Example 1 : Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)).

Compound (I) was prepared according to the scheme shown below:

Compound (III) Compound (IV)

Compound (V)

Compound (I)Compound (II)

Step 1. Preparation of tert-butyl 4-(5-cyano-2-methoxyphenoxy)piperidine-l- carboxylate (Intermediate 2). 3-hydroxy-4-methoxybenzonitrile (Compound (X), 6.00 g, 39.62 mmole), tert-butyl (4-methanesulfonyloxy)piperidine-l-carboxylate (16.6 g, 59.44 mmoles) (Chemical & Pharmaceutical Bulletin 2001, 49(7), 822-829); and potassium carbonate (6.71 g, 47.55 mmoles) were suspended in isopropanol (78.98 g) and the mixture was heated at reflux with stirring. Additional tert-butyl (4-methanesulfonyloxy)piperidine-l- carboxylate (2.08 g, 7.43 mmoles) was added to push the reaction to completion. The mixture was then cooled and quenched by the addition of water (100.47 g). Seeding with intermediate 2 followed by cooling to 0⁰C resulted in a crystalline product, which was isolated by filtration. The filter cake was washed with a mixture of water (8.86 g) and isopropanol (6.97 g), followed by water (23.64 g) and then dried to give Intermediate 2 (10.75 g, 80% yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 (s, 9 H) 1.48 (m, 2 H) 1.88 (m, 2 H) 3.13 (m, 2 H) 3.67 (m, 2 H) 3.83 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.13 (d, J=8.4 Hz, 1 H) 7.42 (dd, J=8.4, 1.9 Hz, 1 H) 7.51 (d, J=1.9 Hz, 1 H); Mass Spectrum: m/z (M + H)⁺ 333.1. Step 2. Preparation of 4-methoxy-3-(piperidin-4-yloxy)benzonitrile (Compound

(VI)). Intermediate 2 (39.31 g, 118.26 mmoles) was suspended in ethanol (155.53 g) and heated to 40 ⁰C. To this slurry was slowly added HCl (46.61 g, 573.04 mmoles). The mixture was heated to 60 ⁰C and held for 3 hours. The reaction mixture was cooled to 20⁰C and seed was charged initiating crystallisation. The resulting solid was isolated by filtration at 0⁰C, washed twice with ethanol (62.21 g) and then dried to give compound (VI) as the hydrochloride salt (29.84 g, 77% yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.84 (m, 2 H) 2.09 (m, 2 H) 3.02 (ddd, J=12.7, 8.9, 3.4 Hz, 2 H) 3.20 (m, 2 H) 3.84 (s, 3 H) 4.63 (tt, J=7.7, 3.6 Hz, 1 H) 7.15 (d, J=8.5 Hz, 1 H) 7.45 (dd, J=8.5, 1.9 Hz, 1 H) 7.56 (d, J=1.9 Hz, 1 H) 9.16 (br. s, 2 H); Mass Spectrum: m/z (M + H)⁺ 233.2. Step 3. Preparation of 2-[4-(5-cyano-2-methoxyphenoxy)piperidin-l-yl]-JV- methylacetamide (Compound (V)). Compound (VI) (28.36 g, 95.82 mmoles), 2-chloro-N- methylacetamide (12.37 g, 114.98 mmoles) and potassium carbonate (33.11 g, 239.55 mmoles) were suspended in acetonitrile (161.36 g). The reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to 20⁰C and water (386.26 g) was charged. The reaction was heated to 75°C and the volume reduced by distillation. Upon cooling crystallisation occurred. The resulting solid was isolated by filtration, washed twice with water (77.25 g and 128.75 g) and then dried to give compound (V) (27.95 g, 94% yield); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.68 (m, 2 H) 1.91 (m, 2 H) 2.29 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.67 (m, 2 H) 2.88 (s, 2 H) 3.83 (s, 3 H) 4.41 (tt, J=8.3, 4.0 Hz, 1 H) 7.11 (d, J=8.4 Hz, 1 H) 7.40 (dd, J=8.4, 1.9 Hz, 1 H) 7.47 (d, J=I.9 Hz, 1 H) 7.68 (q, J=4.7 Hz, 1 H); Mass Spectrum: m/z (M + H)⁺ 304.2.

