tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamate → tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamate

HRID 1296090Notes

Reaction equation

HRID 1296090 reaction equation
[Cl-].[CH2:2]([Zn+])[C:3]([CH3:6])([CH3:5])[CH3:4].[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:12][C@H:13]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:14]([OH:28])[CH2:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[O:20][CH2:19][CH2:18]1>C1COCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:12][C@H:13]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[C@H:14]([OH:28])[CH2:15][NH:16][C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:2][C:3]([CH3:6])([CH3:5])[CH3:4])[CH:25]=2)[O:20][CH2:19][CH2:18]1

Participants

6

Reactant 2

HCID 57718592tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamateHCID 178445885HCID 178445885, compound

Product 1

HCID 57718585tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-neopentyl-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamate

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

To neopentyl zinc chloride (prepared as previously described) (51 ml, 11 mmol, 0.2 M in THF) under a nitrogen atmosphere at r.t. was added tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-{[(4S)-6-iodo-3,4-dihydro-2H-chromen-4-yl]amino}propylcarbamate (1.3 g, 2.2 mmol) and Pd(dppf)Cl2 (0.09 g, 0.1 mmol) as solids. The reaction mixture was stirred at r.t. for 12 h and then heated to 50° C. for 8 h. The reaction was cooled to r.t. then quenched with 20 ml of aqueous NH4Cl and extracted with EtOAc (3×100 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield a brown oil. The residue was dissolved in CH2Cl2 and absorbed onto 6 g of silica gel. Flash chromatography (3–5% MeOH/CHCl3 with 20 drops of NH4OH/L, Biotage 40M) yields the desired product, which is identical to the material prepared by the previously described methods.

Workup

  1. customat r.t.
  2. temperatureheated to 50° C. for 8 h
  3. temperatureThe reaction was cooled to r.t.
  4. customthen quenched with 20 ml of aqueous NH4Cl
  5. extractionextracted with EtOAc (3×100 ml)
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated in vacuo
  8. customto yield a brown oil
  9. customabsorbed onto 6 g of silica gel

Sources & evidence

ORD record
ord-43ffd181292c42c4b4cc0e1bbddc1966
Source dataset
uspto-grants-2007_07
Patent number
US07244725B2

Reaction notes

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