Phosphorus oxychloride → 2-Chloro-5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine

HRID 1591677Notes

Reaction equation

HRID 1591677 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[CH2:16][C:15](=O)[NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:20])=O>CC1C=CC(C)=CC=1>[Cl:20][C:15]1[NH:14][C:11]2=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]2[CH:16]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 469120855-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one

Product 1

HCID 469120842-Chloro-5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridineYield 56.3%

Reagents, catalysts & solvents 1

HCID 7809P-XyleneSolvent

Conditions

Temperature
102.5 °C

Procedure

A suspension of 5 (16.52 g, 72.4 mmol) in neat P(O)Cl3 (21.5 mL, 0.231 mol) was stirred at 100-105° C. for 4 h. The mixture was then cooled to r.t., diluted with p-xylene (100 mL) and concentrated to dryness in vacuum. The residue was separated between saturated aqueous NaHCO3—AcOEt. 10% aqueous solution of Na2CO3 was added to basify the aqueous layer to pH 9. Organic phase was separated and the aqueous layer was extracted with AcOEt (8×300 mL). Combined organic solutions were dried MgSO4, concentrated, and the residue was purified by silicagel chromatography (SGC) using CH2Cl2:AcOEt as eluent in gradient to afford recovered starting material 5 (0.76 g, 5%). The desired product was then crystallized from acetone to afford 6 (10.06 g, 56%), thin tan needles. 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 7.08 (tdd, J=8.1, 2.3, 1.5 Hz, 1H), 7.33 (ddd, J=9.9, 2.3, 1.6 Hz, 1H), 7.38-7.48 (m, 2H), 8.03 (d, J=2.1 Hz, 1H), 8.53 (d, J=2.1 Hz, 1H), 11.46 (bs, 1H).

Workup

  1. temperatureThe mixture was then cooled to r.t.
  2. concentrationconcentrated to dryness in vacuum
  3. customThe residue was separated between saturated aqueous NaHCO3—AcOEt
  4. addition10% aqueous solution of Na2CO3 was added
  5. customOrganic phase was separated
  6. extractionthe aqueous layer was extracted with AcOEt (8×300 mL)
  7. concentrationconcentrated
  8. customthe residue was purified by silicagel chromatography (SGC)
  9. customAcOEt as eluent in gradient to afford
  10. customrecovered
  11. customThe desired product was then crystallized from acetone

Sources & evidence

ORD record
ord-91df447f6da94e068d29a2045121146e
Source dataset
uspto-grants-2007_11
Patent number
US07291630B2

Reaction notes

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