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With NaH; In water; ethyl acetate; N,N-dimethyl-formamide; |
(b) tert-butyl (3-bromophenyl)methylcarbamate 9.33 g (0.22 mol) of NaH at 60% in oil and 250 ml of DMF are introduced under nitrogen into a round-bottomed flask. 53 g (0.18 mol) of (3-bromophenyl)carbamic acid tert-butyl ester in solution in 150 ml of DMF are added dropwise. After 10 minutes, 14.5 ml (0.22 mmol) of methyl iodide are added dropwise. The mixture is stirred at room temperature for 30 minutes. After filtration of the NaI and evaporation of the DMF, the medium is solubilized in 350 ml of ethyl acetate and washed with twice 300 ml of water. After drying over sodium sulphate and evaporation of the solvents, 55 g (98%) of tert-butyl (3-bromophenyl)methylcarbamate are obtained in the form of a yellow liquid. |
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With sodium hydride; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;Heating / reflux; |
A solution of 3-bromoaniline Compound 21a (2 mL, 18.4 mmol), di-tert-butyl dicarbonate (4. [05G,] 18.6 mmol) in THF (20 mL) was heated to reflux for 30 h under [N2.] The mixture was evaporated under reduced pressure, and the residue was dissolved in EtOAc. The solution was washed with saturated [NAHC03] solution and brine. The organic layer was dried over [MGS04,] filtered, and evaporated, to yield Compound 21b. MS (ES+) m/z [256. 8/258.] 8 [(M-CH3).] Sodium hydride (60% in oil; 0. [78G,] 19.5 mmol) was added in small portions to a solution of Compound 21b (4. [18G,] 15.4 mmol) and methyl iodide (1.21 mL, 19.5 mmol) in DMF [(50] mL) at [0 C.] The resulting mixture was allowed to warm to rt and stirred for 1 h. The mixture was poured in ice-water and extracted with EtOAc. The organic layer was separated, dried over [MGS04,] filtered, and evaporated under reduced pressure to yield Compound [21C.] MS, (ES+) m/z 270.9/272. 9 [(M-CH3).] [ ] Using the procedure described in Example 12 for converting Compound 12b to Compound 12d, Compound 21c was converted to Compound 21d. MS (ES+) m/z 455.0 [ (M+NA+).] Using the procedure described in Example 12 for converting Compound 12d to Compound 12e, Compound 21d was converted to Compound 21e. MS (ES+) m/z 510.9 [(M+NA+).] Using the procedure described in Example 12 for converting Compound 12e to Compound 12f, Compound [21E] was converted to Compound 21f. MS (ES+) m/z 512.8 (M+Na+). Using the procedure described in Example 12 for converting Compound 12f to Compound 12g, Compound 21f was converted to Compound 21g. MS (ES+) m/z 291.0 (M+H+). Using the procedure described in Example 12 for converting Compound 12g to Compound 12h, Compound 21g was converted to Compound 21h. MS (ES+) m/z 479.0 [(M+H+).] Using the procedure described in Example 12 for converting Compound 12h to Compound 11, Compound 21h was converted to Compound 79. MS (ES+) m/z 465.0 [(M+H HNMR (DMSO-D6,] 300 MHz) [8] 0.99 [(M,] 2H), 1.21 [(M,] 1H), 1.4-1. 65 [(M,] 3H), 1. [72] (m, 1H), 1.86 [(M',] 2H), 2.3-3. 0 (m, 13H), 3.17 (m, 1H), 3.42 (m, 2H), 3.87 (dd, J= =17. 7 Hz, [J =] 15.2 Hz, 1H), 4.40 (dd, J= 15.2 Hz, J= =11. 6 Hz, [1H),] 6.41 (d, J= [7.] 5 Hz, 1H), 7.1-7. 4 (m, [5H).] |
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General procedure: To a stirred solution of 8a (232 mg, 0.63 mmol) in DMF (7.0 mL) at 0C was added NaH (60%in mineral oil, 61.5 mg, 1.54 mmol) and the reaction mixture was allowed to warm up to RT over30 min. 6c (171 mg, 0.63 mmol) was added and the mixture was stirred for 2 hours. The reactionmixture was added dropwise into 2.0 M HCl (20 mL), extracted with DCM (30 mL × 3), and thecombined organic fractions were concentrated. Purification by silica gel chromatography(40%60% EtOAc/hexanes) afforded 9c (266 mg, 76%) as a white powder. |
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