Hydrochloric Acid → Ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate

HRID 1869424Notes

Reaction equation

[CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].C[N+](C)(C)C.Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]

Participants

Conditions

Temperature: -25 °C

Procedure

1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonium fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 minutes. It is filtered through Celite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine is added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO, and 1.6 g (10 mmol) of pyridine SO3.complex is added in portions over 10 minutes. It is stirred over 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.

Workup

extractionIt is extracted several times with ethyl acetate
washwashed with saturated sodium chloride solution
customdried on sodium sulfate
concentrationconcentrated by evaporation in a vacuum

Sources & evidence

ORD record: ord-5e2c8bf97caf4efda3fd6dbd278855b1
Source dataset: uspto-grants-2009_12
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07638515B2

Reaction notes

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