2,5-Dibromo-4-methylimidazole

To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99percent). +E SI-MS: m/z 239.0 [M+H]+[0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99percent). +E SI-MS: m/z 239.0 [M+H]+[Comparative Example 1]; While a solution of 24.0 g (100.0 mmol) of [Comparative Example 2]; While a mixture of 24.0 g (100.0 mmol) of Step A : (5-Bromo-6-methyl-3 H- 1 ' -azaspiro [imidazo [2, 1 -b] oxazole-2, 3 ' - bicyclo[2.2.2]octan]-l '-yl-8-ium)trihydroborate and (6-bromo-5-methyl-3H-l '- azaspiro[imidazo[2, l-b]oxazole-2, 3 '-bicyclo[2.2.2]octan]- -yl-8-ium)trihydroborate To 2, 4-dibromo-5-methyl-lH-imidazole (0.8 g, 3.3 mmol) in THF (25 niL) was added N-butyllithium (1.3 niL, 3.3 mmol) dropwise at -78C. After 45 minutes, a solution of racemic r-azaspiro[oxirane-2, 3'-bicyclo[2.2.2]octan]-l'-yl-4- ium)trihydroborate (0.56 g, 3.7 mmol) from the reference example, in THF (20 mL) was added dropwise at -78C. The cooling bath was removed and the reaction mixture warmed to room temperature. After 15 minutes, the mixture was heated to 75C for 2 hours and then cooled to room temperature. The reaction was quenched with water and the product was extracted with ethyl acetate (100 mL). The organics were dried with MgS04, filtered and the solvent was removed to yield the crude product. The crude material was purified by chromatography (Biotage) to yield the regioisomeric products. These regioisomers were separated by reverse phase chromatography using a Sunfire column with gradients of acetonitrile-water containing 0.1% of trifluoroacetic acid (TFA), and at 40 mL/min flow rate. The pure fractions for peak 1 and peak 2 were then neutralized with 1 N NaOH (pH ~8-9) and the products were extracted with ethyl acetate. The organic layers were dried with MgS04, filtered and the solvent was removed to yield racemic (5-bromo-6-methyl-3H-l'-azaspiro[imidazo[2, l-b]oxazole-2, 3'- bicyclo[2.2.2]octan]-l'-yl-8-ium)trihydroborate (0.32 g, 1.0 mmol, 30.8 % yield) XH NMR (500MHz, DMSO-d6) delta 4.23 (d, J=9.8 Hz, IH), 4.12 (d, J=9.9 Hz, IH), 3.36 (dd, J=15.2, 2.5 Hz, IH), 3.19 (dd, J=15.3, 2.1 Hz, IH), 3.04 - 2.95 (m, IH), 2.91 - 2.73 (m, 3H), 2.35 (br. s., IH), 2.03 - 1.88 (m, 4H), 1.84 - 1.67 (m, 3H), 1.64 - 1.11 (m, 3H). MS (LC/MS) R.T. = 2.09; [M+2]+ = 300.04 and racemic (6-bromo-5-methyl-3H-l'- azaspiro[imidazo[2, l-b]oxazole-2, 3'-bicyclo[2.2.2]octan]-r-yl-8-ium)trihydroborate (0.33 g, 1.1 mmol, 31.7 % yield) as powders. NMR (500MHz, DMSO-de) delta 4.32 (d, J=10.1 Hz, IH), 4.12 (d, J=10.2 Hz, IH), 3.36 (d, J=2.4 Hz, IH), 3.18 (dd, J=15.2, 2.2 Hz, IH), 2.99 (d, J=2.9 Hz, IH), 2.93 - 2.78 (m, 3H), 2.31 (d, J=2.0 Hz, IH), 2.06 - 1.94 (m, 4H), 1.84 - 1.69 (m, 3H), 1.62 - 1.22 (m, 3H). MS (LC/MS) R.T. = 2.64; [M+2]+ = 300.04.[0304] To a solution of 18-1 (3.6 g, 15 mmol) and K2C03 (4.1 g, 30 mmol) in DMF ( 18 mL) was added iodomethane ( 1 .4 mL, 23 mmol) at 25C. The solution was stirred for 1 5 h. The mixture was poured into water and extracted with EA The combined organic phase was dried over anhydrous Na'S04, and the residue was purified by chromatography on silica gel (EA/hexane) to giv e 18-2 (1 .6 g, 41 %). NMR (400 MHz, CDC13): delta 3.52 (s. 3H). 2.21 (s, 3H).[0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS ( 14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2: 1 ) provided 3-2 as white solid (9.6 g, 99%). +E SI-MS: m/z 239.0 [M+H]+[Example 6];

Molecular Weight:239.90
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:239.87207
Monoisotopic Mass:237.87412
Topological Polar Surface Area:28.7
Heavy Atom Count:8
Complexity:88.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes