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With sodium carbonate;palladium diacetate; triphenylphosphine; In propan-1-ol; water; for 1.0h;Heating / reflux;
Solid 3,4-methoxyphenylboronic acid (1.22 g, 6.72 mmol, 1.05 equiv) was added to a solution of <strong>[270912-79-3](5-bromopyrimidin-2-yloxy)acetic acid</strong> 3e (1.5 g, 6.4 mmol) in 1-propanol (50 mL). The suspension was stirred until all ingredients had dissolved. The resulting solution was treated with Pd(OAc)2 (29 mg, 0.13 mmol, 0.02 equiv), PPh3 (103 mg, 0.39 mmol, 0.06 equiv), 2M Na2CO3 (12 mL, 24 mmol, 3.8 equiv), and deionized water (10 mL). The mixture was heated at reflux under N2 for 1 h. Additional water (20 mL) was added and the N2 inlet removed. After cooling to rt, the solution was acidified with 4M HCl. The resulting precipitate was filtered, washed with cold diluted HCl, and dried under vacuum to give 5-(3,4-dimethoxyphenyl)-pyrimidin-2-yloxy)acetic acid 3f as a brown solid (1.30 g, 70%).
The synthesis of (5-bromopyrimidin-2-yloxy)acetic acid 3e followed the protocol described for similar analogues [Coppola, G. M.; Hardtmann, G. E.; Huegi, B. S. J. Heterocyl. Chem. 1980, 17, 1479]. NaH (5.0 g, 60% dispersion in mineral oil, 124 mmol, 1.8 equiv) was washed twice with dry hexane under N2, then added portionwise to a solution of methyl glycolate (9.4 g, 103 mmol, 1.5 equiv) in toluene (150 mL). The mixture was stirred at rt for 30 min, then 5-bromo-3-chloropyrimidine (13.3 g, 69 mmol) in toluene (50 mL) was added. The reaction mixture was heated at 60 C. overnight and concentrated. The residue was stirred rapidly with 1M NaOH (200 mL) for 30 min, washed with ether, then acidified to pH 3 with 4M HCl. The resulting precipitate was collected and washed with cold water. The filtrate was extracted further with ethyl acetate. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The combined materials provided 10.3 g of (5-bromopyrimidin-2-yloxy)acetic acid 3e (64%).
Step 3 The synthesis of (5-bromopyrimidin-2-yloxy)acetic acid followed the protocol described for similar analogues by Coppola, G. M.; Hardtmann, G. E.; Huegi, B. S. J. Heterocyl. Chem., 17, 1479, (1980). Sodium hydride (5.0 g, 60% dispersion in mineral oil, 124 mmol, 1.8 equiv.) was washed twice with dry hexane under N2, then added portionwise to a solution of methyl glycolate (9.4 g, 103 mmol, 1.5 equiv.) in toluene (150 mL). The reaction mixture was stirred at room temperature for 30 min., then 5-bromo-3-chloropyrimidine (13.3 g, 69 mmol) in toluene (50 mL) was added. The reaction mixture was heated at 60 C. overnight and concentrated. The residue was stirred rapidly with 1 M aqueous sodium hydroxide (excess) for 30 min., washed with ether, then acidified to with 4 M hydrochloric acid. The resulting precipitate was collected and washed with cold water. The filtrate was extracted further with ethyl acetate, and the organic phase washed with brine, then dried sodium sulfate and concentrated to give (5-bromopyrimidin-2-yloxy)acetic acid (10.3 g).
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