Step 4. Preparation of 2-[4-(5-cyano-2-methoxy-4-nitrophenoxy)piperidin-l-yl]-N- methylacetamide (Compound (IV)). Compound (V) (8.78 g, 26.11 mmoles) was suspended in acetic acid (22.82 g, 364.87 mmoles) and the resulting reaction mixture cooled to 5°C. To this was added sulfuric acid (23.64 g, 234.95 mmoles) maintaining the reaction temperature below 30⁰C. To the resulting solution was added nitric acid (2.40 g, 26.63 mmoles). The reaction mixture was then heated to 35°C and held for 3 hours. Additional nitric acid (117 mg, 1.31 mmoles) and sulphuric acid (1.31 g 13.1 mmoles) were charged and the reaction mixture was heated at 35°C for 30 minutes. The solution was cooled to 20⁰C and quenched with aqueous ammonia (92.45 g 1.36 moles), resulting in an increase in temperature to 50⁰C. To the resulting slurry was added, propionitrile (61.58 g 1.12 moles) and water (19 g). The reaction mixture was heated to 80 ⁰C resulting in a clear solution, which upon settling gave two layers. The bottom layer was removed. The reaction mixture was cooled to 20 ⁰C resulting in a thick slurry. The solid was isolated by filtration, washed with propionitrile (6.16 g 112.0 mmoles) and dried to afford compound (IV) (7.44 g, 82% yield); ¹H NMR (400 MHz, DMSO-de) δ ppm 1.72 (m, 2 H) 1.97 (m, 2 H) 2.35 (m, 2 H) 2.61 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.90 (s, 2 H) 3.96 (s, 3 H) 4.73 (tt, J=8.4, 4.0 Hz, 1 H) 7.71 (q, J=4.7 Hz, 1 H) 7.82 (s, 1 H) 7.86 (s, 1 H). Mass Spectrum: m/z (M + H)⁺ 349.2

Step 5. Preparation of 2-[4-(4-amino-5-cyano-2-methoxyphenoxy)piperidin-l-yl]-N- methylacetamide (Compound (III)). Compound (IV) (7.42 g, 19.38 mmoles) was suspended in water (44.52 g) and methanol (5.35 g). To this was added sodium dithionite (11.91 g, 58.15 mmoles) and the resulting reaction mixture was heated to 60⁰C. To the reaction mixture was added hydrochloric acid (46.98 g, 463.89 mmoles)), resulting in a solution, which was held at 60 ⁰C for 3 hours. The reaction mixture was then allowed to cool to 20 ⁰C. Aqueous sodium hydroxide (15.51 g 182.2 mmoles) was charged followed by 2-methyltetrahydrofuran (58.0 g). The reaction mixture was heated to 60 ⁰C, which upon settling gave two layers and the lower aqueous layer was discarded. The volume of the reaction mixture was reduced by vacuum distillation and methyl tert-butyl ether (18.54 g) was added to give a slurry which was cooled to 10 ⁰C. and then the solid was collected by filtration. The solid was washed with 2- methyltetrahydrofuran (5.8 g) and dried to give compound (III) (5.4 g, 78% yield); ¹H NMR (400 MHz, DMSO-de) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M + H)⁺ 319.2.

Step 6. Preparation of 2-[4-(5-cyano-4-{[(dimethylamino)methylene]amino}-2- methoxyphenoxy)piperidin-l-yl]-Λ/-methylacetamide (Compound (H)). Compound (III) (18.21 g, 52.05 mmoles) was suspended in 2-methyltetrahydrofuran (99.62 g). To this was added acetic acid (162.79 mg), and N,N-dimethylformamide dimethyl acetal (DMA) (8.63 g, 70.27 mmoles) and the resulting reaction mixture was heated at 76 ⁰C for 16 hrs. Additional N,N-dimethylformamide dimethyl acetal (639.41 mg, 5.20 mmoles) was added to the reaction mixture to ensure the reaction completed. The reaction mixture was cooled to 30⁰C during which time crystallisation occurred. The resulting solid was isolated by filtration, washed with 2-methyltetrahydrofuran (14.23 g) and dried to afford compound (II) (19.53 g, 97% yield); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.65 (m, 2 H) 1.86 (m, 2 H) 2.24 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.66 (m, 2 H) 2.87 (s, 2 H) 2.95 (s, 3 H) 3.04 (s, 3 H) 3.81 (s, 3 H) 4.19 (tt, J=8.2, 3.8 Hz, 1 H) 6.72 (s, 1 H) 7.15 (s, 1 H) 7.67 (q, J=4.7 Hz, 1 H) 7.90 (s, 1 H); Mass Spectrum: m/z (M + H)⁺ 374.2.

Step 7. Preparation of compound (I). 2-[4-(5-cyano-4-

{ [(dimethylamino)methylene] amino } -2-methoxyphenoxy)piperidin- 1 -yl] -JV-methylacetamide (compound (II), 7.00 g, 17.71 mmoles), was suspended in methoxybenzene (35.8 g). Acetic acid (16.6 g) was charged and to the resulting solution was added 3-chloro-2-fluoroaniline (2.71 g, 18.07 mmoles). The reaction mixture was heated at 90 ⁰C for 20 hours then cooled to 20⁰C. Water (37.04 g) was charged to the reaction mixture, and the organic layer discarded. To the resulting aqueous mixture was charged isopropanol (39.00 g), followed by aqueous ammonia (20.79 g, 25%). The reaction mixture was heated to 30 ⁰C and seeded with compound (I), which induced crystallisation. The reaction was then cooled to 0⁰C and the product isolated by filtration. The filter cake was washed twice with a mixture of water (7.28 g) and isopropanol (4.68 g), then dried to afford the compound (I) (5.65 g, 55% yield); ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.79 (m, 2 H) 2.04 (m, 2 H) 2.38 (m, 2 H) 2.62 (d, J=4.5 Hz, 3 H) 2.74 (m, 2 H) 2.94 (s, 2 H) 3.93 (s, 3 H) 4.56 (tt, J=8.1, 3.8 Hz, 1 H) 7.21 (s, 1 H) 7.28 (m, 1 H) 7.50 (m, 2 H) 7.73 (q, J=4.5 Hz, 1 H) 7.81 (s, 1 H) 8.36 (s, 1 H) 9.56 (br.s, 1 H); Mass Spectrum: m/z (M + H)⁺ 474.2, 476.2.

Example 2: Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline (Compound (I)). Compound (I) was prepared according to the scheme shown below:

Compound (III) Compound (IV)

Compound (V)

Compound (Xl)

Compound (I)

Steps 1, 2, 3 and 4 as set forth in Example 1.

Step 5, alternate 1. Preparation of compound (III). 2-[4-(5-Cyano-2-methoxy-4- nitrophenoxy)piperidin-l-yl]-N-methylacetamide (compound (IV), 15.00 g, 42.50 mmoles) was suspended in water (90.00 g) and methanol (59.38 g). To this was added sodium dithionite (30.47 g, 148.75 mmoles) and water (90.00 g), the resulting reaction mixture was heated to 30 ⁰C and held for 2 hrs. To the reaction mixture was added hydrochloric acid (27.98 g, 276.25 mmoles)), resulting in a solution, which was held at 60⁰C for 2 hours. Aqueous sodium hydroxide (30.60 g 382.49 mmoles) was added followed by a line wash of water (30.00 g). The reaction mixture was cooled to 25°C to give a slurry which was collected by filtration. The solid was washed with water (30.00 g) and dried to give compound (III) (13.50 g, 82% yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)⁺ 319.2.

Step 5, alternate 2. Preparation of compound (III). Compound (IV) (8.00 g, 22.67 mmoles) and 1% platinum + 2 % vanadium catalyst on carbon (1.23 g, 0.023 mmoles) were suspended in Acetonitrile (94.00 g). The reaction mixture was hydrogenated at a pressure of 3 Bar G and at a temperature of 35°C for 3 hrs. Once complete, the reaction mixture was filtered to remove the catalyst which is washed with acetonitrile (31.33 g). The volume of the reaction mixture was reduced by vacuum distillation to give a slurry which was cooled to 0⁰C and then the solid was collected by filtration. The solid was washed with acetonitrile (12.53 g) and dried to give compound (III) (5.88 g, 78% yield); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62 (m, 2 H) 1.82 (m, 2 H) 2.20 (m, 2 H) 2.60 (d, J=4.7 Hz, 3 H) 2.65 (m, 2 H) 2.86 (s, 2 H) 3.72 (s, 3 H) 4.00 (tt, J=8.3, 4.0 Hz, 1 H) 5.66 (br. s, 2 H) 6.39 (s, 1 H) 6.94 (s, 1 H) 7.65 (q, J=4.7 Hz, 1 H). Mass Spectrum: m/z (M+H)⁺ 319.2.

Step 6. Preparation of N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)). 3-chloro-2-fluroaniline (51.21 g, 341.22 mmoles) was suspended in cyclohexane (87.07 g). To this ethyl orthoformate (22.28 g, 150.32 mmoles) and acetic acid (0.94 g, 15.03 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 48°C for 12 hours. Following this the reaction mixture was cooled to 20⁰C over 12 hours and the solid product was isolated by filtration. The filter cake was washed with cylcohexane (26.12 g) and dried in vacuo at 40 ⁰C to give compound (XI) as a white crystalline product (33.95 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 7.14 (t, 2 H) 7.22 (m, 2 H) 8.14 (s, 1 H), 9,98 (s, 1 H); Mass Spectrum (by GC-MS EI): m/z (M⁺) 300.0.

Step 7, alternate 1 : Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (10 g, 29.84 mmol) and TV, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (11.46 g, 37.3 mmol) were suspended in 2-methyltetrahydrofuran (30.4 ml) and heated to 80⁰C. To this yellow suspension was added acetic acid (7.6 ml, 127.33 mmol) and the resulting solution was heated to 92°C for 6 hours. 2-methyltetrahydrofuran (66.5 ml) and water (28.5 ml) were added and mixture was cooled to 55⁰C before adding 50%w/w sodium hydroxide (7 ml, 131.29 mmol) resulting in a temperature rise to 63°C. The temperature was raised further to 69°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 20 ml) and each aqueous phase was discarded after settling. 2- methyltetrahydrofuran (100 ml, 997 mmol) was added and the volume reduced by distillation. Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (19 ml) and dried under vacuum at 40⁰C to yield compound (I) as a white solid (12.14 g, 95%). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.12 (d, J= 6Hz, 1.3H), 1.26 -1.36 (m, 0.4H), 1.75-1.97 (m, 3.3H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.52-3.59 (m, 0.4H), 3.72-3.87 (m, 0.86H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data above includes signals for the 2-methyltetrahydrofuran solvent which is present in a 0.43 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 1.12, 1.26-1.36, 3.52-3.59 and 3.72-3.87. The cluster at 1.75-1.93 contains signals for the solvent and the parent compound. The XRPD for this compound is shown in Figure 2.

Step 7, alternate 2. Preparation of compound (I). Compound (III) (15 g, 44.76 mmol) and compound (XI) (17.19 g, 55.95 mmol) were suspended in 2-methyltetrahydrofuran (45.6 ml) and heated to 83°C. To this yellow suspension was added acetic acid (11.4 ml, 190.99 mmol) and the resulting solution was heated to 92°C for 3 Vi hours. 2-methyltetrahydrofuran (105 ml) and water (50 ml) were added and mixture was cooled to 49°C before adding 50%w/w sodium hydroxide (10.74 ml, 201.4 mmol), resulting in a temperature rise to 62°C. The temperature was maintained at 62°C and after settling the aqueous phase was discarded. The organic phase was washed with water (3 x 30 ml) and each aqueous phase was discarded after settling. The mixture was cooled to 15°C and seed was added to induce crystallisation. The crystalline form was initially obtained following a spontaneous crystallisation from the experiment as described. The resulting solid was isolated by filtration, washed twice with 2- methyltetrahydrofuran (21 ml) and dried under vacuum at 40⁰C to yield compound (I) as a white solid (20.12 g, 95%). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.75-1.86 (m, 2H), 2.02- 2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.95 (s, 3H), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7.4Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The XRPD for this compound is shown in Figure 3.

