Pharmaceutical Intermediates Afatinib API and intermediates N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quina

(54-Chloro-7-fluoro-6-nitroquinazoline 1f (7.15 g, 0.031 mol), 4-fluoro-3-chloroaniline (4.58 g, 0.031 mol), triethylamine (3.52 g, 0.035 mol ) Was added to 70 mL of isopropanol and stirred for 1.5 hours.The reaction solution was concentrated under reduced pressure, 30 mL of dichloromethane was added, filtered and the filtrate was concentrated under reduced pressure to give the title compound N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitroquinazoline-Amine (10.50 g, yellow solid), yield: 100percent.7-fluoro-6-nitro-4-chloroquinazoline (14.73, g, 65 mmol) was combined with 3-choro-4-fluoroaniline (9.49 g, 65 mmol) and triethylamine (10 mL, 72 mmol) in 150 mL of isopropanol. The reaction was stirred at room temperature for 1.5 hours, resulting in a yellow slurry. The solid was collected by filtration, rinsing with isopropanol and then water. The solid was dried in a 40 deqC. vacuum oven overnight to give 19.83 g (91percent) of the product as an orange solid. MS (APCI, m/z, M+1): 337.0 NaH (60percent in mineral oil, 3.55 g, 88 mmol) was added, in portions, to a solution of 2-fluoroethanol (5.19 g, 80 mmol) in 200 mL THF. The reaction was stirred for 60 minutes at room temperature. To the reaction was added 7-fluoro-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (18.11 g, 54 mmol) as a solid, rinsing with THF. The reaction was heated to 65deq C. for 26 hours. The reaction was cooled to room temperature and quenched with water. THF was removed in vacuo. The resulting residue was sonicated briefly in water then the solid collected by filtration. The solid was triturated with MeOH, filtered and dried in a 40deq C. vacuum oven overnight to 12.63 g of the product. Additional product was obtained by concentrating the MeOH filtrate to dryness and chromatography eluting with 50percent EtOAc/hex. The isolated material was triturated with MeOH (2times), filtered and dried. 3.90 g Total yield: 16.53 g, 81percent MS (APCI, m/z, M+1): 381.0 7-(2-fluoroethoxy)-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (0.845 g, 2.2 mmol) in 50 mL THF was hydrogenated with Raney nickel (0.5 g) as the catalyst over 15 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.77 g of product. (99percent) MS (APCI, m/z, M+1): 351.2 Methyl 4-bromocrotonate (85percent, 20 mL, 144 mmol) was hydrolyzed with Ba(OH)2 in EtOH/H2O as described in J.Med.Chem. 2001, 44(17), 2729-2734. MS (APCI, m/z, M-1): 163.0 To a solution of 4-bromocrotonic acid (4.17 g, 25 mmol) in CH2Cl2 (20 mL) was added oxalyl chloride (33 mL, 38 mmoL) and several drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in 10 mL THF and added to a 0deq C. mixture of 6-amino-7-(2-fluoroethoxy)-4-(3-chloro-4-fluoroaniline)quinazoline (5.28 g, 15 mmol) and triethylamine (5.2 mL, 37 mmol). The reaction was stirred at 0deq C. for 1 hour. Water was added to the reaction and the THF removed in vacuo. The product was extracted into CH2Cl2 (400 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 0-4percent MeOH/CH2Cl2. An isolated gold foam was isolated. Yield: 4.58 g, 61percent MS (APCI, m/z, M-1): 497.1 Piperidine (0.75 mL, 6.7 mmol) was added to a solution of the above compound (3.35 g, 6.7 mmol) and TEA (2.80 mL, 20 mmol) in 10 mL DMA at 0deq C. The reaction was stirred at 0deq C. for 17 hours. Water was added to the reaction until a precipitate was evident. The reaction was sonicated for 40 minutes and the liquid decanted. The residue was dissolved in CH2Cl2, dried over MgSO4, filtered and concentrated. The material was chromatographed on silica gel eluting with 4-10percent MeOH/CH2Cl2. The isolated residue was triturated with acetonitrile (2times) and collected by filtration. Impurity found: Michael addition of piperidine (2.2percent in first trituration of acetonitrile). Additional material can be obtained from the acetonitrile filtrates. Yield: 0.95 g, 27percent MS (APCI, m/z, M+1): 502.3Step 1: To the solution of compound 3 (50.0 g, 0.220 mol), isopropanol (400 mL), triethylamine (34 mL), 3-choro-4-fluoroaniline was added at room temperature. Sequentially to 400 ml of isopropanol by adding 50.0g of 7-fluoro-6-nitro-4-chloriquine oxazoline (IV), 32.3g of 4-fluoro-3-chloroaniline, to the reaction liquid to carry out polyreaction 34.0 ml triethylamine, room temperature stirring 1.5h. After the reaction, filtration, with isopropanol and water washing, drying, the filtrate water enlarges the quantity solid precipitation, filtration, washing, drying, merging, shall be 65.0g crocatus solid, in other words, 4 - [(3-chloro-4-fluoro-phenyl) amino] - 6-nitro-7- [...] (V), yield: 87.8percent.To 40 mL of isopropyl alcohol was added 50.0 g of 7-fluoro-6-nitro-4-chloroquinazoline, 32.3 g of 4-fluoro-3-chloroaniline, 34.0 mL of triethylamine was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 1.5 h.After completion of the reaction, the filter cake was washed with isopropyl alcohol and water, dried, and the filtrate was stirred with a large amount of water to precipitate a solid, suction, washed with water, dried and combined to give 65.0 g of a dark yellow solid, 4 - [(3-chloro-4-fluorophenyl) amino] -6-nitro-7-fluoroquinazoline in a yield of 87.8percent.a. synthesis of N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine method 1 (one-pot reaction): (0123) (0124) Compound 7-fluoro-6-nitro-4-hydroxyquinazoline (5 g, 23.9 mmol) was added into a 100 mL one-neck flask, then phosphorus oxychloride (44.6 mL, 478 mmol) was added, heated to reflux at 150°C for 5 h, the phosphorus oxychloride in the reaction solution was evaporated, the residue was diluted with anhydrous dichloromethane and evaporated again. Repeat the procedure for 3 times and diluted with acetonitrile (100 mL), then compound 3-chloro-4-fluoroaniline (2.3 g, 15.8 mmol) was added. A yellow solid was precipitated after heating at reflux overnight. The yellow solid in the reaction solution was filtrated and dried to deliver the product N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine (4.8 g, 56percent yield). Compound 2-amino-4-fluoro-5-nitrobenzonitrile (7.2 g, 40 mmol) was dissolved into toluene (70 mL), DMF-DMA (N, N-dimethylformamide dimethyl acetal, 4.7 g, 40 mmol) and acetic acid (1 mL) was added, stirring to react at 105°C for 2 h, after concentration by evaporation, acetic acid (140 mL) and 3-chloro-4-fluoroaniline (6.9 g, 48 mmol) were added, stirring toreact at 125°C for 3 h. The reaction mixture was cooled to room temperature, poured into ice-water, after the pH value was adjusted to 9 with ammonia, then ethyl acetate 40 mL was added, stirred for 1 h, filtrated, dried to deliver the product N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine (8.3 g, 62percent yield).

Molecular Weight:336.68
XLogP3:4.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:7
Rotatable Bond Count:2
Exact Mass:336.0225595
Monoisotopic Mass:336.0225595
Topological Polar Surface Area:83.6
Heavy Atom Count:23
Complexity:442
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes