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

HRID 634234ノート

反応式

HRID 634234 の反応式
[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

参加物

5

反応物 3

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

生成物 1

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

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒2 回

反応条件

温度
-10 °C

実験手順

(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).

後処理

  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)

出典と根拠

ORDレコード
ord-3ca0c3f450994a34976f15af6756679a
出典データセット
uspto-grants-2016_04
特許番号
US09321756B2

反応ノート

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