3-Formyl-2-nitrobenzoic acid methyl ester

Step C; Methyl 3-Formyl-2-nitrobenzoate; Add N-methylmorpholine oxide (NMO, 6.10 g, 52.07 mmol) to a mixture of methyl 3-bromomethyl-2-nitrobenzoate (7.13 g, 26.023 mmol) and 4 A molecular sieves (35.32 g) in acetonitrile (150 mL) = at room temperature under nitrogen and stir for 1.5 h. Dilute the mixture with ethyl acetate (600 mL), filter the mixture by vacuum filtration and wash the filtrate with water (100 mL), 1 N HC1 (100 mL) and brine (150 mL) and dry over Na2S04. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1: 3), to provide methyl 3-formyl-2-nitrobenzoate as an off-white solid (4.04 g, 74percent) : 1H NMR (CDC13) 8 3.95 (s, 3H), 7.77 (t, 1H), 8. 18 (dd, 1H), 8.28 (dd, 1H), 9. 98 (s, 1H).Take Niraparib Intermediate 1 (0.88 mol) 160g In a Erlenmeyer flask with reflux and stirrer, 230 g (2.64 mol) of AMD (activated manganese dioxide) was added, 55 mL of 65percent nitric acid (0.6 mol) was slowly added with stirring to 40 ° C, Reflux 5-7h. Hot filter, After standing, the oil phase is separated, With 0.1kg / L sodium bicarbonate solution repeatedly washed to neutral, Dried with anhydrous sodium sulfate, Niraparib Intermediate 2 was 130.98 g, The yield was 66.4percent.Compound 10 (90.0 g, 0.36 mol) was added to 350 mL of DMF, Sodium periodate (192.6 g, 1.44 mol) was dissolved in 490 mL, Was added dropwise to the reaction solution, Half an hour plus finished, after the drop is completed, The reaction was carried out at room temperature for 3 hours, and the mixture was stirred at 650 mL with water, The solid was filtered off and washed with water and dried under reduced pressure(45 ° C)To give 77.2 g of a brown solid.To compound 10 (90.0 g, 0.36 mol) were added 350 mL of DMF, Sodium periodate (192.6 g, 1.44 mol) was dissolved in 490 mL and added dropwise to the reaction mixture, After the addition was completed in half an hour, the reaction was carried out at room temperature for 3 hours. The mixture was stirred with 650 mL of water and precipitated. The solid was filtered off and washed with water and dried under reduced pressure (45 ° C) to give a brown solid77.2g.Example 74; Synthesis of (3S)-3-amino-1-hydroxy-8-(morpholin-4-ylmethyl)-3, 4-dihydroquinolin-2(1H)-one, trifluoroacetic acid salt (104); Methyl 3-formyl-2-nitrobenzoate (98); N, N-Dimethylformamide dimethyl acetal (10 g, 84 mmol) and methyl 3-methyl-2-nitrobenzoate (8.0 g, 41 mmol) were combined and heated to 120° C. for 42 h. After cooling, the mixture was concentrated under reduced pressure to provide methyl 3-[(E)-2-(dimethylamino)vinyl]-2-nitrobenzoate (9.0 g, 88percent), which was dissolved in a 1:1 mixture of water and THF. After addition of sodium periodate (99percent, 23.3 g, 108 mmol), the reaction was allowed to stir for 18 h, then was filtered. The filtrate was washed with water and with saturated aqueous sodium chloride solution, then dried over sodium sulfate. Filtration and removal of solvent under reduced pressure provided a residue, which was purified using silica gel chromatography (Gradient: 0percent to 80percent EtOAc in heptane) to provide the product as a solid (2.2 g, 29percent). To the reaction solution obtained in the previous step was added 2.5 g of tetrabutylammonium bromide (molecular weight 322.4, 7.75 mmol), and 100 g of a 10% zinc chloride aqueous solution (molecular weight 136.3, 73.4 mmol) was added, and the mixture was kept at 20 C to 30 C with stirring and holding.During the incubation process, a 10% sodium bicarbonate aqueous solution was added dropwise to maintain the pH of the reaction system at 6 to 8 to prevent ester group hydrolysis. After 5 hours of reaction, a sample was taken and controlled.The remaining methyl 3-dichloromethyl-2-nitrobenzoate is 0.6%.The lower organic layer was washed once with 50 g of water, Dichloromethane was recovered by pressure distillation, and 150 g of toluene was added to the remaining solid material.Add to 50 to dissolve, cool the material to 0 5 , maintain crystallization at 0 5 for 0.5 hoursFiltration, the filter cake is rinsed with 30 g of toluene at 0 ~ 5 C, and dried at 40 C in the air.43.3 g of a pale yellow solid product was obtained. The purity by HPLC chromatography was 99.1% and the yield was 81%.

Molecular Weight:209.16
XLogP3:1.1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:209.03242232
Monoisotopic Mass:209.03242232
Topological Polar Surface Area:89.2
Heavy Atom Count:15
Complexity:272
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes