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With iodine; potassium carbonate In N,N-dimethyl-formamide at 25℃;
EXAMPLE 1: Preparation of N-(5-(hydroxycarbamoyl)pentyl)-2-(3-((E)-2- (pyridin-2-yl)vinyl)-lH-indazol-6-ylthio)benzamide (Compound 15) Step Ia. 3-Iodo-6-nitro-lH-indazole (Compound 102) To a solution of 6-nitroindazole (23 g, 141 mmol) in DMF (100 mL) was added potassium carbonate (39 g, 282 mmol) while maintain reaction temperature to be <30 0C. A solution of iodine (62 g, 244 mmol) pre-dissolved in DMF (50 mL) was added over a period of 2 h while the reaction temperature was maintained <35 0C. The reaction mixture is stirred at 25 0C. After reaction complete, the mixture was then added a solution of sodium thiosulfate (34 g, 215 mmol) and potassium carbonate (0.23 g) pre-dissolved in water (228 ml) while the solution temperature is maintained <30 0C. The mixture is agitated for 20 min at room temperature. Water (340 mL) is added which precipitates solids and the slurry is agitated for 20 min at room temperature. The solid are filtered, washed with water (2x50 mL), and dried in a vacuum oven for 12 h (500C and 25 mmηg) to provide the title compound 102 as a yellow solid (39 g, 95percent yield): LCMS: 289 [M+l]; 1H NMR (DMSOd6): 514.21 (s, 1η), 8.47 (s, 1η), 7.97-8.01 (m, 1η), 7.67-7.70 (d, J= 8.7 Hz, IH).
93.6%
With iodine; potassium carbonate In N,N-dimethyl-formamide at 22 - 35℃; for 6 - 11 h;
6-Nitroindazole (45.08 Kg) is dissolved in DMF (228 Kg) and powdered potassium carbonate (77 Kg) is added while the solution temperate is maintained at <= 3O0C. A solution of iodine (123 Kg) dissolved in DMF (100 Kg) is added over 5 to 6 hours while the reaction temperature is maintained <= 350C. (Caution: the reaction is exothermic). The reaction mixture is agitated for 1 to 5 hours at 220C (until the reaction is complete by HPLC). The mixture is then added to a solution of sodium thiosulfate (68 Kg) and potassium carbonate (0.46 Kg) dissolved in water (455 Kg) while the solution temperature is maintained <= 300C. The mixture is agitated for1.5 hours at 220C. Water (683 Kg) is added which precipitates solids and the slurry is agitated for1 to 2 hours at 220C. The solids are filtered, washed with water (2 x 46 Kg), and dried in a vacuum oven for 24 to 48 hours (5O0C and 25 mm Hg) to provide 74.7 Kg of 3-iodo-6- nitroindazole as a yellow white solid (93.6percent yield with a purity of 86percent by HPLC; KF is 0.2percent).
93.6%
With iodine; potassium carbonate In N,N-dimethyl-formamide at 22 - 35℃; for 6 - 11 h;
Example 1; Preparation of 3-iodo-6-nitroindazole; 6-Nitroindazole (45.08 Kg) is dissolved in N,N-dimethyl formamide (228 Kg) and powdered potassium carbonate (77 Kg) is added while the solution temperate is maintained at <= 3O0C. A solution of iodine (123 Kg) dissolved in N.N-dimethyl formamide (100 Kg) is added over 5 to 6 hours while the reaction temperature is maintained <= 350C. (Caution: the reaction is exothermic). The reaction mixture is agitated for 1 to 5 hours at 220C (until the reaction is complete by HPLC). The mixture is then added to a solution of sodium thiosulfate (68 Kg) and potassium carbonate (0.46 Kg) dissolved in water (455 Kg) while the solution temperature is maintained <= 3O0C. The mixture is agitated for 1.5 hours at 220C. Water (683 Kg) is added which precipitates solids and the slurry is agitated for 1 to 2 hours at 220C. The solids are filtered, washed with water (2 x 46 Kg), and dried in a vacuum oven for 24 to 48 hours (5O0C and 25 mm Hg) to provide 74.7 Kg of 3-iodo-6-nitroindazole as a yellow white solid (93.6percent yield with a purity of 86percent by HPLC; KF is 0.2percent).
79%
With iodine; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
A solution of (39-1) (5 g, 30.6 mmol) was treated with a solution of iodine (6.71 g, 52.9 mmol) in DMF (10 mL) and the mixture was stirred in the presence of Potassium carbonate (8.45 g, 61.2 mmol) at room temperature for 2 hours. After consumption of starting material 39-1, as evident from TLC, an aqueous solution of sodium thiosulfate and water (250 mL) was added. The resulting solution was stirred for 15 min, during which time a precipitate formed. The precipitate was filtered, washed with water and dried in vacuo to afford (39-2) (7.00 g, 24.2 mmol, 79 percent) as a light yellow solid. LCMS: ES- 287.7.
76.2%
With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1 h;
The 6-nitro-indazole 8 (0.500g, 3.07mmol), was dissolved in DMF (30mL) was added iodine (1.55 g), potassium hydroxide (0.640 g), stirred at room temperature for 1h, followed by the addition of 10percent sodium bisulfite solution (100 mL) to the system, and extracted twice with diethyl ether (80mL), the organic phase was washed with water, saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the solvent was spin-dried to give a yellow solid 0.675g, 76.2percent yield,
6.2 g
With iodine; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3 h;
To a solution of 6-nitro-1 /-/-indazole (5 g) and potassium carbonate (8.47 g) in DMF (60 mL) was added a solution of iodine (13.46 g) in DMF (60 mL) dropwise over 15 min, and the reaction mixture was stirred at RT for 3 hr. The reaction mixture was quenched by the addition of saturated sodium thiosulfate (aq) (120 mL) and then diluted with water (150 mL). The resulting solid was collected by filtration and dried under vacuum to afford the titled compound (6.2 g). LCMS m/z 288.14 (M-H)".
Reference:
[1] Organic Process Research and Development, 2015, vol. 19, # 7, p. 849 - 857
[2] Patent: WO2009/36066, 2009, A1, . Location in patent: Page/Page column 51
[3] Patent: WO2006/48745, 2006, A1, . Location in patent: Page/Page column 21
[4] Patent: WO2006/48761, 2006, A2, . Location in patent: Page/Page column 30
[5] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 5, p. 1327 - 1333
[6] Patent: WO2017/197046, 2017, A1, . Location in patent: Page/Page column 335; 336
[7] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 22, p. 5095 - 5099
[8] Patent: CN105753841, 2016, A, . Location in patent: Paragraph 0119; 0120; 0121
[9] Justus Liebigs Annalen der Chemie, 1927, vol. 451, p. 285,302
[10] Patent: US2004/176325, 2004, A1, . Location in patent: Page/Page column 20
[11] Patent: US6531491, 2003, B1,
[12] Patent: US2007/49633, 2007, A1, . Location in patent: Page/Page column 24
[13] Patent: US2010/29733, 2010, A1, . Location in patent: Page/Page column 40
[14] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 1, p. 650 - 662
[15] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1852 - 1856
[16] Patent: CN103739550, 2016, B, . Location in patent: Paragraph 0229-0232
[17] Patent: WO2016/123629, 2016, A1, . Location in patent: Paragraph 0214
[18] Patent: WO2017/153952, 2017, A1, . Location in patent: Page/Page column 211
With dmap; triethylamine In methanol; acetonitrile
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 2h;
1.2
Step 2. 3-Iodo-6-nitro-indazole-1-carboxylic acid tert-butyl ester 3-Iodo-6-nitro-1H-indazole (7.01 g, 24.25 mmol), 4-(dimethylamino)pyridine (4.44 g) and 6.34 mL of N,N-diisopropyl ethylamine were dissolved in 500 mL of CH2Cl2 and the mixture was cooled to 0° C. (BOC)2)O (7.94 g) was added to the stirring mixture, and the mixture was allowed to warm to room temperature with stirring for 2 hours at room temperature. The reaction was quenched by addition of 400 mL H2O, and the organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated under reduced perssure. The residue was chromatographed with silica gel (hexanes/EtOAc 0-80%) to give 7.81 g of 3-Iodo-6-nitro-indazole-1-carboxylic acid tert-butyl ester.
With copper(I) cyanide; In DMF (N,N-dimethyl-formamide); at 185℃; for 0.166667h;Irradiation;
5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (1) cyanide (2 mmol) and N, N-dimethylfonnamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185 C for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10/1 mixture of 3-cyano-6- nitroindazole and 6-nitroindazole as a yellow solid. The 10/1 mixture of 3-cyano-6- nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the bright orange solution was heated at 100 C for 1 h. The mixture was allowed to cool to room temperature and carefully acidified (pH = 1) with 3 N hydrochloric acid. The solid was isolated and triturated with EtOAc to provide 51mg of 6-nitroindazole-3-carboxylic acid as a brown solid. The acid was coupled with the bicyclobase according to procedure A.
With copper(I) cyanide; In DMF (N,N-dimethyl-formamide); at 185℃; for 0.166667h;Microwave irradiation;
A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and N, N-dimethylformamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185 C for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10 to 1 mixture of 3-cyano-6- nitroindazole and 6-nitroindazole as a yellow solid. The 10 to 1 mixture of 3-cyano-6- nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the bright orange solution was heated at 100 C for 1 h. The mixture was allowed to cool to room temperature and carefully acidified to pH 1 with 3 N hydrochloric acid. The solid was isolated and triturated with EtOAc, thus providing 51 mg of 6-nitroindazole-3-carboxylic acid as a brown solid. 3-Iodo-6-nitroindazole was prepared from 6-nitroindazole using the method of Collot, V.; et. al. Tetrahedron 1999, 55, 6917.
In DMF (N,N-dimethyl-formamide); at 185℃; for 0.166667h;Microwave irradiation;
A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and N, N-dimethylformamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185 C for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10/1 mixture of 3- cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The 10/1 mixture of 3- cyano-6-nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the bright orange solution was heated at 100 C for 1 h. The mixture was allowed to cool to room temperature and carefully acidified (pH = 1) with 3 N hydrochloric acid. The solid was isolated and triturated with EtOAc to provide 51mg of 6-nitroindazole-3- carboxylic acid as a brown solid. The acid was coupled with 1,4- diazabicyclo [3.2.2]nonane according to procedure A.
In N,N-dimethyl-formamide; at 185℃; for 0.166667h;Microwave;
A 5 mL microwave reaction vessel was charged with 3-iodo-6-nitroindazole (1 mmol), copper (I) cyanide (2 mmol) and N,N-dimethylformamide (3 mL). The vessel was sealed and subjected to microwave irradiation at 185 C. for 600 sec. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL) and the mixture was filtered through Celite. The organic layer was collected, washed with brine, dried (magnesium sulfate), and concentrated to give 122 mg of a 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole as a yellow solid. The 10/1 mixture of 3-cyano-6-nitroindazole and 6-nitroindazole was dissolved in 10 N sodium hydroxide and the bright orange solution was heated at 100 C. for 1 h. The mixture was allowed to cool to room temperature and carefully acidified (pH =1) with 3 N hydrochloric acid. The solid was isolated and triturated with EtOAc to provide 51 mg of 6-nitroindazole-3-carboxylic acid as a brown solid. The acid was coupled with the bicyclobase according to procedure A. 3-Iodo-6-nitroindazole was prepared from 6-nitroindazole using the method of Collot, C., et al., Tetrahedron, 55, 6917 (1999).
With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine In toluene at 70 - 80℃; Autoclave;