Ethylene Glycol → 2-{[6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}ethanol

HRID 2200810Notes

Reaction equation

[CH2:1]([OH:4])[CH2:2][OH:3].Cl[C:6]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=1.[H-].[Na+]>O1CCCC1>[O:20]1[C:16]2([CH2:21][CH2:22][CH:13]([O:12][C:10]3[N:9]=[C:8]([C:23]([F:26])([F:25])[F:24])[N:7]=[C:6]([O:3][CH2:2][CH2:1][OH:4])[CH:11]=3)[CH2:14][CH2:15]2)[O:17][CH2:18][CH2:19]1

Participants

Conditions

Temperature: 0 °C

Procedure

1,2-Ethanediol (60 μL, 1.1 mmol) and 4-chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (91 mg, 0.27 mmol) were dissolved in tetrahydrofuran (1.4 mL) and cooled to 0° C. Sodium hydride (60%/mineral oil, 22 mg, 0.56 mmol) was added and stirred for 30 minutes at 0° C., then at 22° C. for 20 hours. LCMS analysis showed no remaining starting material, and as the main component, formation of the product, M+H 365. The reaction was quenched with aqueous bicarbonate. The aqueous solution was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (Na2SO4) and the solvent removed in vacuo. The product was purified by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 38% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 56%; 60 mL/min; detector set at M+H 365; retention time, 5.7 min. HPLC found the UVmax as 240 nm. The solvent was removed by rotary evaporation to give 56 mg of product (57% yield). The compound of Example 56 was then obtained by following the steps described for Example 45.

Workup

waitat 22° C. for 20 hours
customThe reaction was quenched with aqueous bicarbonate
extractionThe aqueous solution was extracted with ethyl acetate
washthe organic extracts were washed with water, saturated NaCl
dry with materialdried (Na2SO4)
customthe solvent removed in vacuo
customThe product was purified by preparative LCMS
custom38% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient
customretention time, 5.7 min
customThe solvent was removed by rotary evaporation

Sources & evidence

ORD record: ord-24bf9f6c865d4c34b8c3e83565fd6a04
Source dataset: uspto-grants-2016_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09359358B2

Reaction notes

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