2-(4-bromo-2-methoxyphenyl)acetic acid

Preparation 6(S)-3-(4-Bromo-2-hydroxy-phenyl)-pyrrolidine-l-carboxylic acid tert-bntyl ester The synthetic procedure described in this Preparation was carried out according to the process shown in Scheme G. EPO Step 2: Preparation of 2-(4-bromo-2-methoxypheηyl)acetic acid; A mixture of 2-(4-bromo-2-methoxyphenyl)acetonitrile (873 mg, 3.86 mmol), water (5 ml_), sodium hydroxide (463 mg, 11.6 mmol), and methanol (20 ml_) was heated at 8OA drop of DMF was added to a solution of oxalyl chloride (0.02 mL, 0.25 mmol) and 2-(4-bromo-2-methoxy-phenyl)acetic acid (200.0 mg; 0.78 mmol; 1.0 eq.) was dissolved in NMP (3.00 ml) then MeNH2 solution (2M solution in MeOH, 3.88 ml; 7.75 mmol; 9.93 eq.) and DIPEA (276 pL; 1.55 mmol; 2.00 eq.) were added followed by the addition of propylphosphonic anhydride (50% solution in THF, 1.19 ml; 1.94 mmol; 2.49 eq.) by portion. The mixture was stirred 5h at rt, then poured into water and extracted with EtOAc (3x). Combined organic layers were washed with brine, dried over MgS04 and concentrated. The residue was triturated in water and filtered to give 2-(4-bromo-2-methoxy-phenyl)-N-methyl-acetamide (99.0 mg; 50 %) as a white solid, used directly in the next step without purification.Sodium nitrite (90 mg, 1.27 mmol) was added to a solution of 4-bromo-2-methoxy-1-(2-nitroethyl)benzene (132 mg, 0.51 mmol) in DMSO (1.27 mL) and glacial acetic acid (0.29 mL, 5.07 mmol) and the reaction stirred at 60 C overnight. Then the reaction mixture was allowed to cool to r.t. and acidified to pH 1 with a 2M aqueous solution of HCl. This mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water, a saturated solution of brine, dried over sodium sulfate, filtered and solvent removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in Pet. Ether afforded 2-(4-Bromo-2-methoxy-phenyl)acetic acid (2 g, 8.16 mmol) and NCS (1.14 g, 8.57 mmol) were dissolved in MeCN (40.8 mL) and stirred at 50 C for 22 hours. The resulting mixture was concentrated in vacuo and the residue purified by chromatography on silica eluting with 20-100% EtOAc in heptane. The product was further purified by dissolving in EtOAc (100 mL) and extracting into saturated aqueous NaHCO3 (3 x 100 mL). The combined aqueous extracts were acidified with 1M HCl and extracted with EtOAc (3 x 150 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the titled compound as a colourless solid.1H NMR (250 MHz, DMSO-d6) delta 11.97 (s, 1H), 7.46 (s, 1H), 7.34 (s, 1H), 3.79 (s, 3H), 3.50 (s, 2H).LC-MS (Method E): Rt 1.07 mins; MS m/z not observed = [M+H]+2-(4-Bromo2methoxyphenyl)acetic acid (500 mg, 2 049 mmol) was dssoNed in 5 m of diy toluene Thionyi rhlonde (1 2 eq , 246 mmol 292 7 mg, 178 3 ul) was addedfollowed by a drop of DMF and the reaction heated to reflux (1 20C) for 3 hours The reaction was cooled to r t then piopargylamine (2 5 eq 5 12 mrnol, 282 2 rug 0 328 ml) and triethylamine (2.5 eq., 512 mmcl, 0714 nil) added and the raction left to stir for 20 hours DCM and water were added to the mixture and the orgarvr layer sepai atcd drieo otor MgSO and concentrated n varuo The pi oduct wa punfied bycolumn chromatography, MeOH/DCM (03 %) to give a cream coloured solid t458 2 mg, 1 631 mmcl 79 6 %) 1H NMR (500 MHz CDCl3, 3 7 13 7 07 (m 2H) 7 04 (s IH) 578(s, 1ll)399(ddJ52 26, 2H)386s, 3H), 351 (6, 2H)221-2 16(m 1H); nC NMR (126 MHz, CDl3 S i701 1 (C), 15779 (C), 132.32 (CH), 124, 16 (CH), 12235(C) 12207(C) l1450(CH) 7953(C) 7145CH) 5585(CH3) 3802(CH, 29.23 (CH2); MS (ES +ve) (M+H::281.6/283.6, 303.8/306.0 (+Na)

Molecular Weight:245.07
XLogP3:2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:243.97351
Monoisotopic Mass:243.97351
Topological Polar Surface Area:46.5
Heavy Atom Count:13
Complexity:184
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes