Isonicotinic Acid → [2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl Isonicotinate

HRID 1374701Notes

Reaction equation

HRID 1374701 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[C:31]([O:17][CH2:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:18]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[C:11]2[CH:12]=1)(=[O:32])[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1

Participants

7

Reactant 4

HCID 5922Isonicotinic AcidHCID 8471TriethylamineHCID 76257Diethyl cyanophosphonateHCID 99667962-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine

Product 1

HCID 10159364[2-(4-Fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridin-5-yl]methyl Isonicotinate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21226206Ethyl acetate hexaneSolvent

Procedure

2-(4-Fluorophenyl)-5-hydroxymethyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (Example 6. 30 mg, 0.094 mmol) and 4-pyridinecarboxylic acid (0.12 mmol) are dissolved in dimethylformamide (0.5 mL) and diethyl cyanophosphonate (35 mg, 0.2 mmol, 93% grade), followed by triethylamine (35 mg, 0.35 mmol) are added dropwise. The resulting solution is stirred at room temperature until the reaction is complete as determined by TLC and then diluted with hexane/ethyl acetate (30 mL of a 1:1 mixture) and washed with water (3×). The organic phase is then shaken with dilute hydrochloric acid. In cases were the hydrochloride salt of the product deposits at this stage it is filtered off, washed with water and then hexane and dried. If no deposit is observed, the acidic phase is separated, washed once with hexane/ethyl acetate (15 mL of a 1:1 mixture) and basified with saturated sodium bicarbonate solution. This is then extracted with dichloromethane (15 mL) five times and the dichloromethane solution dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (d6-DMSO) δ 5.43 (s, 2H), 7.15 (d, J=6.9 Hz, 1H), 7.25 (t, J=8.8 Hz, 2H), 7.30 (d, J=5.9 Hz, 2H), 7.50–7.53 (m, 2H), 7.84–7.87 (m, 3H), 8.55 (d, J=5.7 Hz, 2H), 8.79 (d, J=5.9 Hz, 2H), 8.82 (d, J=7.1 Hz, 1H); APESI-MS m/z 425 (M+1)+.

Workup

  1. additionare added dropwise
  2. washwashed with water (3×)
  3. stirringThe organic phase is then shaken with dilute hydrochloric acid
  4. filtrationis filtered off
  5. washwashed with water
  6. dry with materialhexane and dried
  7. customthe acidic phase is separated
  8. washwashed once with hexane/ethyl acetate (15 mL of a 1:1 mixture) and
  9. extractionThis is then extracted with dichloromethane (15 mL) five times
  10. dry with materialthe dichloromethane solution dried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-6a2fa1ed4e3545fea60581f505e652b3
Source dataset
uspto-grants-2007_01
Patent number
US07166597B2

Reaction notes

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