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Industrial Scale Preparation of Regorafenib (Stivarga)
2015-05-10 07:04:29

Industrial Scale Preparation of  Regorafenib (Stivarga)

瑞格非尼(瑞戈非尼, Regorafenib)的制备方法
摘要:4-(4-氨基-3-氟苯氧基)-2-(甲基氨甲酰基)吡啶,与4-氯-3-(三氟甲基)苯异氰酸酯缩合

Industrial Scale Preparation of Stivarga-Regorafenib from Bayer for metastatic colorectal cancer- Regorafenib的制备方法

Preparation of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride

420 g of a solution of 4-chloro-N-methylpyridine-2-carboxamide (prepared according to WO2006/034796) in toluene (approx. 30 % w/w) and 48.8 g of ethanol were charged into a reaction flask. 67.2 g of acetyl chloride was added with stirring to such a degree that the temperature of the reaction mixture did not exceed 30°C. After stirring further at room temperature for 1.5 h the product was filtered off, washed with toluene (212 g) and dried under reduced pressure (30°C, 80 mbar) . In this way 156 g (quantitative yield) of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride were obtained. purity: >98% (Rt = 17.9 min.). m.p. 173.5-174.5°C 1H-NMR (500MHZ, DMSO-d6): δ [ppm]= 2.93 (d, 3H), 7.79 – 7.97 (m, 1H), 8.13 – 8.26 (m, 1H), 8.71 (d, 1H), 9.03 (br. s., 1H), 13.16 (br. s., 1H). MS [DCI, NH3]: m/e = 171 [M+H]+ (M = free base).

Preparation of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

Method A (use 3-methyl-2-butanone to prepare the imine compound): A reaction flask with stirrer was charged with 41.4 g of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g of toluene as solvent. After addition of 68.4 g of water and 19.6 g of an aqueous sodium hydroxide solution (45 %> w/w) the reaction mixture was stirred for 30 minutes. The two phases were separated and the aqueous layer was discarded. The organic layer was concentrated by distillation under vacuum and toluene was substituted by 1 -methyl-2-pyrrolidinone (70 g) to yield a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1 -methyl-2-pyrrolidinone. A second reaction flask with stirrer was charged with 26.7 g of 4-amino-3-fluorophenol and 100 g of 3-methyl-2-butanone. By heating to reflux and additional stirring for 3 hours water was removed by azeotropic distillation. Then the excess 3-methyl-2-butanone was removed by distillation under vacuum and substituted by 1 -methyl-2-pyrrolidinone (70 g) to prepare a solution containing the imine compound. To the resulting reaction mixture the solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1 -methyl-2-pyrrolidinone was added. The reaction mixture was heated to approximately 100°C. 123.2 g of potassium-t-butoxide in tetrahydrofuran (20%> w/w) was added dropwise (within approx. 3 hours) whilst tetrahydrofuran was removed by distillation. Thereafter the reaction mixture was stirred for additional 2.5 hours at 100°C to complete the reaction. After adjusting to 80°C 350 ml of toluene of 392 ml water and of 8 g acetic acid were added. The mixture was stirred for 10 minutes at 80°C, cooled down to 50°C and seeded with crystals of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. After cooling to 0°C the suspension was stirred for approximately 30 minutes. The product was filtered off, washed with methanol / water (1 :3 v/v, 144 ml) and dried under reduced pressure (30°C, 80 mbar). In this way 44.4 g ( 84 % of theory) of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide were obtained as light brown crystals. purity: >99% (Rt = 9.1 min.). m.p. 142.2-142.8°C 1H-NMR (400MHZ, DMSO-d6): δ [ppm]= 2.83 (d, 3H), 5.27 (s, 2H), 6.78 – 6.85 (m, 1 H), 6.86 -6.94 (m, 1 H), 7.01 – 7.07 (m, 1 H), 7.09 – 7.14 (m, 1H), 7.41 (d, 1H), 8.49 (d, 1H), 8.71 – 8.87 (m, 1H). MS [ES]: m/e = 262 [M+H]+

Method B (use 4-methyl-2-pentanone to prepare the imine compound): A reaction flask with stirrer was charged with 41.4 g of 4-chloro-N-methyl-pyridine-2-carboxamide hydrochloride and 100 g of toluene as solvent. After addition of 68.4 g of water and 19.6 g of an aqueous sodium hydroxide solution (45 % w/w) the reaction mixture was stirred for 30 minutes. The two phases were separated and the aqueous layer was discarded. The organic layer was concentrated by distillation under vacuum and toluene was substituted by 1 -methyl-2-pyrrolidinone (70 g) to yield a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1 -methyl-2-pyrrolidinone. A second reaction flask with stirrer was charged with 26.7 g of 4-amino-3-fluorophenol and 100 g of 4-methyl-2-pentanone. By heating to reflux and additional stirring for 1 hour water was removed by azeotropic distillation. Then the excess 4-methyl-2-pentanone was removed by distillation under vacuum and substituted by 1 -methyl-2-pyrrolidinone (70 g) to prepare a solution containing the imine compound. To the resulting reaction mixture the solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1 -methyl-2-pyrrolidinone was added. The reaction mixture was heated to approximately 100°C. 123.2 g of potassium-t-butoxide in tetrahydrofuran (20%> w/w) was added dropwise (within approx. 70 minutes) whilst tetrahydrofuran was removed by distillation. Thereafter the reaction mixture was stirred for additional 3 hours at 100°C to complete the reaction. After adjusting to 80°C 350 ml of toluene, of 392 ml water and 8 g of acetic acid were added. The mixture was stirred for 10 minutes at 80°C, cooled down to 50°C and seeded with crystals of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide. After cooling to 0°C the suspension was stirred for approximately 30 minutes. The product was filtered off, washed with methanol / water (1 :3 v/v, 144 ml) and dried under reduced pressure (30°C, 80 mbar). In this way 40.7 g (78 % of theory) of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide were obtained as brown crystals. purity: >97% (Rt = 9.2 min.). m.p. 140.5-141.2°C 1H-NMR (400MHZ, DMSO-d6): δ [ppm]= 2.86 (d, 3H), 5.24 – 5.35 (s, 2H), 6.80 – 6.86 (m, 1 H), 6.89 – 6.99 (m, 1 H), 7.01 – 7.09 (m, 1H), 7.09 – 7.15 (m, 1H), 7.45 (d, 1H), 8.49 (d, 1H), 8.75 -8.85 (m, 1H). MS [ES]: m/e = 262 [M+H]+

4-{4-[({[4-chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate (Regorafenib monohydrate, active ingredient of f Stivarga®)

A reaction flask with stirrer was charged with 20.0 g of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide and 180 g of tetrahydrofuran as solvent. A solution of 18.7 g of 4-chloro-3-trifluoromethyl-phenylisocyanate and 21.1 g of toluene was added dropwise within approximately 90 minutes at room temperature. The resulting solution was stirred for 3 hours to complete the reaction. After then 30 g of tetrahydrofuran and 7.8 g of methanol were added to the reaction mixture. Following 9.0 g of acetyl chloride were added dropwise within 15 minutes to the reaction mixture. After additional stirring for approximately 2 hours the suspension was filtered and the solid was washed with tetrahydofuran (18.2 g) and acetone (136.4 g). The solid was added to a mixture of acetone (268.6 g), water (55.8 g) and an aqueous sodium hydroxide solution (8.2 g, 45 % w/w) at 40°C. The mixture was stirred for additional 30 minutes. Then the crystallization was initiated by seeding with crystals of 4- {4-[({[4-chloro-3-(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide monohydrate. After cooling to 20°C 31.6 g of water were added. The suspension was cooled down to approx. 3°C and stirred for 30 minutes. The product was filtered off, washed with a cold mixture of acetone (106 g) and water (44 g) and dried under reduced pressure (30°C, 80 mbar). In this way 31.8 g (83 % of theory) o f 4- {4-[({ [4-chloro-3 -(trifluoromethyl)-phenyl] amino} carbonyl)amino] -3 -fluorophenoxy} -N-methylpyridine-2-carboxamide monohydrate were obtained as white crystals. 1H-NMR (500MHz, METHANOL-d4) : δ [ppm]= 2.94 (s, 3H), 6.96 – 7.01 (m, 1H), 7.05 -7.1 1 (m, 2H), 7.49 – 7.53 (m, 1H), 7.56 – 7.59 (m, 1H), 7.61 – 7.65 (m, 1H), 8.00 – 8.03 (m, 1H), 8.15 – 8.20 (m, 1H), 8.46 – 8.51 (m, 1H). MS [ES] : m/e = 483 [M+H]+

References for the Preparation of Regorafenib (Stivarga)

1)Stiehl, juergen;heilmann, werner ;lögers, michael;rehse, joachim;gottfried, michael;wichmann, saskia; Process for the preparation of 4- {4-[({[4 -chloro-3 -(trifluoromethyl)-phenyl]amino}carbonyl)amino]-3-fluorophenoxy}-n-methylpyridine-2-carboxamide, its salts and monohydrate; PCT Int. Appl.,WO2011/128261

2)Stephen Boyer, Jacques Dumas, Bernd Riedl, Scott Wilhelm; Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions; US patent Publication number: US 2005/0038080 A1; PCT Int. Appl., WO2005009961

Note:

4-chloro-N-methylpyridine-2-carboxamide and its hydrochloride acid salt is commercially  available or can be prepared as described in patent application WO2006/034796, or WO2005/009961 or in Bankston et al. Organic Process Research and Development, 2002, 6, 777-781

4-chloro-3-trifluoromethyl-phenylisocyanate is commercially available or can be prepared as described in patent application WO2000/42012


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