| 62% |
With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 50℃; for 18h;Product distribution / selectivity; |
iii) 5-(4-acetyl-[1,4]diazepan-1-yl)-pentanoic acid [5-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-amide5-bromo-pentanoic acid [5-(4-methoxy-phenyl)-1H-pyrazol-3-yl]amide (1.5 g, 4.26 mmol) was dissolved in DMF (15 mL), and sodium iodide (0.64 g, 4.26 mmol) was added followed by N-acetylhomopiperazine (0.56 mL, 4.26 mmol) and diisopropylethylamine (0.74 mL, 4.26 mmol). The reaction was stirred under N2 at 50 C. for 18 hrs. Upon reaction completion (as monitored by LCMS), the solvent was removed at reduced pressure and the resulting oily residue was dissolved in DCM (20 mL), washed with sat. Na2CO3 (2×20 mL) and sat. NaCl (2×20 mL), and dried over Na2SO4. Upon solvent removal, 1.7 g of crude product as a thick oil were obtained. The product was purified by SiO2 chromatography (10 g cartridge-flash SI II from IST) employing DCM and DCM:MeOH 9:1 to yield 0.92 g of pure product and 0.52 g of less pure product. A second purification of the impure fractions using a 5 g SiO2 cartridge was performed using the same eluent. Overall, 1.09 g of 5-(4-acetyl-[1,4]diazepan-1-yl)-pentanoic acid [5-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-amide were obtained (2.64 mmol, 62% yield) as a thick light yellow oil. MS (ES+): 414.26 (M+H)+. |
| 62% |
With N-ethyl-N,N-diisopropylamine; sodium iodide; In N,N-dimethyl-formamide; at 50℃; for 18h;Product distribution / selectivity; |
To a solution of 5-(4-methoxyphenyl)-lH-pyrazol-3-ylamine (12 g, 62.8 mmol) and 7V,7V-diisopropylethylamine (10.96 mL, 62.8 mmol) in dry N,N- <n="63"/>dimethylformamide (150 mL) at -10 0C was added a solution of 5-bromovaleryl chloride (8.4 mL, 62.8 mmol) in dry 7V,7V-dimethylformamide (50 mL) slowly (-40 min) and the reaction mixture was allowed to stir at -10 to 0 0C for 8 hrs. Sodium iodide (9.44 g, 62.8 mmol) was added at 0 0C and followed by N-acetylhomopiperazine (8.24 mL, 62.8 mmol) and 7V,7V-diisopropylethylamine (10.96 mL, 62.8 mmol) and the reaction mixture was allowed to stir at 50 0C for 18 hrs. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (500 mL) and saturated aqueous sodium bicarbonate (500 mL) and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated, dried over sodium sulfate, and the solvent was removed in vacuo to provide 25.8 g (99%) of 5-(4-acetyl-l,4-diazepan-l-yl)-N-(5-(4-methoxyphenyl)-lH- pyrazol-3-yl)pentanamide as a thick light yellow oil (crude).[00228] Then to a solution of the crude 5-(4-acetyl-l,4-diazepan-l-yl)-N-(5-(4- methoxyphenyl)-lH-pyrazol-3-yl)pentanamide (as a free base) in methylene chloride (270 mL) at room temperature was added hydrogen chloride (65 mL, 1.0 M in ethyl ether) slowly. The resulting suspension was allowed to stir at room temperature for 1 hour. The solvent was removed in vacuo to afford 33 g as a yellow foam, mono hydrochloride salt. The foam was dissolved in solvents (330 mL, acetonitrile : methanol = 33 : 1) at 60-70 0C and a crystal seed was added. The mixture was slowly cooled down to the room temperature and allowed to stir at room temperature for 15 hours. The resulting precipitate was filtered and dried to give 20.5 g (72%) of the title compound as a white crystal, mono hydrochloride salt. MS [M-H]" m/z 412.3; mp. 132-133 0C. 1H NMR (400 MHz, DMSO-fc) delta 10.6-10.8 (br, IH), 10.45 (s, IH), 7.64 (d, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz, 2H), 6.74 (s, H), 4.00(m, IH), 3.77 (s, 3H), 3.4-3.6 (m, 6H), 2.9-3.0 (m, 5H), 2.34 (m, 2H), 2.0 (s, 3H), 1.65-1.70 (m, 2H), 1.55-1.65 (m, 2H).;5-bromo-pentanoic acid [5-(4-methoxy-phenyl)-lH-pyrazol-3-yl]amide(1.5 g, 4.26 mmol) was dissolved in DMF (15 mL), and sodium iodide (0.64 g, 4.26 mmol) was added followed by N-acetylhomopiperazine (0.56 mL, 4.26 mmol) and diisopropylethylamine (0.74 mL, 4.26 mmol). The reaction was stirred under N2 at 50 0C for 18 hrs. Upon reaction completion (as monitored by LCMS), the solvent was removed at reduced pressure and the resulting oily residue was dissolved in DCM (20 mL), washed with sat. Na2CO3 (2 x 20 mL) and sat. NaCl (2 x 20 mL), and dried over Na2SO4. Upon solvent removal, 1.7 g of crude product as a thick oil were obtained. The product was purified by SiO2 chromatography (1O g cartridge-flash SI II from 1ST) employing DCM and DCM:MeOH 9: 1 to yield 0.92 g of pure product and 0.52 g of less pure product. A second purification of the impure fractions using a 5 g SiO2 cartridge was performed using the same eluent. Overall, 1.09 g of 5-(4-acetyl-[l,4]diazepan-l-yl)-pentanoic acid <n="67"/>[5-(4-methoxy-phenyl)-lH-pyrazol-3-yl]-amide were obtained (2.64 mmol, 62% yield) as a thick light yellow oil. MS (ES+): 414.26 (M+H)+. |
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Bromopyrazole is mixed with K2CO3 and KI in 10 volumes of acetone at room temperature and N-acetylhomopiperazine was added over 1 hr. The reaction mixture was stirred until the reaction was complete. The mixture was filtered, removing the inorganics, washed with acetone and distilled to 2 volumes. The freebase was extracted into methyl THF/ EtOH and washed with NaCl and NaHCO3. The solvent was replaced with EtOH, a strength of the solution was determined, and 0.93 eq of HCl based on the available freebase was added to a mixture of acetone, ethanol and water. Careful <n="65"/>monitoring of the pH yielded crystalline product in a 70% overall yield and the desired form 1.;To a cylindrical, jacketed 3 L reactor equipped with nitrogen inerting, agitator, condenser/distillation head, and temperature control, 5-bromo-pentanoic acid [5- (4-methoxy-phenyl)-lH-pyrazol-3-yl]amide (0.15 kg, 0.426 mol), potassium carbonate (0.059 kg, 0.426 mol), potassium iodide (0.071 kg, 0.426 mol), and acetone (1.18 kg, 1.5 L) were added (at 20 0C) to form a white mixture. The mixture was stirred (235 rpm) at 25-30 0C for a minimum of 15 min. N-acetylhomopiperazine (0.062 kg, 0.057 L, 0.434 mol) was added via addition funnel to the reactor over a minimum of 45 min., maintaining the temperature in the range of 25-30 0C. The addition funnel was rinsed with 0.05 L acetone. A white mixture persisted. The mixture was stirred (235 rpm) in the range of 25-30 0C for a minimum of 16 h, forming a white/yellow mixture. The reaction progress was monitored by HPLC and was considered complete when there was < 2% of the starting material (bromopyrazole) and < 2% of the iodopyrazole present. [00240] The reactor contents were cooled to 5-15 0C over a minimum of 15 min with agitation (295 rpm) to form a white/yellow mixture that was then stirred for a <n="68"/>minimum of 1 h. To remove inorganics, the mixture was then filtered on a Buchner funnel with filter paper using house vacuum for 1.5 min. The cake was washed twice with acetone (total of 0.24 kg, 0.30 L) at 5-15 0C. The wash was combined with the mother liquor from the prior filtration and used to rinse the reactor. The filtrate was concentrated to a volume of approximately 0.45 L to form a clear solution. |
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