N4-(3-Chloro-4-fluorophenyl)-7-methoxy-4,6-quinazolinediamine

(3-Chloro-4-fluoro-phenyl)-(7-fluoro-6-nitro-quinazolin-4-yl)-amine was suspended in 100 ml methanol and 2 ml 50percent NaOH in water was added and the mixture was heated at 70deg C. for 2 hours. The mixture was then poured into water and stirred vigorously for 30 minutes, then filtered and washed with water and dried under vacuum at 60deg C. overnight to give 7.2 g of (3-Chloro-4-fluoro-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine. 7.1 g of (3-Chloro-4-fluoro-phenyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine was reduced using Raney nickel catalyst in THF, then filtered and evaporated to give 6.4 g N4-(3-Chloro-4-fluoro-phenyl)-7-methoxy-quinazoline-4, 6-diamine (99percent yield). This product was reacted with 4-Chloro-but-2-enoyl chloride as described in Scheme 1 to provide 4-Chloro-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide. 300 g of 4-Chloro-but-2-enoic acid [4-(3-chloro4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide and 78 mg azepane were dissolved in 5 ml THF and purged with nitrogen. 0.25 ml DIEA was added and the mixture was stirred at 70deg C. for 2 days. The mixture was then diluted with 20 ml ethyl acetate, washed with water and brine and dried over Na2SO4. The resulting solids were flash chromatographed with 0-4percent methanol in chloroform. The product was dissolved in CH2Cl2 and treated with excess HCl and ether, then evaporated to dryness to give 115 mg of 4-Azepan-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (33percent yield). (M+H)+ @484.To a solution of N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4- amine (10 g, 28.6 mmol) in a mixture of ethanol (200 mL), THF (100 mL), HThe synthesis of compound 8 was similar to the compound 7.The solution of compound 5b (11.2 g, 0.032 mol) and ethanol (370 mL) was stirred at 60 °C, an appropriate amount of activated carbon (3.5 g) and ferric chloride (1.3 g) were added at the temperature, the mixture was heated to 80 °C and 80 percent hydrazine hydrate (16 mL) was added to the solution. Step 2) NWill be raw materialsΝ(1-chloro-4-fluorophenyl) -7-methoxy-6-nitroquinazolin-4-amine lh (1.50 g, 4.30 mmol)Was added to 30 mL of tetrahydrofuran, stirred to dissolve, Raney nickel (lg) was added, and the hydrogen was replaced three times, and the reaction was stirred for 3 hours. The reaction solution was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound N4- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine li(Lg, brown solid), Total yield: 73percent.(2) (2) The preparation of 4-(3-chloro-4-fluorophenyl)amino-6-amino-7-methoxyquinazoline [0081] 4-(3-chloro-4-fluorophenylamino)-6-nitro-7-methoxyquinazoline (25.3 g, 72.7 mmol) was dissolved in 500 mL tetrahydrofuran. To the solution was added 7.6 g Raney-Ni. To the resulting mixture was added hydrogen gas. The mixture was stirred at room temperature for 24 h, filtered and rotary-evaporated to remove the solvent. The resulting residue was washed with ethyl acetate to produce 13.345 g 4-(3-chloro-4-fluorophenyl)amino-6-amino-7-methoxyquinazoline as yellow solid in a yield of 57.7percent.[0083] A mixture of compound 0307 (3.5 g, 10.0 mmol) and iron dust (11.2 g, 200.0 mmol) and ethanol (100 mL) and concentrated hydrochloric acid (2 mL), and water (30 mL) was heated to reflux for 1 hour. Removed iron dust by filtration. The filtrate was concentrated to 1/5 volume. The precipitate was isolated and dried to give the title compound 0308 (2.2 g, 69percent). Step 22f. N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine (Compound 0308); A mixture of compound 0307 (3.5 g, 10.0 mmol) and iron dust (11.2 g, 200.0 mmol) and ethanol (100 mL) and concentrated hydrochloric acid (2 mL), and water (30 mL) was heated to reflux for 1 hour. Removed iron dust by filtration. The filtrate was concentrated to 1/5 volume. The precipitate was isolated and dried to give the title compound 0308 (2.2 g, 69percent). (100.00 mg, 304.33 mmol) and isoamyl nitrite (71.31 mg, 608.67 mmol) were dissolved in acetonitrile (3.00 mL), then added with copper bromide (135.95 mg, 608.67 mmol), and stirred under nitrogen protection at 65 C for 10 hours. The target compound was detected by liquid chromatography mass spectrometry and TLC showed that the raw materials were not completely consumed. The reaction mixture was filtered with DCM: MeOH = 10:1 (22 mL), then concentrated, separated and purified by TLC (DCM: MeOH = 12:1) to give compound 2D finally. 1H NMR (400MHz, METHANOL-d4) delta = 8.71 (s, 1H), 8.53 (br. s., 1H), 8.05 (d, J=4.5 Hz, 1H), 7.75 - 7.64 (m, 1H), 7.32 - 7.19 (m, 2H), 4.05 (s, 3H). LCMS (ESI) (5-95AB): m/z: 382.1 [M+1].

Molecular Weight:318.73
XLogP3:3.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:3
Exact Mass:318.0683669
Monoisotopic Mass:318.0683669
Topological Polar Surface Area:73.1
Heavy Atom Count:22
Complexity:378
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes