2-Bromo-6-methoxybenzothiazole

Dry copper (II) bromide (2.70 g, 11.6 mmol), isobutyl nitrite (2 mL, 15.0 mmol) andWas added to acetonitrile (150 mL) at room temperature under an argon atmosphere, and then a solution of 6-methoxybenzo [d] thiazol-2-amine (1.80 g, 9.99 mmol) in acetonitrile (50 mL) . The resulting mixture was heated to 65 ° C. and stirred for 4 hours under an argon atmosphere while maintaining this temperature.The reaction mixture was allowed to cool to room temperature, 2 M hydrochloric acid (30 mL) was added, and the mixture was extracted with chloroform (3 × 150 mL). The combined organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (silica gel 200 g; hexane: ethyl acetate (2: 1)) to give 2-bromo-6-methoxybenzo [d] thiazole (2.32 g, yield 95percent) as a red-brown solid. The measured physical properties of the product are as follows39.1.1) Compound 4 (500 mg, 2.77 mmol) in acetonitrile (15 mL) to dissolve was then, t-butylnitrite (286 mg, 2.77 mmol) and CuBr2 (744 mg, 3.33 It was added mmol) and stirred for 2 hours at 80 ° C. After checking thecompletion of the reaction, then cooled at room temperature, then evaporated under reduced pressure to remove the solvent. Theconcentrated residue was extracted with ethyl acetate (10 ml) and water (8 ml). After the extracted organic layer was filtered anddried over anhydrous magnesium sulfate, and distilled under reduced pressure of the filtrate. As a result, the 5 compound (574 mg, yield: 85percent) was obtained.To a solution of copper (II) bromide (0.74 g, 3.33 mmol) in acetonitrile (12.5 mL) at 0 To a solution of copper bromide (7.4 g, 0.0336 mol) and polyethylene glycol (14 g) in acetonitrile (150 mL) was added isoamyl nitrite (4.9 g, 0.042 mol) portionwise at room temperature. A solution of 6-methoxybenzo[b]thiazol-2-amine (5 g, 0.028 mol) in acetonitrile (100 mL) was then added dropwise to the mixture under nitrogen over a period of 10 minutes. The mixture was then stirred at 65 °C for 3 hours. After being cooled to room temperature, the mixture was poured into a 20percent aq. hydrochloric acid solution (200 mL) and organics were extracted with dichloromethane (3 x 50 mL). The organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography [petroleum ether/ethyl acetate=15: l] to give compound B-120 (5.3 g, 78percent yield) as a white solid. LCMS: (ES+) m/z (M+H)To a black solution of Copper (II) bromide (149 mg, 0.666 mmol) in Acetonitrile(1 mL) was added t-Butyl nitrite (0.095 mL, 0.72 1 mmol) at room temperature followedby 6-methoxybenzo[d]thiazol-2-amine (100mg, 0.555 mmol). Immediate bubbling and amild exotherm was observed upon benzothiazole addition. After 3 hours, the reactionmixture was diluted with EtOAc and washed with 1.0 M HC1, saturated NaHCO3, andthen Brine. The organic phase was dried over Mg504, filtered and concentrated to areddish-brown solid. The crude material was purified by ISCO flash chromatography (0-15percent EtOAc/Hex over 20 mm, 12 g silica gel cartridge, Product at 5percent). The desiredfractions were combined and concentrated to yield Intermediate 253A (84 mg, 0.344mmol, 62.0 percent yield) as an off-white solid. LC-MS. Method H, RT = 1.12 mm, MS (ESI)m/z: 244.0, 246.0 (M+H). ‘H NMR (400MHz, CHLOROFORM-d) 7.89 (d, J9.0 Hz, 1H), 7.28 (1H under CDC13), 7.09 (dd, J9.0, 2.6 Hz, 1H), 3.90 (s, 3H)6- Methoxybenzo[d]thiazol-2-amine (5.0 g; 27.7 mmol) was dissolved in 125 mL CHa. A cooled solution of crude {2-[4-(2-hydroxyethyl)piperidin-l-yl]pyrimidin-5-yl}boronic acid (Intermediate 5, 370 pmol), formed as described above, was diluted with dioxane (1.5 ml), and 6-methoxy-2-bromobenzothiazole (91 mg, 1 eq) was added followed by bubbling of N2 for 2 min. Then 2 M K2CO3 (561 pi, 3 eq) was added, followed by Pd(dppf)CI2 DCM complex 1:1 (16 mg, 5 mol%). The solution was again bubbled with N2 for 3 min then the vial was capped. The reaction was run in a preheated oil bath at 90 C overnight. The reaction mixture was cooled, diluted with ethyl acetate/water, and filtered through celite. The organic portion was separated, washed with water, treated with brine, dried with MgS04, filtered, and the solvent was removed in vacuo to give the crude product. (0503) The crude product was purified on the ISCO (12 g column, applied with hot DCM, eluted with 50-60% over 5 min) to give a solid, which was then refluxed with ether, cooled, filtered, and washed with ether to give 2-{l-[5-(6-methoxy-l, 3-benzothiazol-2-yl)pyrimidin-2- yl]piperidin-4-yl}ethan-l-ol (65 mg solid, 47% yield, HPLC Rf 3.25 min, MS m/z (M+l) 371.1). TLC: 75% ethyl acetate/ hexane Rf 0.33.-Bromo-6-methoxy-l, 3-benzothiazole (0.73 g, 3.0 mmol) and (6-chloro-3-pyridyl)boronic acid (0.61 g, 1.3 eq) were weighed into a 20 ml microwave vial and dissolved in DMF (8 ml). N2 was bubbled through the mixture. Tetrakis (0.21 g, 6 mol %) was then added followed by 2 M potassium carbonate (3 ml, 2 eq). N2 was again bubbled through the mixture for 1 min and the vial was capped. The reaction mixture was subjected to the microwave at 75 C for 4 h. The reaction mixture was diluted with ethyl acetate, treated with brine, dried over anhydrous MgS04 and the solvent was removed in vacuo. The crude product was purified on the ISCO (40 g silica column, applied with DCM, eluted with 10- 40% ethyl acetate / hexane over 14 min) to give 2-(6-chloropyridin-3-yl)-6- methoxy-l, 3-benzothiazole (240 mg solid, 37% yield). 1H-NMR (DMSO-d6) d 9.04 (dd, 1 H), 8.43 (dd, 1 H), 7.99 (d, 1 H), 7.77 (d, 1 H), 7.70 (dd, 1 H), 7.17 (dd, 1 H), 3.86 (s, 3 H).

Molecular Weight:244.11
XLogP3:3.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:242.93535
Monoisotopic Mass:242.93535
Topological Polar Surface Area:50.4
Heavy Atom Count:12
Complexity:169
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes