IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVE AS KINASE INHIBITOR (Thu, 09 Apr 2015)
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| Applicants: | DAIICHI SANKYO CO LTD |
https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=3621180C3C0EB083D28A2B4331B0C9E3.wapp2nC?docId=EP132319905&recNum=1&maxRec=392&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3A%28daiichi+sankyo%29&tab=PCTDescription
[Reference Example 39]
tert-Butyl N-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate
[0201]
[Step 1]
tert-Butyl N-[1-(hydroxymethyl)cyclopropyl]carbamate
[0202] A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid (5 g) in tetrahydrofuran was cooled to -20°C. Isobutyl chloroformate (3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and the mixture was stirred at the same temperature as above for 20 minutes. Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto, and the mixture was further stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.24 g).
1H-NMR (CDCl3) δ: 0.81-0.85 (4H, m), 1.44 (9H, s), 3.43 (1H, br s), 3.59 (2H, d, J = 4.8 Hz), 5.07 (1H, br s).
[Step 2]
[1-(tert-Butoxycarbonylamino)cyclopropyl]methyl methanesulfonate
[0203] The title compound (3.93 g) was obtained by the same procedures as in step 1 of Reference Example 25 using the compound (3.21 g) obtained in the preceding step 1.
1H-NMR (CDCl3) δ: 0.92-0.96 (4H, m), 1.44 (9H, s), 3.03 (3H, s), 4.25 (2H, s), 5.06 (1H, br s).
[Step 3]
tert-Butyl N-[1-[(4-bromophenoxy)methyl]cyclopropyl]carbamate
[0204] The title compound (0.43 g) was obtained by the same procedures as in step 2 of Reference Example 25 using the compound (2.05 g) obtained in the preceding step 2. 1H-NMR (CDCl3) δ: 0.89-0.92 (4H, m), 1.43 (9H, s), 3.94 (2H, s), 5.11 (1H, br s), 6.77 (2H, d, J = 9.1 Hz), 7.36 (2H, d, J = 9.1 Hz).
[Step 4]
tert-Butyl N-[1-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl]cyclopropyl]carbamate
[0205] The title compound (0.39 g) was obtained by the same procedures as in step 2 of Reference Example 1 using the compound (0.43 g) obtained in the preceding step 3. 1H-NMR (CDCl3) δ: 0.89-0.92 (4H, m), 1.33 (12H, s), 1.42 (9H, s), 3.99 (2H, s), 5.14 (1H, br s), 6.88 (2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz).
