Sodium hydride → HCID 58005107, compound

HRID 1879255Notes

Reaction equation

HRID 1879255 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]1OCCOCCOCCOCCOCCOC1.[H-].[Na+].[Br:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]Br)[CH:45]=2)[CH:41]=[CH:42][CH:43]=1.[Si](C=[N+]=[N-])(C)(C)C>CN(C=O)C>[Br:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][O:16][C@H:14]3[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:10]([O:12][CH3:17])=[O:11])[CH2:13]3)[CH:45]=2)[CH:41]=[CH:42][CH:43]=1

Participants

7

Reactant 5

HCID 24758Sodium hydrideHCID 2855718-Crown-6HCID 88804(2S,4R)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acidHCID 167693TrimethylsilyldiazomethaneHCID 58005152HCID 58005152, compound

Product 1

HCID 58005107HCID 58005107, compoundYield 78%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

(4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (1.0 eq.) in DMF was added to a 0° C. cooled suspension of 18-crown-6 (0.1 eq.) and NaH (3.0 eq.) in DMF (0.5 M final concentration). The reaction mixture was allowed to warm up to RT and stirred for 1 h. A 0.5M solution of 3-bromo-3′-(bromomethyl)biphenyl 95 (1.0 eq.) in DMF was added dropwise and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with aqueous HCl (1N) at 0° C. and diluted with EtOAc. The organic layer was separated, washed with aqueous HCl (1N) and brine, dried (Na2SO4) and evaporated to a solid. MS (ES+) m/z 498, 500 (M+Na)+. A 0.5 M solution of the crude material in a mixture of toluene:MeOH (2:1) was cooled to 0° C. and treated dropwise with TMS-diazomethane (1.5 eq.). The reaction mixture was allowed to warm up to RT and stirred for 1 h. The solvents were evaporated under reduced pressure and the residue was purified by flash chromatography (SiO2, PE:EtOAc=8:2) to afford the title compound 96 as a yellow oil (78%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.90-7.86 (m, 1H), 7.71 (d, J 7.7, 1H), 7.69-7.58 (m, 3H), 7.54-7.44 (m, 2H), 7.40 (d, J 7.7, 1H), 4.66-4.55 (m, 2H), 4.31-4.21 (m, 2H), 3.74-3.65 (m, 3H), 3.60-3.45 (m, 2H), 2.51-2.37 (m, 1H), 2.10-2.00 (m, 1H), 1.44-1.31 (m, 9H). MS (ES+) m/z 512, 514 (M+Na)+.

Workup

  1. temperaturecooled
  2. concentrationconcentration)
  3. stirringthe reaction mixture was stirred at RT overnight
  4. customThe reaction mixture was quenched with aqueous HCl (1N) at 0° C.
  5. additiondiluted with EtOAc
  6. customThe organic layer was separated
  7. washwashed with aqueous HCl (1N) and brine
  8. dry with materialdried (Na2SO4)
  9. customevaporated to a solid
  10. additionA 0.5 M solution of the crude material in a mixture of toluene:MeOH (2:1)
  11. temperaturewas cooled to 0° C.
  12. temperatureto warm up to RT
  13. stirringstirred for 1 h
  14. customThe solvents were evaporated under reduced pressure
  15. customthe residue was purified by flash chromatography (SiO2, PE:EtOAc=8:2)

Sources & evidence

ORD record
ord-3766217f21c046febbdd622c631969fc
Source dataset
uspto-grants-2012_11
Patent number
US08314062B2

Reaction notes

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