Propylphosphonic anhydride → 3-(4-cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide

HRID 2272709Notes

Reaction equation

HRID 2272709 reaction equation
[NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O[C:21](=O)[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23])C.CC(C)([O-])C.[K+].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.O>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:8]2[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=[C:21]2[C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[CH:10][C:11]=1[F:17])#[N:14]

Participants

8

Reactant 5

HCID 111923Propylphosphonic anhydrideHCID 516892Sodium BicarbonateHCID 23665647Potassium tert-butoxideHCID 28710173Ethyl (cyclopropylamino)(oxo)acetateHCID 867300704-[(3-Aminopyridin-2-yl)amino]-2-fluorobenzonitrile

Product 1

HCID 783222933-(4-cyano-3-fluorophenyl)-N-cyclopropyl-3H-imidazo[4,5-b]pyridine-2-carboxamide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
120 °C

Procedure

To a mixture of 4-[(3-aminopyridin-2-yl)amino]-2-fluorobenzonitrile (C15) (3.9 g, 17 mmol) and ethyl(cyclopropylamino)(oxo)acetate (P1) (4.03 g, 25.6 mmol) in 1-methylpyrrolidin-2-one (17 mL) was added potassium tert-butoxide (2.88 g, 25.7 mmol). The reaction mixture was stirred at 120° C. for 30 minutes, cooled to room temperature, and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P) (˜50% weight solution, 20.3 mL, 32 mmol). After the reaction mixture had been stirred at 120° C. for 18 hours, it was allowed to cool. Water (10 mL) was added and stirring was continued for 10 minutes. Saturated aqueous sodium bicarbonate solution (20 mL) was introduced, and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, filtered, and concentrated in vacuo Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether) afforded the product as a white solid. Yield: 2.29 g, 7.13 mmol, 42%. LCMS m/z 322.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=4.7, 1.4 Hz, 1H), 8.17 (dd, J=8.2, 1.5 Hz, 1H), 7.79-7.85 (m, 1H), 7.69 (br s, 1H), 7.38-7.45 (m, 3H), 2.83-2.90 (m, 1H), 0.87-0.93 (m, 2H), 0.68-0.73 (m, 2H).

Workup

  1. temperaturecooled to room temperature
  2. stirringAfter the reaction mixture had been stirred at 120° C. for 18 hours
  3. temperatureto cool
  4. stirringstirring
  5. waitwas continued for 10 minutes
  6. extractionthe mixture was extracted with ethyl acetate (3×50 mL)
  7. washThe combined organic layers were washed with saturated aqueous sodium chloride solution
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo Silica gel chromatography (Gradient: 10% to 50% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-8a2ced191d604efeabe3f4cb3c2549c7
Source dataset
uspto-grants-2015_09
Patent number
US09120788B2

Reaction notes

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