N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide → N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(4-methyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide

HRID 1296098Notes

Reaction equation

HRID 1296098 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:26])[CH3:25])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=2)[O:13][CH2:12][CH2:11]1.[Cl-].[CH2:32]([Zn+])[C:33]([CH3:36])([CH3:35])[CH3:34]>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:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][C@H:6]([NH:23][C:24](=[O:26])[CH3:25])[C@H:7]([OH:22])[CH2:8][NH:9][C:10]1([CH3:21])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:18]=2)[O:13][CH2:12][CH2:11]1

Participants

4

Reactant 2

HCID 60206838N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamideHCID 178445885HCID 178445885, compound

Product 1

HCID 10322674N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(4-methyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide

Reagents, catalysts & solvents 1

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)Catalyst

Procedure

To a 20 ml serum capped vial containing N-{(1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(6-iodo-4-methyl-3,4-dihydro-2H-chromen-4-yl)amino]propyl}acetamide (0.20 g, 0.37 mmol) and Pd(dppf)Cl2 (0.015 g, 0.018 mmol) under nitrogen was added 3.7 ml of a 0.5 M neopentyl zinc chloride (1.85 mmol) prepared as previously described. The mixture was shaken on an orbital shaker for 12 h at which time LC/MS indicated only a trace of the desired compound. An additional 5 eq. of the zinc reagent and another 5 mol % of catalyst was added and the reaction mixture was warmed to 40° C. After 6 h LC/MS indicated complete consumption of SM. The reaction mixture was quenched with NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacou to yield a light brown solid (150 mg) after flash chromatography (4% MeOH/CHCl3 Biotage 40S). This material was subjected to a final reverse phase preparative column (1% TFA in H2O/0.6% TFA in CH3CN) to yield 50 mg of a light yellow solid. This material was dissolved in 4 ml of CH2Cl2 and treated with 0.5 g of 3-mercaptopropyl functionalized silica gel and stirred at r.t. for 30 min. The mixture was filtered through Celite® to remove the resin and the filtrate concentrated in vacuo to yield a white powder (44 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J=2.07 Hz, 1H), 6.87 (dd, J=8.29, 2.07 Hz, 1H), 6.78 (m, 3H), 6066 (d, J=8.29 Hz, 1H), 4.27 (m, 1H), 4.12 (m, 1H), 4.04 (m, 1H), 3.54 (m, 1H), 3.06 (dd, J=13.99, 3.63 Hz, 1H), 2.56 (m, 2H), 2.45 (bs, 2H), 2.37 (dd, J=11.82, 7.67 Hz, 1H), 2.25 (m, 1H), 1.81 (s, 3H), 1.78 (m, 1H); 1.49 (s, 3H), 0.91 (s, 9H). MS (ESI+) for C27H36N2O3F2 m/z 475.2772 (M+H)+; found, 475.2774.

Workup

  1. customTo a 20 ml serum capped vial
  2. customprepared

Sources & evidence

ORD record
ord-bb04bfdbc1eb4f7eb7afdff22198b906
Source dataset
uspto-grants-2007_07
Patent number
US07244725B2

Reaction notes

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