Triethylamine → 2-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamide

HRID 1058310Notes

Reaction equation

HRID 1058310 reaction equation
N[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH:27][C:28]1([C:41]([N:43]2[CH2:50][CH2:49][CH2:48][C@H:44]2[C:45](O)=[O:46])=[O:42])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2.C([N:53](CC)CC)C.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[C:16]([Si:13]([CH3:14])([CH3:15])[O:12][CH2:11][CH:10]([C:4]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=1[CH2:2][C@@:44]1([C:45]([NH2:53])=[O:46])[CH2:48][CH2:49][CH2:50][N:43]1[C:41]([C:28]1([OH:27])[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:42])[NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH3:17])([CH3:18])[CH3:19]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 181649HOAtHCID 590382169-hydroxy-9-fluorenylcarbonyl-L-prolineHCID 69939402N-(1-[2-(aminomethyl)-4-chlorophenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-methylpropane-2-sulfinamide

Product 1

HCID 865857742-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamideYield 61%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of diastereomer A of N-(1-[2-(aminomethyl)-4-chlorophenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-methylpropane-2-sulfinamide (from the previous step, 67 mg, 0.16 mmol, 1.07 eq), 1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-proline (48 mg, 0.15 mmol, 1.0 eq (43 mg, 0.22 mmol, 1.5 eq), triethylamine (22 μL, 0.16 mmol, 1.07 eq) and HOAt (10 mg, 0.08 mmol, 0.5 eq) in anhydrous DMF (1 mL) was stirred at room temperature overnight. Most of the DMF was removed in vacuo and the residue was purified by silica gel chromatography (isocratic elution, 1:1 EtOAc:hexanes) to afford diastereomer A of N-(2-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamide as a white solid (66 mg, 61%). 1H NMR (400 MHz, CDCl3): δ 7.66-7.64 (m, 2H), 7.44-7.00 (m, 9H), 5.91 (m, 1H), 4.71-4.58 (m, 3H), 4.40 (m, 1H), 4.35 (br s, 1H), 3.75 (dd, J=4.4, 10.3 Hz, 1H), 3.67 (apparent t, J=9.7 Hz, 1H), 2.38-2.28 (m, 2H), 2.02 (m, 1H), 1.81 (m, 1H), 1.65 (m, 1H), 1.45 (m, 1H), 1.23 (s, 9H), 0.91 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H). LCMS RT=3.05 min, (M+H)=724.6. Diastereomer B of the amine (17 mg from previous step) was coupled and purified under similar conditions to afford diastereomer B of N-(2-{2-{[tert-butyl(dimethylsilyl)oxy}-1-[(tert-butylsulfinyl)amino]ethyl}-5-chlorobenzyl)-1-[(9-hydroxy-9H-fluoren-9-yl)carbonyl]-L-prolinamide a a pale yellow oil (20 mg) which still contained traces of triphenylphosphine oxide from the previous step. LCMS RT=3.01 min, (M+H)=724.6.

Workup

  1. customMost of the DMF was removed in vacuo
  2. customthe residue was purified by silica gel chromatography (isocratic elution, 1:1 EtOAc:hexanes)

Sources & evidence

ORD record
ord-47b147706a9b44c88fd47437681e4086
Source dataset
uspto-grants-2003_02
Patent number
US06515011B2

Reaction notes

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