4-BENZYLOXY-5-METHOXY-2-NITRO-BENZOIC ACID

The compound (20g, 69.62 mmol) obtained in A solution of 4-(benzyloxy)-5-methoxy-2-nitrobenzaldehyde (32) (8.0 g, 28 mmol) in acetone (300 mL) was quickly charged with a hot (70 °C) solution of potassium permanganate (16.5 g, 104 mmol) in water (150 ml). The mixture was then stirred at 70 °C for 4 h. The reaction mixture was then allowed to cool to room temperature and passed through a pad of celite, which was then washed with hot water (120 mL). A solution of sodium bisulfite in hydrochloric acid (1 M, 120 mL) was added to the filtrate, which was then extracted with dichloromethane (2 x 200 mL). The combined organic extracts were subsequently dried over sodium sulfate, filtered and concentrated to give the title compound (6.7 g, 79percent) as a yellow solid, which was used in the subsequent step without further purification. (1547) NMR (400 MHz, CDCIPREPARATION 80 To a solution of methyl 4-(benzyloxy)-5-methoxy-2- nitrobenzoate (Harve Chem, 15 g, 47.3 mmol) in tetrahydrofuran (THF, 350 mL) was added a solution of aq. NaOH (56.7 mL, 142 mmol, 2.5M). The reaction was stirred at 50 °C for 5 h. The reaction was cooled to room temperature (RT) and then concentrated in vacuo to remove the THF. The remaining aqueous layer was acidified with aq. HC1 (6 N) to pH 2. The resulting yellow precipitate was filtered, washed with water, and dried under vacuum to give 4- (benzyloxy)-5-methoxy-2-nitrobenzoic acid (14.32 g, 100percent yield). LCMS (M+H) = 304.08; NMR (400MHz, METHANOL-dTo a rt solution of methyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (15 g, 47 mmol) inTHF (350 mL) was added 2.5 M aq. NaOH (56.7 mL, 142 mmol). The reaction was stirred at 50°C for 5 h. The reaction was cooled to rt and then concentrated in vacuo to remove the THF. Theremaining aqueous layer was acidified with 6 N aq. HCl to pH 2. The resulting yellow precipitatewas filtered, washed with water, and dried under vacuum to provide S1 (14.32 g, quant.).4-Benzyloxy-5-methoxy-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated. Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring. Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield).4-benzyloxy-5-methoxy-2-nitro-benzoic acid methyl ester (9.1 g, 29 mmol) was dissolved in methanol (145 mL) and sodium hydroxide (6 M solution, 24 mL) was added at once. Reaction mixture was stirred for 1 h at 50 degrees and methanol was evaporated.Concentrated hydrochloric acid (12 mL) was added slowly to the residue with stirring.Formed precipitate was filtered off, washed with water and dried to afford 8.1 g of 3 (92percent yield). A solution of 40 (2.3 g, 7.25 mmol) in MeOH (20 mL) was added a solution of LiOH (2.25 mL, 36.24 mmol) in water (5 mL). To a solution of compound 3 (2.50 kg, 7.93 mol) in THF (20 L) and H4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2CI2 (400 ml) and I lOAc (100 ml) was added HNOExample 9. 4-(benzyloxy)-5-methoxy-2-nitrobenzoic acid 4-(Benzyloxy)-3-methoxybenzoic acid (63.5 g, 246.0 mmol) in the mixture of CH2C12(400 ml) and FIOAc (100 ml) was added HNO3 (fuming, 25.0 ml, 528.5 mmoi). The mixture was stirred for 6 h, concentrated, crystallized with EtOH, dried over the oven at 40 °Cwith vacuum to afford the title compound (63.3 g, 85percent yield). ESI MS mlz+ 326.1 (M +Na).To a solution of compound 238 (63.5 g, 246.0 mmol) in CHCompound 33a (20 g, 77 mmol) was added as a thick suspension in anhydrous dichloromethane (100 mL) and was cooled to 0° C. Acetic acid (191 mL) was added, resulting in a clear solution which stirred at 0° C. until cool. Nitric acid (26 mL, 581 mmol) was added slowly dropwise through an addition funnel. The ice bath was removed and the solution continued to stir at room temperature. After 3 hours, the reaction was diluted with deionized water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the filtrate concentrated in vacuo. The crude residue was recrystallized using ethyl acetate and hexanes. The solid was filtered and washed with hexanes to give compound 33b as a yellow fluffy solid (13.8 g, y=59percent).

Molecular Weight:303.27
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:5
Exact Mass:303.07428713
Monoisotopic Mass:303.07428713
Topological Polar Surface Area:102
Heavy Atom Count:22
Complexity:390
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes