detected.We also postulated that increasing the [µOH]: [HOCH2CH2Oµ] ratio would favour attack at C-6 of the 5,6-dihydroimidazo[4,5-c]oxazolo[3,2-a]pyridine intermediate 16 by µOH since this pathway should be the least susceptible to steric hindrance. When we carried out the deprotection of 15 using 10 M NaOH–ethane-1,2-diol (1:1, i.e. just enough solvent to solubilise the mixture) the products were 7 (25%), 17 (14%) and 22 (5%). While a pathway via 16 explains this product distribution, 7 may also be derived, at least in part, from 15 by the ‘normal’ hydrolysis mechanism BAC2,15,16 i.e., nucleophilic attack at the carbonyl carbon and oxygen–acyl ring cleavage. With the knowledge gained from this reaction sequence the preparation of the isomeric BW567C analogue, 9, proved straightforward.Thus, hydrolysis of oxazolidinone 31 gave 9 along with the rearrangement product 32 (Scheme 5). Interestingly, however, base-catalysed hydrolysis of oxazolidin- 2-one 3324 gave a tricycle 34 as the sole product (Scheme 6).This reaction probably occurs by a similar BAL mechanism and will be described in detail elsewhere. Oxypropanolamines 7 and 9 were found to be inactive as inotropic agents (cf. diol 6 and oxazolidinone 15, which are moderately potent inotropes). 7 was also devoid of b-blocking properties but 9 was found to be a b-adrenoceptor antagonist (pKB 5.9). We are indebted to J. W. Black, R. A. Hull and P. Randall (James Black Foundation, London) for provision of pharmacological data, to the staff in the Department of Physical Sciences, Wellcome Research Laboratories, for spectroscopic data, and to Jenny Lane for preparation of this manuscript.Techniques used: IR, mass spectrometry, 1H NMR, NOE, spin decoupling References: 25 Schemes: 6 Received, 16th December 1996; Accepted, 5th March 1997 Paper E/6/08407I References and notes cited in this synopsis 1 P. Barraclough, W. R. King, M. S. Nobbs and S.Smith, J. Chem. Res., 1996, (S) 408; (M) 2336. 2 P. Barraclough, J. W. Black, D. Cambridge, D. Collard, D. Firmin, V. P. Gerskowitch, R. C. Glen, H. Giles, A. P. Hill, R. A. D. Hull, R. Iyer, W. R. King, C. O. Kneen, J. C. Lindon, M. S. Nobbs, P. Randall, G. P. Shah, S. Smith, S. J. Vine, M. V. Whiting and J. M. Williams, J. Med. Chem., 1990, 33, 2231. 3 Prepared by a similar route to that shown in Scheme 1 involving reaction of 10 with solketal. 4 T. Talik and E. Plazek, Roczn.Chem., 1955, 29, 1019. 5 Z. Talik and E. Plazek, Roczn. Chem., 1956, 30, 1139. 6 R. J. Rousseau and R. K. Robins, J. Heterocycl. Chem., 1965, 2, 196. 7 Fujimoto Pharm. Co., Jap. Pat., 81 40,674 (Chem. Abstr., 1981, 85, 115521z). 8 S. Hamaguchi, M. Asada, J. Hasegawa and K. Watanabe, Eur. Pat. Appl., 123,719 (Chem. Abstr., 1985, 102, 132025w). 9 G. Cardillo, M. Orena and S. Sandri, J. Org. Chem., 1986, 51, 713. 10 M. E. Dyen and D. Swern, Chem. Rev., 1967, 67, 197 and references cited therein. 15 Physical and Mechanistic Organic Chemistry, ed. R. A. Y. Jones, Cambridge University Press, Cambridge, 1979, pp. 227–233. 16 J. O. Branstad, Acta Pharm. Suecica, 1969, 6, 49 (Chem. Abstr., 1969, 70, 114325k). 24 Prepared via reaction of 11 with 4-chloro-3-nitropyridin- 2-amine. Scheme 2 Scheme 5 Reagents and conditions: i, KOBut, ButOH, 80 °C (36%); ii, H2 10% Pd–C, MeOH (60%); iii, 2,4-dimethoxybenzoyl chloride, pyridine (73%); iv, POCl3, pyridine (74%); v, 10 M NaOH–ethane-1,2-diol (1:1), 120 °C, 31h9 (36%), 32 (12%) Scheme 6 Reagent: i, 10 M NaOH–ethane-1,2-diol (1:10), 120 &d