849217-64-7

479690-10-3

849217-48-7

849217-64-7

Example 3: Preparation of N-[3-fluoro-4-({6-(methoxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide (Compound I, Form B). 3.1: Preparation of compound (I), crystalline form B. [0079] To a dry reactor (Reactor 1) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (21.5 kg), THF (76 kg), and N,N-dimethylformamide (DMF, 0.09 kg), and stirred at 20 °C until completely dissolved. The reactor was cooled to about 15 °C and oxalyl chloride (12.7 kg) was slowly added over 38 min while controlling the internal temperature of the reactor below 20 °C. After the addition was complete, the transfer line was flushed with THF (3 kg). After 1 hour of reaction at about 20°C, oxalyl chloride (0.6 kg) and THF (2 kg) were added again to the reactor and the process was repeated once. Subsequently, smaller amounts of oxalyl chloride (0.13 kg) and THF (2 kg) were added a third time. To another dry reactor (reactor 2) was added water (60 L), K2CO3 (11.1 kg), 3-fluoro-4-[(6-methoxy-7-{[3-(4-morpholinyl)propyl]oxy}-4-quinolinyl)oxy]aniline (32.5 kg, see CAS Reg. No. 479690-10-3 and US2004/0242603 ) and THF (177 kg), and the temperature of the reactor contents was adjusted to about 15 °C. The contents of Reactor 1 were slowly added to Reactor 2 while keeping the temperature of Reactor 2 below 20°C. Rinse Reactor 1 with THF (5 kg) and transfer the rinse solution to Reactor 2. The temperature of the contents of Reactor 2 was adjusted to about 20 °C and the reaction was carried out for about 3 hours. Subsequently, 0.8M K2CO3 aqueous solution (171 kg) and isopropyl acetate (119 kg) were added, stirred for 10 minutes, left to stratify, and the lower aqueous phase was discarded. Repeatedly added 0.8M K2CO3 aqueous solution (171kg), mixed and left to stratify, again discarded the aqueous phase. Water (137 kg) was added, mixed and allowed to partition, and the aqueous phase was discarded. Steam-activated powdered activated carbon (Darco G-60, Norit Americas, Inc., 3.4 kg) and isopropyl acetate (3 kg) were added, stirred for about 2.5 hours, and then filtered through a filter containing diatomaceous earth into another reactor (Reactor 3). The reactor 2 was rinsed twice with isopropyl acetate (33 kg each time) and the rinsate was combined with the material in reactor 3 through the above mentioned filter. The material in Reactor 3 was concentrated to about 104 L under vacuum, keeping the temperature below 50°C. Isopropanol (161 kg) was added and again concentrated under vacuum to about 104 L, keeping the temperature below 50°C. Repeatedly added isopropanol (161 kg) and concentrated to about 100 L. Heated the material in Reactor 3 to about 75°C, held for 80 minutes, and then cooled to about 55°C. Heptane (1 kg) containing about 1% isopropanol was added and held at about 55°C for 70 minutes until crystallization was observed. Subsequently, heptane (46 kg) containing about 1% isopropanol was added and the reactor contents were kept at about 55°C for 75 minutes. The reactor contents were cooled to about 20°C over a period of about 5 hours and held at that temperature for about 12 hours. Further cooling to about 5°C and holding for 1 hour. The material in reactor 3 was transferred to a filter drier and rinsed with a mixture of isopropanol (18 kg) and heptane (8 kg). Drying at about 50°C for about 56 hours gave 42.8 kg (89% yield) of compound (I) crystalline form B as an off-white powder.