4,5-Dichloro-2-(methylsul...

A suspension of 5-chloro-2-(methylthio)pyrimidin-4(3H)-one (24 g, 0.136 mol) in POCI3 (200 mL) was heated at reflux for 2 hrs. The reaction mixture was then cooled to room temperature and was concentrated to remove excessive of POCI3. The residue was then treated with HCompound 51. To a mixture of compound 49 (976 mg, 5.13 mmol, 2 eq.), compound 50 (0.5 g, 2.56 mmol, 1 eq.) , Pd(PPh3)2Cl2 (360 mg, 512 mumol, 0.2 eq.), and CuI (244 mg, 1.28 mmol, 0.5 eq.) in THF (10 mL) was added TBAF (1 M, 2.56 mL, 1 eq.) in one portion at 0 C under N2. The reaction mixture was stirred at 60 C under N2 for 10 h. The mixture was partitioned between H2O(100 mL) and EtOAc(200 mL). The combined organic phase were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EtOAc: 1/0 to 50 /1) and prep- TLC (PE/EtOAc: 20:1) to afford compound 51 (0.3 g, 1.26 mmol, 49% yield) as a brown oil. 1H NMR (CDCl3, 400 MHz) delta 8.47 (s, 1H), 2.61 (d, J = 5.9 Hz, 2H), 2.56 (s, 3H), 1.13-1.03 (m, 1H), 0.61-0.52 (m, 2H), 0.36 (q, J = 4.9 Hz, 2H).A mixture of 4, 5-dichloro-2-methylsulfanyl-pyrimidine (18 mg, 0.09 mmol), 5-amino- 3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (intermediate A1 , 20 mg, 0.08 mmol) and N-ethyl-N-isopropyl-propan-2-amine (20.5 D l_, 0.12 mmol) in DMF (0.50 ml_, 0.16 M) was heated in the microwave to 120 °C for 30 minutes. The mixture was diluted with water, acidified to pH 5 by addition of 10percent citric acid and extracted with DCM (5ml_ x 3). The combined organics were evaporated under reduced pressure. The product was purified by prep HPLC (ACE 5 C18-PFP column (5mu, 250x21.2mm), 15 minute gradient elution from 40:60 to 25:75 water: methanol (both modified with 0.1 percent formic acid) at a flow rate of 20mL/min) to give 5-[(5-chloro-2-methylsulfanyl-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1- methyl-benzimidazol-2-one (27 mg) as a white solid. 1 H NMR (DMSO-d6, 500 MHz): delta 8.43 (1 H, br s), 8.24 (1 H, s), 7.41 (1 H, d, J 1.6 Hz), 7.27 (1 H, dd, J 8.4, 1.6 Hz), 7.13 (1 H, d, J 8.4 Hz), 3.87 (2H, m), 3.32 (3H, s), 2.38 (3H, s), 1.72 (2H, m), 1.17 (6H, s). OH not observed. LCMS (Method T4) Rt 2.80 min, m/z 408.1208, expected 408.1255 for C18H23CIN5O2S [M+H]+./V, A/-Diisopropylethylamine (0.89 ml_, 5.13 mmol) was added to 4, 5-dichloro-2- (methylsulfanyl)pyrimidine (0.50 g, 2.56 mmol) and benzene-1 , 2-diamine (0.28 g, 2.56 mmol) in n-butanol (12 ml_). The resulting solution was stirred at 110 °C for 3 hours. The reaction mixture was evaporated and the residue was stirred with aqueous HCI (0.1 M, 10 ml.) for 30 minutes. The solid was collected by filtration and dried under vacuum. The crude solid was triturated with DCM and filtrated. The filtrate was evaporated to give Lambda/1-[5- chloro-2-(methylsulfanyl)pyrimidin-4-yl]benzene-1 , 2-diamine (0.46 g, 1.73 mmol, 67percent) as a pale orange solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 8.58 (br s, 1 H), 8.18 (s, 1 H), 7.08 (dd, J = 8.0, 1.5 Hz, 1 H), 7.03-6.95 (m, 1 H), 6.78 (dd, J = 8.0, 1.5 Hz, 1 H), 6.62-6.55 (m, 1 H), 4.84 (br s, 2H), 2.27 (s, 3H). LC-MS: [M+H]+ = 267. (23 g, 0.1 18mol) was added to aq. HI (250 mL). The resulting mixture was stirred at room temperature for 24 h. TLC (Petroleum ether: EtOAc=4:1 ) indicated that the reaction was complete. The solid formed was collected and was treated with H2O (250 mL). The mixture was then adjusted to pH= 7-8 with solid K2CO3 and was extracted with CH2CI2 (100 mL chi 4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and dried on vacuum to give title compound (29 g, 86percent) as a light yellow solid.

Molecular Weight:195.07
XLogP3:2.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:193.9472247
Monoisotopic Mass:193.9472247
Topological Polar Surface Area:51.1
Heavy Atom Count:10
Complexity:114
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes