Cyclopropanecarboxaldehyde → 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(cyclopropyl(hydroxy)-methyl)-2-fluorobenzamide

HRID 1849755Notes

Reaction equation

HRID 1849755 reaction equation
[C:1]12([CH2:11][O:12][C:13]3[C:28](I)=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:30])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:38]1([CH:41]=[O:42])[CH2:40][CH2:39]1>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[C:28]([CH:41]([CH:38]4[CH2:40][CH2:39]4)[OH:42])=[CH:27][C:16]([C:17]([NH:19][S:20]([N:23]4[CH2:26][CH2:25][CH2:24]4)(=[O:22])=[O:21])=[O:18])=[C:15]([F:30])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2

Participants

5

Reactant 3

HCID 123114CyclopropanecarboxaldehydeHCID 867036064-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamideHCID 178461733HCID 178461733, compound2×

Product 1

HCID 867036374-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-(cyclopropyl(hydroxy)-methyl)-2-fluorobenzamideYield 8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 4-(adamantan-1-ylmethoxy)-N-(azetidin-1-ylsulfonyl)-2-fluoro-5-iodobenzamide (0.20 g, 0.36 mmol) in anhydrous tetrahydrofuran (5 mL) was added isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 0.69 mL, 0.90 mmol) at −40° C. After 1 hour at −40° C., additional isopropylmagnesium chloride lithium chloride complex (1.3 M solution in tetrahydrofuran, 0.28 mL, 0.36 mmol) was added, the reaction mixture warmed to 0° C., and stirred for 1 hour. Cyclopropanecarboxaldehyde (excess) was then added, the reaction mixture was allowed to warm to ambient temperature, and stirred for 16 hours. After quenched with 1 N hydrochloric acid (3 mL), the mixture was diluted with ethyl acetate (50 mL). The combined organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. Concentration of the filtrate in vacuo gave a residue which was purified by reverse-phase preparative HPLC to afford the title compound as a colorless solid (0.015 g, 8%): 1H NMR (300 MHz, DMSO-d6) δ 11.69 (br s, 1H), 7.73 (d, J=8.7 Hz, 1H), 6.91 (d, J=12.7 Hz, 1H), 5.14 (d, J=4.5 Hz, 1H), 4.61 (dd, J=5.7, 4.9 Hz, 1H), 4.02-3.90 (m, 4H), 3.66 (d, J=9.3 Hz, 1H), 3.56 (d, J=9.3 Hz, 1H), 2.19-2.06 (m, 2H), 2.03-1.95 (m, 3H), 1.76-1.57 (m, 12H), 1.18-1.05 (m, 1H), 0.40-0.25 (m, 4H); MS (ES−) m/z 491.2 (M−1).

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstirred for 16 hours
  3. customAfter quenched with 1 N hydrochloric acid (3 mL)
  4. additionthe mixture was diluted with ethyl acetate (50 mL)
  5. washThe combined organic phase was washed with brine (5 mL)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. customConcentration of the filtrate in vacuo gave a residue which
  9. customwas purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-e41712c9f0864e3b82f48169194d1997
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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