Benzoic acid, 4-amino-3-hydroxy-, methyl ester

4-amino-3-hydroxybenzoic acid ( 5.0 g, 32.6 mmol) was added dropwise to a 0 °C solution of an HCI 1 .25 M solution in MeOH(100 mL) and MeOH (100 ml_). After 5 min of final addition the mixture was allowed to warm up to room temperature and stirred overnight. HPLC monitoring of the reaction showed remaining starting material and the mixture was stirred at ambient temperature for 48 hours. The solvent was then removed under reduced pressure and the residue was treated with saturated aqueous bicarbonate solution and the aqueous phase was extracted with AcOEt (2 x ). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to dryness obtaining the title compound (5.37 g, 97percent yield) as a crystalline solid.LRMS (m/z): 168 (M+1 )Intermediate 75.methyl 4-amino-3-hydroxybenzoate4-amino-3-hydroxybenzoic acid ( 5.0 g, 32.6 mmol) was added dropwise to a 0 °C solution of an HCI 1 .25 M solution in MeOH(100 mL) and MeOH (100 ml_). After 5 min of final addition the mixture was allowed to warm up to room temperature and stirred overnight. HPLC monitoring of the reaction showed remaining starting material and the mixture was stirred at ambient temperature for 48 hours. The solvent was then removed under reduced pressure and the residue was treated with saturated aqueous bicarbonate solution and the aqueous phase was extracted with AcOEt (2 x ). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated to dryness obtaining the title compound (5.37 g, 97percent yield) as a crystalline solid.LRMS (m/z): 168 (M+1 )A solution of 4-amino-3-hydroxybenzoic acid (24.5g, 159mmol) in methanol (650ml) was cooled in an ice bath and treated with gaseous HCl for about 20min. (about 60g). Stirring was continued overnight and then the solution was concentrated under reduced pressure. The residue was triturated with EtOAc (200ml) and dried to a brown solid (24.5g, 92percent) which was used without further purification. Mass spec. 168.2, NMR (300MHZ, DMSO-d6, 30°C) 9.3-9.4 (1H, s), 7.2-7.3 (2H, m), 6.55-6.65 (1H, d), 5.3-5.4 (2H, s(broad)), 3.6-3.8 (3H, s).To a stirred solution of anhydrous MeOH (4 L) in an ice bath was added dropwise CHActivity Result +ve at l Oym, EDso = 1. Ain To a 500ml round bottomed flask was added 4-amino-3-hydroxybenzoic acid (5. 0g, 32. 65mmol) and methanol (140ml). Concentrated sulfuric acid (3. 5ml) was added dropwise slowly. The reaction mixture was heated to reflux (65°C) in an oil bath for 36 hours. The solution remaining was evaporated in vacuo to dryness. Ice water (125ml) was added and the pH of the solution was adjusted to 5 using a 2M NaOH solution. The brown precipitate which was formed was filtered through a sinter funnel and washed with water (50ml). The product WSP 1017 was isolated pure as a brown solid. Yield 3.360g (20. 10mmol, 62percent); mp 116-117°C ; lH NMR (300MHz, d4-MeOD) 8 3.82 (3H, s, Cl-H), 6.67 (1H, d, J=8. 20 Hz, C4-H), 7.32 (1H, d, J=1. 89 Hz, C7-H), 7.36 (1H, d, J=1. 89 Hz and 8. 20 Hz, C3-H) ; 13C NMR (75MHz, d4-MeOD) 8 52.4 (Cl), 114.9 (C4), 116.3 (C7), 119.8 (C3), 124.6 (C8), 143.7 (C6), 145.2 (C5), 169. 8 (C2) ; ES+ m/z 167.5 (M+), 189.9 (M+Na+).Step 1: To a stirred solution of anhydrous MeOH (4L) in an ice bath was added dropwise CH