Step 7, alternate 3. Preparation of compound (I). Compound (III) (15.1 g, 45.06 mmol) and compound (XI) (17.31 g, 56.32 mmol) were suspended in 2-methyltetrahydrofuran (46 ml) and heated to 80⁰C. To this yellow suspension was added acetic acid (12 ml, 458 mmol) and the resulting solution was heated to 92° C for 7 hours. 2-methyltetrahydrofuran (100 ml) and water (43 ml) were added and mixture was cooled to 59°C before adding 50%w/w sodium hydroxide (11 ml, 207 mmol), resulting in a temperature rise to 71.5°C. The temperature was adjusted to 69°C and the aqueous phase was discarded after settling. The organic phase was washed with water (2 x 43 ml) and each aqueous phase was discarded after settling. 2-methyltetrahydrofuran (72 ml) was removed by distillation at atmospheric pressure and was replaced by addition of isopropyl alcohol (72 ml). A further 72 ml of solvent was removed by distillation at atmospheric pressure and replaced by isopropyl alcohol (72 ml). Seed was added to induce crystallisation and the resulting mixture was cooled to 15°C. The solid was isolated by filtration, washed twice with isopropylalcohol (32 ml) and dried under vacuum at 40⁰C to yield compound (I) as a white solid (20.86 g, 87%). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 1.04 (d, J= 6Hz, 6H),1.75-1.88 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.7Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.73-3.84 (m, IH), 3.95 (s, 3H), 4.34 (d, J = 4.2Hz, IH), 4.53-4.63 (m, IH), 7.22 (s, IH), 7.29 (dt J= IHz J= 8Hz, IH), 7.51 (dt J= 7Hz, J= 18Hz, 2H), 7.71-7.77 (m, IH), 7.82 (s, IH), 8.37 (s, IH), 9.57 (s, IH). Mass Spectrum: m/z (M+H)+ 474.0. The NMR data include signals for 1 mole equivalent isopropanol present. The XRPD for this compound is shown in Figure 4.

Example 3. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy } quinazoline di- [(2E)-but-2-enedioate] (compound (I) difumarate salt). Compound (I) difumarate salt was prepared according to the scheme shown below:

Compound (III) Compound (IV) Compound (V)

Compound (Xl)

Difumarate Compound (I)

Steps 1, 2, 3, 4, 5 and 6 were performed as set forth in Example 2. Step 7. Preparation of compound (I) difumarate salt. Compound (III) (17.90 mmoles) and N, ΛT-bis(3-chloro-2-fluorophenyl)imidoformamide (compound (XI)) (7.04 g, 23.27 mmoles) were suspended in tert-butyl alcohol (88.95 g). To this suspension fumaric acid (10.39 g, 89.52 mmoles) was added and the mixture was heated to 80⁰C, with stirring, for 2.5 hrs. Water (11.40 g, 632.80 mmoles) was charged and the reaction continued for a further 21.5 hrs. The reaction was cooled to 20⁰C over 12 hours, during which time crystallisation occurred. The resulting solid was isolated by filtration and was washed with a mixture of water (1.00) and tert-butyl alcohol (7.80 g) followed by a wash with a mixture of water (0.50 g) and tert-butyl alcohol (7.30 g). The solid was dried in vacuo at 40 ⁰C to give compound (I) difumarate salt (8.17 g, 61.40%) as a mustard yellow powder; ¹H NMR (400 MHz, DMSO- dβ) δ ppm 1.83 (m, 2 H, broad) 2.07 (m, 2 H, broad) 2.64 (d, J=5.0 Hz, 3 H) 2.80 (m, 2 H, broad) 3.03 (s, 2 H) 3.94 (s, 3 H) 4.58 (m, 1 H) 6.63 (s, 4 H) 7.22 (s, 1 H) 7.29 (td, J=8.5, 1.0 Hz, 1 H) 7.51 (m, 2 H) 7.82 (m, 2 H) 8.37 (s, 1 H); Mass Spectrum: m/z (M+H)⁺ 474.0. Example 4. Preparation of 4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-{[l-(N- methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline (compound (I)).

Compound (I) was prepared according to the scheme shown below:

Compound (III) Compound (IV)

Compound (V)

Compound (XII)

Compound (I)

Steps 1, 2, 3, 4 and 5 were performed as set forth in Example 2.

