Diethyl methylmalonate → Diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonate

HRID 634234Notes

Reaction equation

HRID 634234 reaction equation
[CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>C1COCC1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]([CH3:1])([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:19]([F:23])=[CH:18][N:17]=1

Participants

5

Reactant 3

HCID 11857Diethyl methylmalonateHCID 24758Sodium hydrideHCID 2507052,4-Dichloro-5-fluoropyrimidine

Product 1

HCID 86725111Diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonateYield 83.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

(Prepared according to Butters, M. et al. Org. Proc. Res. Dev. 2001, 5, 28-36). Diethyl 2-methylmalonate (2.35 mL, 13.78 mmol) was treated with THF (80 mL) and cooled to −10° C. in a brine/ice bath. It was then treated with NaH (60 wt % suspension in mineral oil, 1.10 g, 27.6 mmol) and stirred at this temperature for 30 min. 2,4-Dichloro-5-fluoropyrimidine (2.00 g, 11.98 mmol) was suspended in THF (20 mL) and added to the cooled solution via pipette over 10 min. The solution turned an opaque yellow color. After stirring 20 min at −10° C. it was quenched by the addition of H2O (100 mL), DCM (150 mL) and glacial HOAc (ca. 1 mL to pH 6). The DCM layer was then separated and dried over MgSO4, filtered and concentrated affording a viscous oil. Purification with flash chromatography (eluting with 100% DCM) afforded diethyl 2-(2-chloro-5-fluoropyrimidin-4-yl)-2-methylmalonate (3.04 g, 83%) as a pale yellow viscous oil. MS (ESI, pos. ion) m/z: 305.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.44 (1H, d, J=2.0 Hz), 4.24-4.33 (4H, m), 1.90 (3H, s), 1.24-1.33 (9H, m).

Workup

  1. custom(Prepared according to Butters, M. et al. Org. Proc. Res. Dev. 2001, 5, 28-36)
  2. additionadded to the cooled solution via pipette over 10 min
  3. stirringAfter stirring 20 min at −10° C. it
  4. customwas quenched by the addition of H2O (100 mL), DCM (150 mL) and glacial HOAc (ca. 1 mL to pH 6)
  5. customThe DCM layer was then separated
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customaffording a viscous oil
  10. customPurification
  11. washwith flash chromatography (eluting with 100% DCM)

Sources & evidence

ORD record
ord-3ca0c3f450994a34976f15af6756679a
Source dataset
uspto-grants-2016_04
Patent number
US09321756B2

Reaction notes

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