Sodium Carbonate → Methyl 4-[(2R)-2-[((tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoate

HRID 896899Notes

Reaction equation

HRID 896899 reaction equation
[Si:1]([O:8][C@H:9]([C:39]1[CH:40]=[N:41][C:42]([N:45]2[C:49]([CH3:50])=[CH:48][CH:47]=[C:46]2[CH3:51])=[CH:43][CH:44]=1)[CH2:10][N:11]([CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[O:21]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:53]1[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCOCC1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd]>[C:14]([O:13][C:12]([N:11]([CH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:53]3[CH:62]=[CH:61][C:56]([C:57]([O:59][CH3:60])=[O:58])=[CH:55][CH:54]=3)[CH:26]=2)[O:21]1)[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[C:39]1[CH:40]=[N:41][C:42]([N:45]2[C:49]([CH3:50])=[CH:48][CH:47]=[C:46]2[CH3:51])=[CH:43][CH:44]=1)=[O:18])([CH3:16])([CH3:15])[CH3:17]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 69273Methyl 4-iodobenzoateHCID 86591803Tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate

Product 1

HCID 59118169Methyl 4-[(2R)-2-[((tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]-oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}benzoateYield 69.1%

Reagents, catalysts & solvents 3

HCID 178506421HCID 178506421, compoundCatalystHCID 1140TolueneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

Argon was bubbled through a solution of tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethyl{[(2R)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 370, 395 mg, 0.55 mmol) in toluene (15 mL) and 1,4-dioxane (3 mL) for 10 minutes. Bis(diphenylphosphino)ferrocene-palladium (40 mg) and methyl 4-iodobenzoate (216 mg, 0.83 mmol) were added, and bubbling with argon was continued for another 5 minutes. 2 N aq. sodium carbonate solution (3 mL, 6 mmol) was added and the reaction mixture was heated (85° C.) for 16 hours. After cooling, the mixture was filtered through a pad of silica gel and Celite® using ethyl acetate to rinse. The filtrate was concentrated in vacuo and then flash chromatography of the residue over silica gel using 20% ethyl acetate/hexanes afforded 276 mg (69%) of the desired product. The product had: 1H NMR (CDCl3, δ): 8.65 (d, J=20.0 Hz, 1 H), 8.13 (d, J=7.9 Hz, 2 H), 7.91 (dd, J=16.8, 8.1 Hz, 1 H), 7.67 (d, J=7.6 Hz, 2 H), 7.24-7.47 (m, 3 H), 6.93 (dd, J=8.1, 1.8 Hz, 1 H), 5.98 (d, J=3.9 Hz, 1 H), 5.23 (dd, J=43.5, 5.5 Hz, 1 H), 4.21-4.43 (m, 1 H), 4.00 (s, 3 H), 3.37-3.95 (m, 4 H), 2.84-3.09 (m, 2 H), 2.22 (s, 3 H), 2.20 (s, 3 H), 2.03-2.18 (m, 1 H), 1.74-1.91 (m, 1 H), 1.59 (d, J=10.4 Hz, 9 H), 0.99 (s, 9 H), 0.17 (s, 3 H), 0.00 (s, 3 H); mass spectroscopy gave m/z=726.4 [M+H]+ (calc'd exact mass for C42H55N3O6Si=725.4).

Workup

  1. custombubbling with argon
  2. temperatureAfter cooling
  3. filtrationthe mixture was filtered through a pad of silica gel and Celite®
  4. washto rinse
  5. concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record
ord-4f6ba5b7ea3247808570f2a276b371a6
Source dataset
uspto-grants-2005_07
Patent number
US06919371B2

Reaction notes

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