Step 6. Preparation of N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)). 3-chloro-2-fluroaniline (5.30 g, 35.29 mmoles) was dissolved in 2- methyltetrahydrofuran (52.94 g). To this N,N-dimethylformamide dimethyl acetal (6.07 g, 49.41 mmoles) and acetic acid (0.11 g, 1.76 mmoles) were added. The resulting reaction mixture was heated, with stirring, to 76 ⁰C for 3 hours. Following this the solvent was removed in vacuo at 40⁰C to give compound (XII) as a yellow oil (6.60 g, 93% yield); IH NMR Spectrum (400 MHz, DMSO-d6) δ ppm 2.74 (s, 0.29H), 2.89 (s, 0.31H), 2.94 (s, 2.75H), 3.03 (s, 2.66H), 3.34 (br s, 0.70H), 5.48 (s, 0.06H) 6.91-7.10 (m, 3H), 7.79 (s, 1 H), 7.96 (s, 1 H). The NMR data above includes signals for N,N-dimethylformamide dimethyl acetal which is present in a 0.06 molar equivalence. The signals pertaining to N₅N- dimethylformamide dimethyl acetal are at δ ppm shifts of 3.75, and 6.90-6.95. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum (by LCMS EI): m/z (M+H)⁺ 201.2. Step 7: Preparation of compound (I). 2-[4-(4-Amino-5-cyano-2- methoxyphenoxy)piperidin-l-yl]-N-methylacetamide (compound (III)) (0.50 g, 1.45 mmol) and N’-(3-chloro-2-fluoro-phenyl)-N,N-dimethyl-formamidine (compound (XII)) (0.32 g, 1.52 mmol) were suspended in methoxybenzene (3.1 ml). To this yellow suspension was added acetic acid (1.52 ml, 25.51 mmol) and the resulting solution was heated to 90 ⁰C for 14 hours. The reaction mixture was cooled to 20 ⁰C and water (2.58 mL) was added. The organic layer was removed and the aqueous layer washed with methoxybenzene (1.4 mL). Ethanol (2.45 mL) and ammonia (1.94 ml, 25.55 mmoles) were added to the aqueous layer. The solution was heated to 90⁰C resulting in the loss of some ethanol by evaporation. The solution was cooled to 40 ⁰C. Seed was added to induce crystallisation and the resulting mixture was cooled to 20 ⁰C. The solid was isolated by filtration to yield compound (I) as a white solid (0.61 g, 73% yield). IH NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.87 (m, 2H), 2.02-2.15 (m, 2H), 2.35-2.44 (m, 2H), 2.64 (d, J= 4.8Hz, 3H), 2.72-2.80 (m, 2H), 2.95 (s, 2H), 3.35 (s, 5.4H), 3.75 (s, 1.3H), 3.95 (s, 3H), 4.58 (hept., J=4.0Hz, IH), 6.90-6.95 (m, 1.3H), 7.23 (s, 1.8H), 7.26-7.34 (m, IH), 7.45-7.58 (m 2H), 7.72-7.78 (m, IH), 7.83 (s, IH), 8.38 (s, IH), 9.58 (s, IH). The NMR data above includes signals for the methoxybenzene solvent which is present in a 0.40 molar equivalence. The signals pertaining to the solvent are at δ ppm shifts of 3.75, and 6.90-6.95. The cluster at 7.26-7.34 contains signals for the solvent and the parent compound. The signal at δ ppm 3.35 is due to residual water. Mass Spectrum: m/z (M + H)+ 474.0, 476.0. Example 5. Preparation of compound (I) difumarate Form A – 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (2.7 g, 23.22 mmol) in methanol (95 ml) was added to a mixture of 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (5.62 g at 89% w/w, 10.55 mmol) in isopropanol (100 ml) maintaining the temperature >65°C. The mixture was heated at reflux for one hour before clarification. The reaction mixture was cooled to 30⁰C over 90 minutes and held for 30 minutes to establish crystallisation. The reaction was cooled to 0⁰C over 2 hours and held for 1 hour before isolation by filtration. The filter cake was washed twice with cold isopropanol (2 x 10 ml) and dried in vacuo at 50⁰C to give the title compound as a white solid (5.84 g, 78%); ¹H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 6. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. A solution of fumaric acid (1.4 kg, 12.1 mol) in methanol (26.6 kg) was added to a mixture of 2-[4-({4-[(3-chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (2.93 kg, 84.8% w/w, 5.24 mol) in isopropanol (39 kg) maintaining the temperature >65°C. A line wash of methanol (3.6 kg) was charged. The mixture was heated at reflux for one hour before clarification, followed by a line wash of methanol (7 kg). The reaction mixture was distilled at atmospheric pressure to remove 47 kg of distillates. Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 0⁰C over 8 hours and held for 1 hour before isolation by filtration. The filter cake was washed with cold 50:50 isopropanol:MeOH (4 kg) followed by cold isopropanol (4 kg) and dried in vacuo at 50⁰C to give the title compound as a white solid (3.64 kg, 98%); ¹H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 7. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (60.19 g at 88% w/w, 111.8 mmol) was dissolved in ethyl acetate (1550 ml). The solution was clarified by filtration and the filter washed with ethyl acetate (53 ml). The solution was cooled to 40⁰C. A clarified solution of fumaric acid (26.60 g, 257.0 mmol) in isopropanol (408 ml) was then added over 1 hour. The filter used to clarify the fumaric acid solution was then washed with isopropanol (37 ml). After holding for 1 hour at 40⁰C the reaction was cooled to 20⁰C over 1 hour. The reaction mixture was held for 13.5 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (82 ml) : isopropanol (24 ml) and then dried in vacuo at 40⁰C to give the title compound as a white solid (72.32 g, 90%); ¹H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH). Example 8. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (2.75 g at assumed 100% w/w, 5.80 mmol) was dissolved in ethyl acetate (94 ml) and isopropanol (14 ml). The solution was distilled such that 25.2 ml of distillates were collected. The solution was cooled to 40⁰C. A clarified solution of fumaric acid (1.38 g, 11.90 mmol) in isopropanol (21 ml) was then added over 1 hour. Compound (I) difumarate Form A seed was added (3.7 mg, 5.3 μmol). The filter used to clarify the fumaric acid solution was then washed with isopropanol (2 ml). After holding for 1 hour at 40⁰C the reaction was cooled to 20⁰C over 2 hours. The reaction mixture was held for 15 hours before isolating the product by filtration. The filter cake was washed twice with ethyl acetate (4.3 ml): isopropanol (1.2 ml) and then dried in vacuo at 40⁰C to give the title compound as a white solid (72.32 g, 90%); ¹H NMR Spectrum: (DMSO) 1.85 (m, IH), 2.08 (m, IH), 2.50 (m, IH), 2.66 (d, 3H), 2.83 (m, IH), 3.05 (s, 2H), 3.96 (s, 3H), 4.58 (m, IH), 6.64 (s, 4H), 7.23 (s, IH), 7.28 (m, IH), 7.46 (ddd, IH), 7.55 (m, IH), 7.70 (broad q, IH), 7.85 (s, IH), 8.38 (s, IH).

