2-BROMO-5-BROMOMETHYL-THIAZOLE

Step 1: Synthesis of 2-bromo-5-(bromomethyl)thiazole. A solution of 2- bromo-5-methylthiazole (1 g, 5.6 mmol) and N-bromosuccinimide (1.1 g, 6.18mmol, 1.1 eq) in 40 mL of DCM and 40 mL of H20 was stirred under UVirradiation at 90°C in a round bottom flask outfitted with a reflux condenser for 3 hours. The reaction was then cooled to room temperature, poured into aseparatory funnel, and extracted. The aqueous layer was extracted twice more with DCM, the organic layers combined, dried with MgSO4, filtered through cotton, concentrated and purified by automated chromatography with a 0percent to 3percent gradient of EtOAc in hexanes to yield 1.24 g (78percent). ‘H NMR (400 MHz, CDC13) d 7.46 (d, J 0.9 Hz, 1H), 4.57 (d, J 0.9 Hz, 3H). ‘C NMR (101 MHz, CDC13) d 141.92, 139.80, 137.39, 22.37. MS (ESI): m/z: 255.8 [M+H].Example 3A (1.90 g, 9.79 mmol), carbon tetrabromide (3.57 g, 10.77 mmol), and triphenylphosphine (2.82 g, 10.77 mmol) were combined in tetrahydrofuran (30 mL). The mixture was stirred at room temperature for 2 hours. The solvent was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The residue was purified with silica gel eluting with ethyl acetate/hexane (0percent to 5percent) to give the title compound as a solid (0.70g, 28percent). MS (DCI+) m/z 256, 258, 260, (M+H)(0446) A mixture of A mixture of A mixture of Add acetonitrile (100mL) to the 250mL three-flask.2-bromo-5-bromomethyl-thiazole (10.28g, 40mmol, 1.0eq), Potassium carbonate (11.04g, 80mmol, 2.0eq), Tetrabutylammonium fluoride (12.53g, 48mmol, 1.2eq), TMSCN (4.75g, 48mmol, 1.2eq), after the system is mixed well, react at 40 C for 3h, The reaction solution was cooled to room temperature, filtered, and the organic phase was spin-dried.Add 150 mL of water and extract twice with ethyl acetate (75 mL X 2). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product.Recrystallization using ethyl acetate: petroleum ether = 1/1 to obtain the target product 6.6 g of 2- (2-bromo-1, 3-thiazol-5-yl) acetonitrileThe yield was 82%.To a dry round bottom flask under N2 atmosphere was added Intermediate C (2.00 g, 6.07 mmol) and anhydrous DMF (30 mL). Lithium bromide (2.63 g, 30.3 mmol) was added followed by addition of cesium carbonate (4.94 g, 15.1 mmol), and 2-bromo-5-(bromomethyl)- 1 , 3-thiazole (1.56 g, 6.07 mmol). The mixture was heated to 50 C for 18 h. The reaction was cooled to room temperature and quenched with sat. aq. ammonium chloride (25 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with a 10% by weight aq. lithium chloride solution (30 mL) and dried over sodium sulfate. The organic extract was then concentrated under vacuum. The residue was purified by column chromatography [hexanes/EtOAc = 9: 1-1 : 1] to give ethyl 6-(benzyloxy)-4-[(2- bromothiazol-5-yl)methyl]-5-oxo-4, 5-dihydrothieno[3, 2-]pyridine-7-carboxylate (1.5 g, 48% yield) as a yellow oil. NMR (400 MHz, CDCh) delta 7.63 (s, 1H), 7.62 (d, J = 5.6 Hz, 1H), 7.57- 7.49 (m, 2H), 7.43-7.30 (m, 3H), 7.13 (d, J = 5.6 Hz, 1H), 5.51 (s, 2H), 5.35 (s, 3H), 4.39 (q, J = 7.1Hz, 2H), 1.33 (t, J = 7.1Hz, 3H); LCMS (ES+) m /z (M + H)+ = 506.REFERENCE To a mixture of 1.85g of potassium phthalimide and 20ml of dry DMF were added 2.57g of Step 2: Synthesis of 5-((1H-imidazol-1-yl)methyl)-2-bromothiazole. To a stirring solution of the product of Step 1 (765 mg, 2.98 mmol) in 20 mL of DMSO was added imidazole (202 mg, 2.98 mmol, 1 eq) and K2C03 (1.23 g, 8.94 mmol, 3 eq) and stirred overnight. The reaction was extracted with brine andEtOAc and concentrated in vacuo, and purified by automated chromatography to yield 306.6 mg (42%) of the desired product. MS (ESI): m/z: 243.9 [M+H].

Molecular Weight:256.95
XLogP3:2.6
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:256.83325
Monoisotopic Mass:254.83530
Topological Polar Surface Area:41.1
Heavy Atom Count:8
Complexity:80.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes