Sodium Hydroxide → HCID 59596626, compound

HRID 2264980Notes

Reaction equation

HRID 2264980 reaction equation
C(O[C:4]([C:6]1[N:14]([CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])=[O:5])C.[OH-].[Na+].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:58]([O:60][CH2:61][CH2:62][O:63][NH2:64])=[CH2:59].CCN(C(C)C)C(C)C>C1COCC1.CO[2H]>[CH:58]([O:60][CH2:61][CH2:62][O:63][NH:64][C:4]([C:6]1[N:14]([CH2:15][C:16]#[C:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:26][C:27]1[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=1[F:34])=[O:5])=[CH2:59]

Participants

9

Reactant 6

HCID 14798Sodium HydroxideHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 21867017O-(2-(Vinyloxy)ethyl)hydroxylamineHCID 59596608HCID 59596608, compound

Product 1

HCID 59596626HCID 59596626, compoundYield 30.3%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 123113Methan(2H)olSolvent

Conditions

Temperature
65 °C

Procedure

To a stirred solution of 3-(2-fluoro-4-iodo-phenylamino)-1-[4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl]-1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (147.0 mg, 0.25 mmol) in anhydrous THF (1.0 mL) and MeOD (3.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.51 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow foam. The yellow foam was redissolved in anhydrous THF (7.9 ml). EDCI (103.3 mg, 0.54 mmol, 2.2 eq) and HOBT (72.8 mg, 0.54 mmol, 2.2 eq) were added. The reaction mixture was stirred at room temperature. After 5 minutes O-(2-vinyloxy-ethyl)-hydroxylamine (50.5 mg, 0.49 mmol, 2.0 eq) and DIPEA (0.19 mL, 1.10 mmol, 4.5 eq) were added, and the reaction mixture was stirred at ambient temperature under N2 for 17 h. The reaction mixture was absorbed onto silica and purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100) to give the desired product as a yellow solid (47.2 mg, 30.3%). 1H-NMR (400 MHz, CDCl3) δ ppm 8.60 (s, 1H), 8.40 (d, J=5.95 Hz, 1H), 7.54-7.36 (m, 2H), 7.21 (d, J=8.48 Hz, 1H), 6.43-6.34 (m, 2H), 6.20 (broad s, 1H), 5.49 (s, 2H), 4.71 (m, 1H), 4.26-4.11 (m, 4H), 4.03 (dd, J=6.80, 2.4 Hz, 1H), 3.93-3.86 (m, 2H), 3.80-3.72 (m, 1H), 3.48 (m, 3H), 1.82-1.64 (m, 2H), 1.62-1.44 (m, 4H); LC-MS (method C): [M+H]+=635.1, RT=0.839 min.

Workup

  1. customThe resultant reaction mixture
  2. customwas evaporated in vacuo
  3. customazeotroped with toluene (3×5 ml)
  4. customto give a yellow foam
  5. stirringThe reaction mixture was stirred at room temperature
  6. stirringthe reaction mixture was stirred at ambient temperature under N2 for 17 h
  7. customThe reaction mixture was absorbed onto silica
  8. custompurified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100)

Sources & evidence

ORD record
ord-9f96a7efb9dd495b97b888ec28c23a7f
Source dataset
uspto-grants-2010_12
Patent number
US07855216B2

Reaction notes

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