1-CHLORO-4-METHOXYISOQUINOLINE

Step 1: Preparation of 1-chloro-4-methoxyisoquinoline (0151) To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4percent) as off-white solid. To a solution of 1-chloroisoquinolin-4-ol (5.0 g, 27.8 mmol) in acetonitrile (50 mL) was added TMS-diazomethane (12.73 g, 111.2 mmol) at 0° C. The reaction mixture was allowed to come to room temperature and stirred for 2 h. Solvent was evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-methoxyisoquinoline (2.5 g, 46.4percent) as off-white solid.Step 1: 6-Chloro-1, 3-Oxazino [5, 6-c] isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1percent of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCI3 to give the chloride (Example 226b) in essentially quantitative yield. The crudel-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266mg of 6-chloro-1, 3- oxazino [5, 6-c] isoquinoline (Example 226d, 62.3percent) overall yield from 300mg of 4- methoxy isoquinoline in 4 steps. LC/MS Rt-min([M-HCHO] H+) [method D]: 2.45(192).'H NMR (400 MHz, CHLOROFORM-D)8 ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8. 25, 6. 91, 1. 22 Hz, 1 H) 8.10 (d, J=8. 31 Hz, 1 H) 8.26 (d, J=8. 56 Hz, 1 H). The chloride was found to be unreactive under the alkylation protocol of Example 184. The corresponding 6-fluoro-1, 3-oxazino [5, 6-c] isoquinoline (Example 226) was prepared by the method of [Uchibori, Y.; Umeno, M.; Yoshiokai, H.; Heterocycles, 1992, 34 (8), 1507-1510] cited earlier. The reaction was not allowed to go to completion, and the crude reaction mixture was recovered as a mixture of ratio of 1: 2.4 (Cl : F). Without further purification, the chloride/fluoride mixture was alkylated with the tripeptide using the procedure of Example 184 to give 66mg (50.0percent) of BOCNH-P3(L-t-BuGly)-P2 [ (4R)- ( 1, 3-oxazino [5, 6-c] isoquinoline-6-oxo)-S-proline]-P1 (lR, 2S VinylAcca)-CONHSO2Cyclopropane after preparative HPLC purification. LC/MS Rt-min(MNa+) [method D]: 3.03(764).'H NMR (400 MHz, CD30D)8 ppm 1.01 (s, 9 H) 1.06 (dd, J=8. 07, 1. 96 Hz, 2 H) 1.22 (s, 10 H) 1.34 (d, J=6. 11 Hz, 1 H) 1.42 (m, 1 H) 1.86 (dd, J=8. 07, 5. 38 Hz, 1 H) 2.23 (m, 2 H) 2.59 (dd, J=13. 82, 6. 97 Hz, 1 H) 2.93 (m, 1 H) 4.03 (dd, J=11. 86, 3. 06 Hz, 1 H) 4.23 (s, 1 H) 4.41 (d, J=11. 98 Hz, 1 H) 4.50 (dd, J=9. 66, 6. 97 Hz, 1 H) 4.87 (m, 2 H) 5.11 (d, J=10. 52 Hz, 1 H) 5.28 (d, J=17. 12 Hz, 1 H) 5.34 (s, 2 H) 5.74 (m, 2 H) 7.51 (t, J=7. 46 Hz, 1 H) 7.70 (t, J=7. 58 Hz, 1 H) 7.95 (d, J=8. 31 Hz, 1 H) 8.12 (d, J=8. 31 Hz, 1 H).

Molecular Weight:193.63
XLogP3:3
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:193.0294416
Monoisotopic Mass:193.0294416
Topological Polar Surface Area:22.1
Heavy Atom Count:13
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes