(2S,3R,4R,5S,6R)-2-[3-[(5-ethylthiophen-2-yl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol → 3-Bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene
Reaction equation
[C@@H]1(C2C=CC=C(CC3SC(CC)=CC=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[CH:34]=[C:33]([C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([Br:43])[CH:38]=3)=O)[S:32][C:31]=2[CH:44]=1>>[Br:43][C:39]1[CH:38]=[C:37]([CH2:35][C:33]2[S:32][C:31]3[CH:44]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=3[CH:34]=2)[CH:42]=[CH:41][CH:40]=1Participants
Procedure
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M). (2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was treated in a manner similar to Reference Example 4-(1) to give 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder. ESI-Mass m/Z 195 (M−H). (3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 4-(2) to give 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as colorless powder. APCI-Mass m/Z 240 (M+H). (4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) in tetrahydrofuran (3 ml). The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4). (5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone was treated in a manner similar to Reference Example 5-(2) to give 3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a colorless solid.
Sources & evidence
- ORD record
- ord-6b64b8a3634d40f58278bff59145a8c0
- Source dataset
- uspto-grants-2012_07
- Patent number
- US08222219B2
Reaction notes
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