Tetrahydrofuran → Diethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]malonate

HRID 2200798Notes

Reaction equation

HRID 2200798 reaction equation
O1CC[CH2:3][CH2:2]1.[H-].[Na+].[C:8]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:9][C:10]([O-:12])=[O:11].Cl[C:18]1[CH:23]=[C:22]([O:24][CH:25]2[CH2:34][CH2:33][C:28]3([O:32][CH2:31][CH2:30][O:29]3)[CH2:27][CH2:26]2)[N:21]=[C:20]([C:35]([F:38])([F:37])[F:36])[N:19]=1>C(=O)(O)[O-]>[O:32]1[C:28]2([CH2:33][CH2:34][CH:25]([O:24][C:22]3[N:21]=[C:20]([C:35]([F:38])([F:37])[F:36])[N:19]=[C:18]([CH:9]([C:10]([O:12][CH2:2][CH3:3])=[O:11])[C:8]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=3)[CH2:26][CH2:27]2)[O:29][CH2:30][CH2:31]1

Participants

6

Reactant 4

HCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 3595298Propanedioic acid, monoethyl esterHCID 86676919Chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine

Product 1

HCID 71266663Diethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]malonateYield 90%

Reagents, catalysts & solvents 1

HCID 769Bicarbonate IonSolvent

Conditions

Temperature
64 °C

Procedure

To a mixture of tetrahydrofuran (40 mL) and NaH in mineral oil (1.1 g, 28 mmol) at 0° C. was added ethyl malonate (4.2 mL, 28 mmol), dropwise. 4-chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (3.75 g, 11.1 mmol), was then added. The reaction mixture was stirred at 64° C. After 3 hours, HPLC & LCMS analysis showed 70% reaction completion. Heated for another 6 hours, and then cooled to 20° C. Only a trace of decarboxylation product formed. The reaction was diluted with aqueous bicarbonate, and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, and evaporated in vacuo to give 8.5 g oil (includes excess ethyl malonate and mineral oil). The crude product was purified by chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=EtOAc; flow 60 mL/min; A, 3 min; Gradient to 40% B in 40 min; detector set at 254 nm; collected 47 mL fractions; retention time, 28 min. The combined fractions were evaporated to give 4.6 g, colorless oil, 90% yield. 1H NMR (300 MHz, CDCl3): δ7.05 (s, 1H); 5.30 (m, 1H, OCH); 4.85 (s, 1H, CH); 4.25 (m, 2H, OCH2); 3.95 (s, 4H, OCH2); 1.6-2.1 (m, 8H); 1.28 (t, 3H, CH3).

Workup

  1. custom70% reaction completion
  2. temperatureHeated for another 6 hours
  3. temperaturecooled to 20° C
  4. customOnly a trace of decarboxylation product formed
  5. extractionextracted with EtOAc
  6. extractionThe EtOAc extract
  7. washwas washed with brine
  8. dry with materialdried over Na2SO4
  9. customevaporated in vacuo

Sources & evidence

ORD record
ord-a9e0662206054591b6609bb2c04e2d3a
Source dataset
uspto-grants-2016_06
Patent number
US09359358B2

Reaction notes

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