5-bromo-2-methylisoindolin-1-one

Intermediate 51 b: 5-bromo-2-methyl-isoindolin-1 -one[00531] To a reaction tube containing methyl 4-bromo-2-(bromomethyl)benzoate (1 .2g, 3.gmmol) was added methylamine (2.OM in THF, lOmL, 2Ommol). The tube was sealed and the mixture was stirred and heated at 50 °C overnight. The mixture was then cooled to room temperature, filtered and the precipitate washed with THF. The filtrate was concentrated in vacuo and the residue waspurified by column chromatography using an eluent of 0-100percent EtOAc in heptane to give 5-bromo-2- methyl-isoindolin-1-one (623mg, 2.7Smmol, 71percent yield) as a white solid.1H NMR (CDCI3, 400MHz) O/ppm: 7.73-7.68 (1H, m), 7.64-7.56 (2H, m), 4.36 (2H, 5), 3.19 (3H, 5). MS Method 3: RT: 3.18 mi m/z226.0/228.0 [M+H]Synthesis of 5-bromo-2-methylisoindolin-1-one (2) Step A: 5-bromo-2-methylisoindolin-l-one [0234] Methyl 4-bromo-2-(bromomethyl)benzoate (0.153 g, 0.497 mmol) was suspended in methanamine (2M solution in MeOH, 2.484 mL, 4.97 mmol) and the mixture was heated to reflux (90°C) for 24 hours. The reaction mixture was cooled, concentrated in vacuo, and dried under high vacuum to give the title compound (0.112 g). General procedure: Bromoisoindolin-1-one (2.0 g, 9.43 mmol) was dissolved with warming in DMF (150 mL), then cooled to 0°C. NaH (415 mg, 10.4 mmol) was added and the mixture stirred under N2 at 0°C for 0.5 h. Methyl iodide (0.65 mL, 10.4 mmol) was added dropwise and the reaction allowed to warm to room temperature and stir for another I h. A small quantity of water was added to quench the reaction then the DMF removed under reduced pressure to give an oily yellow residue which was dissolved in EtOAc (150 mL). This solution waswashed with water (3x100 mL), brine (100 mL) and dried (Na2SO4)., Removal of the solvent under reduced pressure gave a solid which was purified by filtration through a plug of silica gel (10percent acetone/CH2C12 as eluant). The title compound was isolated as a very pale yellow crystalline solid (1.64 g, 80percent). ‘ H NMR [400 MHz, (CD3)2S0] ö 7.85 (dd, J= 1.5, 0.6 Hz, 1 H), 7.66 (dd, J= 8.0, 1.7 Hz, 1 H), 7.59 (d, J— 8.0 Hz, I H), 4.46 (s, 2 H), 3.05 (s, 3 H). LRMS (APCI) calcd for C9H8BrNO 226, 228 (MH), found 226, 228.5-Bromo-2-methylisoindolin-1-oneA 150 mL sealed tube was charged with 4-bromo-2- (hydroxymethyl) -N-tnethylbenzamide (3.34 g, 13.7 mmol) and 1, 3- dimethylimidazolidin-2-one (40.4 ml, 369 mmol). The solution was cooled to 0To a mixed solution of compound 1b (5 g, 22 mmol), bisboronic acid pinacol (8.5 g, 33 mmol) and KOAc (3.2g, 33 mmol) in 1, 4 dioxane (50 ml) was added Pd(dppf)2Cl2 (1g), and flushed with nitrogen. The reaction flask wassealed and the reaction was stirred overnight at 85°C. After cooling to room temperature, an aqueous Na2CO3 solution(2.5M, 10ml), Pd(dppf)2Cl2 (1g) and 2, 5-dibromo-3-nitropyridine (9 g, 33 mmol) were added. After flushed with nitrogenfor 10 minutes, the reaction flask was sealed and the mixture was stirred overnight at 85°C. The reaction was pouredinto water and extracted with ethyl acetate. The organic phase mixture was dried over Na2SO4, dried by suction andpurified by silica gel column chromatography (PE:EA=10:1 to 1:1) to provide compound 1c as a yellow solid.HNMR(CDCl3), 9.0(s, 1H), 8.4(s, 1H), 8.0(d, 1H), 7.6-7.7(m, 2H), 4.5(s, 2H), 3.3(s, 3H).MS(ESI)m/z :347.9(M+H)+.Synthesis of 5-bromo-2, 3-dimethylisoindolin-1-one (2) To a solution of Synthesis of 2-methyl-5-((9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)amino)isoindolin-1-one (4) Procedure A: A mixture of 9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-amine (3, 0.10 g, 0.37 mmol),

Molecular Weight:226.07
XLogP3:1.6
Hydrogen Bond Acceptor Count:1
Exact Mass:224.97893
Monoisotopic Mass:224.97893
Topological Polar Surface Area:20.3
Heavy Atom Count:12
Complexity:207
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes