Toluene → 3-Fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride

HRID 1950129Notes

Reaction equation

[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=[O:7].C1(C)C=CC=CC=1>S(Cl)(Cl)=O>[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6]([Cl:1])=[O:7]

Participants

Conditions

Temperature: 110 °C

Procedure

To a solution of 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (2.5 g) in thionyl chloride (25 ml) was added toluene (25 ml), the solution was stirred for 1.5 hours at 110° C., and then the reaction solution was concentrated in vacuo to provide 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (2.2 g). To a solution of 5-methoxy-2-(6-methoxynaphthalen-2-yl)phenylamine (280 mg) in pyridine (3 ml) was added 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoyl chloride hydrochloride (420 mg), and the solution was stirred overnight at room temperature. A saturated aqueous solution of sodium bicarbonate was added thereto, the solution was stirred, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-methanol system) to provide 3-fluoro-N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(3-piperidin-1-ylethoxy)benzamide (448 mg). To a suspension of lithium aluminum hydride (130 mg) in tetrahydrofuran (3 ml) was added aluminum chloride (455 mg) on an ice bath under a nitrogen atmosphere, the solution was stirred for 30 minutes at room temperature, then 3-fluoro-N-[5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]-4-(2-piperidin-1-ylethoxy)benzamide (446 mg) was added thereto followed by stirring overnight at room temperature. Obtained by sequentially adding tetrahydrofuran and aqueous ammonia, the suspension was filtered through celite pad, and then the filtrate was concentrated in vacuo to provide the title compound (396 mg).

Workup

concentrationthe reaction solution was concentrated in vacuo

Sources & evidence

ORD record: ord-b4d035d6532c49cd969005f2b8ca433e
Source dataset: uspto-grants-2013_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08399520B2

Reaction notes

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