Methanol → HCID 135436641, compound

HRID 2111173Notes

Reaction equation

HRID 2111173 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[NH:13]1[C:17]2[CH:18]=[CH:19][S:20][C:16]=2[C:15]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:25][CH:24]=3)=[N:14]1.CO>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]([C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:15]1[C:16]3[S:20][CH:19]=[CH:18][C:17]=3[NH:13][N:14]=1)=[CH:29]2)([OH:33])[CH2:31][CH3:32]

Participants

6

Reactant 4

HCID 887MethanolHCID 79732-BromopyridineHCID 135499784HCID 135499784, compoundHCID 178418339Butyllithium

Product 1

HCID 135436641HCID 135436641, compoundYield 96.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 2-bromopyridine (224 mg, 1.42 mmol) in anhydrous tetrahydrofuran (2 mL) is added n-BuLi (1.6 M in hexane, 0.95 mL, 1.52 mmol) at −78° C. under nitrogen. After stirring for 20 minutes, to it is added a solution of 1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl)-propan-1-one (140 mg, 0.473 mmol, Example 28) in anhydrous tetrahydrofuran (4 mL) drop wise. After 30 minutes, the cooling bath is removed and continued stirring at ambient temp for 30 minutes. The reaction is quenched by the addition of saturated ammonium chloride (4 mL) followed by water (4 mL). The reaction mixture is extracted with ethyl acetate (120 mL). Ethyl acetate phase is washed with water, brine and dried over sodium sulfate. Purification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane) afforded product. It is then dissolved with minimum amount of methanol and triturated with water to give 1-pyridin-2-yl-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (171 mg, 31%, Example 31) as a beige solid; 1H NMR [(CD3)2SO)]: δ 13.195 (1H, s), 11.417 (1H, s), 8.472 (1H, d), 7.742-7.661 (4H, m) 7.259-7.166 (4H, m), 6.59 (1H, s), 5.697 (1H, s, OH), 2.361 (2H, m), 0.785 (3H, t); LC/MS: 375 (M+H).

Workup

  1. waitAfter 30 minutes
  2. customthe cooling bath is removed
  3. stirringcontinued stirring at ambient temp for 30 minutes
  4. customThe reaction is quenched by the addition of saturated ammonium chloride (4 mL)
  5. extractionThe reaction mixture is extracted with ethyl acetate (120 mL)
  6. washEthyl acetate phase is washed with water, brine
  7. dry with materialdried over sodium sulfate
  8. customPurification by chromatography (10 g silica gel cartridge, 30-60% ethyl acetate gradient in heptane)
  9. customafforded product
  10. customtriturated with water

Sources & evidence

ORD record
ord-7c7f1785be224bad86fcb4b53cf689b6
Source dataset
uspto-grants-2009_04
Patent number
US07518000B2

Reaction notes

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