3-Bromo-2-fluoro-4-iodopyridine → 5-(3-Bromo-2-fluoropyridin-4-yl)-N4-(cyclopropylmethyl)pyrimidine-2,4-diamine

HRID 79147

Reaction equation

HRID 79147 reaction equation
C([Mg]Cl)(C)C.[Br:6][C:7]1[C:8]([F:14])=[N:9][CH:10]=[CH:11][C:12]=1I.[CH:15]1([CH2:18][NH:19][C:20]2[C:25](I)=[CH:24][N:23]=[C:22]([NH2:27])[N:21]=2)[CH2:17][CH2:16]1>CCOCC.C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:6][C:7]1[C:8]([F:14])=[N:9][CH:10]=[CH:11][C:12]=1[C:25]1[C:20]([NH:19][CH2:18][CH:15]2[CH2:16][CH2:17]2)=[N:21][C:22]([NH2:27])=[N:23][CH:24]=1

Participants

8

Reactant 3

HCID 404186293-Bromo-2-fluoro-4-iodopyridineHCID 58299566N4-(Cyclopropylmethyl)-5-iodopyrimidine-2,4-diamineHCID 178418918HCID 178418918, compound

Product 1

HCID 582995575-(3-Bromo-2-fluoropyridin-4-yl)-N4-(cyclopropylmethyl)pyrimidine-2,4-diamineYield 80.1%

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

Isopropylmagnesium chloride, 2 M solution in THF (0.814 mL, 1.63 mmol) was added dropwise over 15 minutes to a degassed solution of 3-bromo-2-fluoro-4-iodopyridine (0.468 g, 1.55 mmol) in Et2O (0.150 mL) and THF (0.850) cooled at −78° C. The solution was stirred for 0.5 h. Zinc chloride, 1.0 M solution in diethyl ether (0.776 mL, 0.776 mmol) was then added dropwise to the reaction over 10 minutes. The reaction was allowed to reach room temperature. The reaction warmed to room temperature within 15 min. A solution of compound 238 (0.150 g, 0.517 mmol) and tetrakis(triphenylphosphine)palladium (0.0418 g, 0.0362 mmol) in THF (0.50 mL) was added to the reaction. The reaction was equipped with a reflux condenser and stirred in a 60° C. oil bath. After 2 h the reaction was removed from heat and allowed to stand overnight. Saturated NH4Cl (0.5 mL) and 12% 2-propanol in CH2Cl2 (2 mL) were added. The organics were sequestered and the aqueous was extracted with 12% 2-propanol in CH2Cl2 (4×4 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography (elution 3% methanol in DCM with 0.175% NH4OH additive) afforded compound 240 (0.140 g, 80.1% yield). 1H NMR (500 MHz, CDCl3) δ ppm 0.22 (d, J=4.40 Hz, 2 H) 0.46-0.59 (m, 2H) 0.96-1.07 (m, 1H) 3.21-3.36 (m, 2 H) 4.51 (br. s., 1 H) 5.11 (br. s., 2 H) 7.16 (d, J=4.89 Hz, 1H) 7.69 (s, 1 H) 8.22 (d, J=4.89 Hz, 1 H) ppm.

Workup

  1. customto reach room temperature
  2. temperatureThe reaction warmed to room temperature within 15 min
  3. customThe reaction was equipped with a reflux condenser
  4. stirringstirred in a 60° C. oil bath
  5. customAfter 2 h the reaction was removed
  6. temperaturefrom heat
  7. waitto stand overnight
  8. additionSaturated NH4Cl (0.5 mL) and 12% 2-propanol in CH2Cl2 (2 mL) were added
  9. extractionthe aqueous was extracted with 12% 2-propanol in CH2Cl2 (4×4 mL)
  10. washThe combined organics were washed with brine
  11. dry with materialdried over MgSO4
  12. concentrationconcentrated in vacuo
  13. washSilica gel chromatography (elution 3% methanol in DCM with 0.175% NH4OH additive)

Sources & evidence

ORD record
ord-ce58b208735d4b6092a3ee711a49c5cc
Source dataset
uspto-grants-2014_09
Patent number
US08841312B2

Linked notes

Loading…