5-Benzothiazolecarbonitrile,2-chloro-(9CI)

To a solution of compound B-22 (1.0 g, 5.2 mmol) in dichloromethane (10 mL) at 0 °C was added sulfuryl dichloride (13.5 g, 100 mmol). The mixture was stirred at 25 °C for 3 hours, then poured into water (200 mL), partially concentrated in vacuo to remove dichloromethane and extracted with ethyl acetate (3 x 90 mL). The combined organic phase was washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether ethyl acetate = 15:1 to 10:11 to give compound B-23 (0.4 g, 40percent yield) as a yellow solid. ‘H-NMR (CDC13, 400 MHz): 8.26 (d, J0.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H).To a stirred solution of compound IN (800 mg, 0.52 rnmol) in SOTo a stirred solution of compound IN (800 mg, 0.52 rnmol) in SO2CI2 (3 mL) under argon atmosphere was stiired at RT for 1 li. Then the reaction mixture was heated to 60 'C for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice cold water (20 mL) to obtain the solid. The solid was filtered, washed with -hexane (2 x 20 mL) and dried under reduced pressm'e to obtain compound IO ( 800 mg, 4.12 rnmol, 79%) as a brown solid.To a stined solution of G (800 nig, 4.12 rnmol) in DMSO (20 mL) under argon aimospliere were added potassium carbonate (1.7 g, 12.37 rnmol) and compound IO (993 mg, 4.12 rnmol) at RT. The reaction mixture was stirred at 110 C for 12 b. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice cold water (20 mL) and extracted with CELCf' (2 x 20 mL). The combined organic layers were dried over anhydrous SQ4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: 2% eOH/CH^Cl?) to afford compound IP (450 rag, 1.13 mnioi 46%) as a brown solid. 1H NMR (400 MHz, DMSO-de): delta 8.02 (d, J = 8.2 Hz, 1H), 7.88 (s, Iff), 7.47 (dd5 J= 8.1, 1.6 Hz, IH), 739 (d, J= 9.03 Hz, 2H), 6.96 (d, J= 9.0 Hz, 2H), 3.78-3.71 (rn, 4H)5 3.33-3.31 (m, 4H).Step 1: 2-chloro-l, 3-benzothiazole-5-carbaldehyde (0550) To a solution of 2-chloro-l, 3-benzothiazole-5-carbonitrile {Ark Pharm, catAK-80680 48 mg, 0.25 mmol) in a mixture of toluene (1 mL) and methylene chloride (1 mL) was slowly added 1.0 M diisobutyl aluminum hydride in THF (100. L, 0.10 mmol) at -78 C. The reaction mixture was stirred at -78 C for 2 h then slowly warmed up to -10 C and quenched with Rochells' salt solution. The mixture was stirred vigorously for 1 h. The organic phase was separated, dried over MgS04 then concentrated. The residue was purified by column (0551) chromatography (gradient, 0-30% EtOAc in hexanes) to give the desired product. LC-MS calculated for CsHsClNOS (M+H)+: m/z = 198.0; found 198.0.j00318j To a solution of compound B-22 (1.0 g, 5.2 mmol) in dichloromethane (10 mL) at 0 C was added sulfuryl dichloride (13.5 g, 100 mmol). The mixture was stirred at 25 C for 3 hours, then poured into water (200 mL), partially concentrated in vacuo to remove dichloromethane and extracted with ethyl acetate (3 x 90 mL). The combined organic phase was washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography [petroleum ether ethyl acetate = 15:1 to 10:11 to give compound B-23 (0.4 g, 40% yield) as a yellow solid. 'H-NMR (CDC13, 400 MHz): 8.26 (d, J0.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.68 (dd, J=8.4, 1.6 Hz, 1H).j00616j A mixture of compound B-23 (0.15 g, 0.77 mmol), compound (R)-A-2 (0.12 g, 0.64mmol), dicyclohexyl-[2-(2, 4, 6-triisopropylphenyl)phenyljphosphane-[2-(2-aminoethyl)phenylj -chloro-palladium (0.02 g, 0.03 mmol) and sodium tert-butoxide (2 mol/L in tetrahydrofuran, 0.64 mL)in dioxane (10 mL) at 25 C was degassed and placed under nitrogen. The mixture was stirred at60 C for 2 hours, then filtered and concentrated in vacuo. The residue was purified by prep-HPLC [Jnstmment: GX-A; Column: Phenomenex Gemini C18 250x50 mm, particle size: 10 .im; Mobilephase: 23-24% acetonitrile in H20 (add 0.05% ammonia hydroxide, v/v)j. The resulting solids were dissolved in 0.2 M hydrochloric acid and again lyophilized to give:Compound (R)-29 (99 mg, 40% yield) as a white solid: cSFC analytical (I) tR=3.26 mm., purity: 100%; LCMS (H): tR2.130 mi, (ES) m/z (M+H) = 340.1; 'H-NMR(CD3OD, 400 MHz):8.00 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 7.52 (dd, J1= 8.0 Hz, J2 = 1.2 Hz, 1H), 3.68 (t, J = 16Hz, 2H), 3.58 (d, J = 16.8 Hz, 1H), 3.46-3.33 (m, 5H), 2.44-2.41 (m, 2H), 2.13-2.10 (m, 1H), 2.01-1.92 (m, 2H).

Molecular Weight:194.64
XLogP3:3.1
Hydrogen Bond Acceptor Count:3
Exact Mass:193.9705470
Monoisotopic Mass:193.9705470
Topological Polar Surface Area:64.9
Heavy Atom Count:12
Complexity:224
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes