(S)-tert-butyl (1-(5-fluoro-4-oxo-3-phenyl-3,4-dih

3. preparation of tert-butyl (S)-[1-(5-fluoro-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl)propyl]carbamatePreparation of (S)-[1-(5-fluoro-4-oxo-3- phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl]-carbamic acid tert-butyl ester (4a).; A solution of [1-(2- fluoro-6-nitro-benzoyl) -phenyl-aminocarbonyl]- propyl) -carbamic acid tert-butyl ester 3 (56 g, 125 mmol, 1 eq) in HOAc (500 mL) was treated with Zn (48.4 g, 740 mmol, 6 eq) added in 3 portions, allow- ing the reaction mixture to cool to below 35°C be- tween additions. After stirring for 2 h at ambient temperature, solids were filtered by vacuum filtra- tion and washed with HOAc (50 mL). The filtrate was concentrated in vacuo, dissolved in EtOAc (400 mL), washed with H20 (300 mL), and the water layer was extracted with EtOAc (300 mL). The combined organic layers were washed with H20 (200 mL), satd. NaHC03 (2 x 200 mL), satd. NaCl (100 mL), dried with MgS04, and concentrated to a syrup. The syrup was dissolved in toluene (200 mL) and purified by flash chromatog- raphy on a silica gel plug (13 x 15 cm, 2 L dry silica) eluted with hexanes/EtOAc (10percent, 4 L; 15percent, 4 L; 17.5percent, 8 L; 25percent, 4 L) to yield the product as an off-white foamy solid (33.6 g, 69percent). Add 400g to the reaction flask(S)-N-(2-Boc-aminobutanoyl)-2-fluoro-6-nitro-N-phenylbenzamide, Add 3 L of acetic acid to the reaction flask.Add 85g of zinc powder in batches, Stir for 30min, Warming up to 100 ° C, Conduct a central control reaction, After the reaction is completed, it is concentrated under reduced pressure in that order.Cooling down, filter, Washed, drying, 292 g of the product edlalys intermediate 5-fluoro-3-phenyl-2-[(S)-1-Boc-aminopropyl]-4-(3H)-quinazolin-4-one were obtained.N, N-dimethylformamide (720 ml) was added to the reaction flask, N-Boc-L-2-aminobutyric acid (A, 203 g, 1 mol) was added and stirred to 0-10 ° C with stirring;At this temperature, N-methylafilide (151 g, 1.5 mol) was added dropwise; then isopropyl chloroformate was added dropwise(122.5 g, 1 mol) was added and the mixture was stirred for 1 h;A solution of 2-amino-6-fluorobenzoic acid (155 g, 1 mol) in N, N-dimethylformamide (120 ml) was added dropwise, Stirring 5h, Aniline (139.5 g, 1.5 mol) was added, the temperature was raised to 50 ° C, the reaction was carried out for 14 h, After completion of the reaction, water (5000 ml) was added, the crude product was precipitated, recrystallized from isopropanol, (1- (5-fluoro-4-carbonyl-3-phenyl-3, 4-dihydroquinazolin-2-yl) propyl) carbamic acid tert-butyl ester 365.2 g 92percent), EE value: 99.7percent.Example 3 A solution obtained crude compound of formula II 17.8g, dichloromethane 100ml, aniline (20ml, 219.4mmol) was added to a 1L flask.Stirred until the solids dissolved.It was heated to reflux and the reaction incubated for 2 hours.The reaction mixture was concentrated under reduced pressure to dryness.The residue was added acetonitrile 150ml, and stirred until the oil was dissolved.Triethylamine (121ml), was added dropwise TMSCl (73ml).Dropwise addition, the reaction was heated at reflux for 48 hours.Cooled to room temperature, the reaction mixture was poured into ice water and extracted twice with 200ml of dichloromethane.The organic phase was washed with 0.1M hydrochloric acid solution was washed twice with 200ml minutes, three times with saturated aqueous sodium bicarbonate 200ml.Dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude compound of formula IV under reduced pressure.The crude product was dissolved in ethyl acetate 50ml, 50ml of petroleum ether added dropwise with stirring, the precipitated brown solid was filtered.Cake was washed with 1: 1 ethyl acetate: petroleum ether solvent mixture and recrystallized to give a pale yellow solid 10.9g.A solution of (S) -N-Boc-L-2- aminobutyric acid (655mg, 3.2mmol) and 10ml of methylene chloride were added to 50mL three-necked flask and stirred until the solids dissolved.Was cooled to -20 , were added dropwise NMM (652mg, 8.4mmol), isobutyl chloroformate (440mg, 3.2mmol), incubated for 5 hours.2-amino-6-fluoro-benzoic acid hydrochloride (500mg, 2.6mmol), natural warming to 5 , incubated for 16 hours.Was added dropwise the aniline (600mg, 3.2mmol), naturally warmed to room temperature for 6 hours.The reaction mixture was concentrated under reduced pressure to dryness.The residue was added n-butanol 20ml.Triethylamine (10ml), was added dropwise TMSCl (10ml).Dropwise addition, the reaction flask was placed in an oil bath heated at reflux for 50 hours.Cooled to room temperature, the reaction mixture was poured into ice water and extracted twice with 50ml of dichloromethane.Washed twice with 0.1M hydrochloric acid solution and the organic phase, washed with saturated aqueous sodium hydrogen carbonate three times.Dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude compound of formula IV under reduced pressure.The crude product was dissolved in ethyl acetate 2ml, 2ml petroleum ether added dropwise with stirring, the precipitated brown solid was filtered.Cake was washed with 1: 1 ethyl acetate: petroleum ether solvent mixture and recrystallized to give a pale yellow solid of about 300mg.General procedure: 1.00 g (5.89 mmol) of 2-amino-6-chlorobenzoic acid obtained in step 1 above was mixed with N-Boc-L-alanine (1 equivalent), triphenyl phosphite (1.2 equivalent), and anhydrous pyridine (5 mL). The reaction mixture was stirred at 55° C. for 12 hours, to which aniline (1 equivalent) was added. The mixture was heated for 6 hours, and then cooled down at room temperature. The mixture was concentrated under reduced pressure, followed by acidization with 1N HCl (pH: 5-6). The reaction mixture was extracted by using ethyl acetate to separate an organic layer. The organic layer was washed with saturated brine, separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was separated by column chromatography (SiO2, eluent: hexane/ethyl acetate, 10/1->hexane/ethyl acetate, 1/1) to give 1.63 g of the target compound tert-butyl (S)-(1-(5-chloro-4-oxo-3-phenyl-3, 4-dihydroquinazoline-2-yl)ethyl)carbamate as a yellow solid (4.09 mmol, yield: 69percent). 1H NMR(300 MHz, CDCl3) delta 7.61-7.63 (m, 2H), 7.46-7.57 (m, 4H), 7.36-7.39 (m, 1H), 7.29 (s, 1H), 5.59 (s, 1H), 4.50 (s, 1H), 1.37-1.46 (m, 9H), 1.25 (d, J=6.5 Hz, 3H).To a solution of (S)-tert-butyl- 1- [3-fluoro-2-(phenylcabamoyl)phenylamino] -1 -oxobutan-2- ylcarbamate (10 g, 1 equivalent) in acetonitrile (300 mL) was added triethyl amine (114.1 g, 47 equivalent), followed by the drop wise addition of hexamethyldisilazane (58.1 g, 15 equivalent). The reaction mixture was stirred at reflux temperature for 10-12 hours. After completion of reaction, the reaction mass was concentrated under reduced pressure.Dichloromethane (200 mL) was added to the residue and washed with water followed by brine wash. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield off-white solid of title compound (9.5 g, yield:99.6 percent; Purity> 95 percent).A solution of (S) -N-Boc-L-2- aminobutyric acid (655mg, 3.2mmol) and 10ml of methylene chloride were added to 50mL three-necked flask and stirred until the solids dissolved.Was cooled to -20 , were added dropwise NMM (652mg, 8.4mmol), isobutyl chloroformate (440mg, 3.2mmol), incubated for 5 hours.2-amino-6-fluoro-benzoic acid hydrochloride (500mg, 2.6mmol), natural warming to 5 , incubated for 16 hours.Was added dropwise the aniline (600mg, 3.2mmol), naturally warmed to room temperature for 6 hours.The reaction mixture was concentrated under reduced pressure to dryness.The residue was added n-butanol 20ml.Triethylamine (10ml), was added dropwise TMSCl (10ml).Dropwise addition, the reaction flask was placed in an oil bath heated at reflux for 50 hours.Cooled to room temperature, the reaction mixture was poured into ice water and extracted twice with 50ml of dichloromethane.Washed twice with 0.1M hydrochloric acid solution and the organic phase, washed with saturated aqueous sodium hydrogen carbonate three times.Dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude compound of formula IV under reduced pressure.The crude product was dissolved in ethyl acetate 2ml, 2ml petroleum ether added dropwise with stirring, the precipitated brown solid was filtered.Cake was washed with 1: 1 ethyl acetate: petroleum ether solvent mixture and recrystallized to give a pale yellow solid of about 300mg.

Molecular Weight:397.4
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:397.18016980
Monoisotopic Mass:397.18016980
Topological Polar Surface Area:71
Heavy Atom Count:29
Complexity:640
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes