1,2-Dimethoxyethane → 4-(1-(6-Fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholine

HRID 1622025Notes

Reaction equation

HRID 1622025 reaction equation
Cl[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH3:19])=[CH:14][C:13]=1[C:2]1[CH:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 569244304-Chloro-2-methyl-6-(methylthio)pyrimidineHCID 666111244-(1-(6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine

Product 1

HCID 666008374-(1-(6-Fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholineYield 78.8%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

To a 20 mL microwave vials was added 4-chloro-2-methyl-6-(methylthio)pyrimidine (0.175 g, 1.002 mmol), 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (Example 339 Step 3) (0.305 g, 1.202 mmol), trans-dichlorobis(triphenyl-phosphine)palladium (II) (Strem) (0.056 g, 0.080 mmol), sodium carbonate (JT Baker) (0.531 mg, 5.01 mmol), DME (10 mL), and water (2.5 mL). The vial was degassed by bubbling N2 for 5 min then sealed off and microwave heated at 90° C. for 20 min. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 10% to 20% acetone in hexanes) to afford the product as white solid (275 mg). MS (ESI pos. ion) m/z: 349.1. 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (d, J=6.72 Hz, 3H) 2.33-2.46 (m, 2H) 2.48-2.58 (m, 2H) 2.61 (s, 3H) 2.74 (s, 3H) 3.52 (q, J=6.58 Hz, 1H) 3.71 (t, J=4.46 Hz, 4H) 7.55 (s, 1H) 8.25 (s, 1H) 8.56 (dd, J=9.43, 2.27 Hz, 1H).

Workup

  1. customThe vial was degassed
  2. customby bubbling N2 for 5 min
  3. customthen sealed off
  4. customThe reaction mixture was partitioned between EtOAc and water
  5. extractionThe aqueous layer was extracted with EtOAc (2×10 mL)
  6. dry with materialThe combined organic layers were dried over MgSO4
  7. concentrationconcentrated
  8. customThe crude product was purified by column chromatography (40 g, 10% to 20% acetone in hexanes)

Sources & evidence

ORD record
ord-589d611a5c354e1cad4b788f63d4c76a
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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