Example 9. Preparation of compound (I) difumarate Form A: 2-[4-({4-[(3-Chloro-2- fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide di- [(2E)-but-2-enedioate] Form A. 2-[4-({4-[(3-Chloro-2-fluorophenyl)amino]-7- methoxyquinazolin-6-yl}oxy)piperidin-l-yl]-N-methylacetamide (compound (I)) (1 g, 1.86 mmoles) and fumaric acid (0.44 g, 3.81 mmoles) were suspended in water (4.4 g) and heated to 85°C. The reaction mixture was cooled to 60⁰C at l°C/minute and compound (I) Form A seed was added when the temperature was 77°C. The resulting solid was isolated by filtration, washed twice with acetone (0.7O g per wash) and dried in a vacuum oven at 40⁰C to afford the title compound (0.89 g, 68% yield), IH NMR (400 MHz, DMSO-d6) d ppm 1.84 (m, 2 H) 2.08 (m, 2 H) 2.55 (m, 2 H) 2.63 (d, J=4.7 Hz, 3 H) 2.86 (m, 2 H) 3.12 (s, 2 H) 3.93 (s, 3 H) 4.59 (tt, J=7.8, 3.7 Hz, 1 H) 6.62 (s, 4 H) 7.21 (s, 1 H) 7.27 (td, J=8.1, 1.3 Hz, 1 H) 7.49 (m, 2 H) 7.86 (m, 2 H) 8.36 (s, 1 H) 9.63 (br. s., 1 H). Compound (I) difumarate Form A is a free flowing powder.