3-Fluorobenzaldehyde → toluene-4-sulfonic acid 3-[3-[(3-fluoro-phenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester

HRID 729831Notes

Reaction equation

HRID 729831 reaction equation
I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:3]=1.[Li]C(C)(C)C.[F:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH:47]=[O:48]>C1COCC1.CCCCC>[F:43][C:44]1[CH:45]=[C:46]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([O:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=5)(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:3]=2)[CH:49]=[CH:50][CH:51]=1

Participants

6

Reactant 3

HCID 680093-FluorobenzaldehydeHCID 59699703toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl esterHCID 178418306HCID 178418306, compound

Product 1

HCID 86602995toluene-4-sulfonic acid 3-[3-[(3-fluoro-phenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl esterYield 52.5%

Reagents, catalysts & solvents 2

HCID 8003PentaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

To a solution of toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared as exemplified in method 6) in THF (2 mL) at −90° C. under nitrogen atmosphere was added a solution of tBuLi in pentane (1.7 M, 90 uL) dropwise. After stirring for 5 min, 3-fluoro-benzaldehyde (40 uL, 0.38 mmol) was added and the reaction mixture was slowly warmed up to 10° C. over 2 h, then quenched with a saturated solution of ammonium chloride and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 26 mg of toluene-4-sulfonic acid 3-[3-[(3-fluoro-phenyl)-hydroxy-methyl]-1-(toluene-4-sulfonyl)-1H-pyrrolo [2,3-b]pyridine-5-yl]-phenyl ester. The material was dissolved in dichloromethane (0.3 mL) under nitrogen atmosphere. Triethylsilane (24 uL, 0.149 mmol) was added, followed by boron trifluoride etherate (7 μL, 0.149 mmol) dropwise. After stirring for 15 h, the reaction was quenched with a saturated solution of sodium bicarbonate and extracted with dichloromethane three times. The extracts were combined and concentrated under vacuum. The crude was treated with 2 mL of EtOH and 2 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 70° C. for 1 h. The mixture was acidified to pH 4 with 1 N aqueous HCl, and extracted with EtOAc three times. The extracts were combined and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(3-fluoro-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol as a beige solid (8 mg, 66% yield). 1H NMR (500 MHz, DMSO-d6) δ 4.11 (s, 3H), 6.74 (dd, J=2.5, 8.5 Hz, 1H), 6.97 (dt, J=2.0, 8.5 Hz, 1H), 7.00 (s, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.13 (d, J=10.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H), 7.30 (q, J=8.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 9.56 (broads, 1H), 11.6 (s, 1H). MS: m/z 319 (M+H+).

Workup

  1. customquenched with a saturated solution of ammonium chloride
  2. extractionextracted with EtOAc three times
  3. customPurification on silica gel with a gradient of MeOH/CH2Cl2

Sources & evidence

ORD record
ord-7137f4ac54a842599216ae2d1d66ac8f
Source dataset
uspto-grants-2009_09
Patent number
US07582637B2

Reaction notes

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