Formaldehyde → 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid

HRID 541157Notes

Reaction equation

C(O[C:4](=[O:31])[CH:5]([N:7]1[CH:11]=[C:10]([C:12]2[C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:16]=3[CH:15]=[C:14]([F:30])[CH:13]=2)[CH:9]=[N:8]1)[CH3:6])C.C=[O:33].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)[CH:54]=[O:55]>O1CCCC1>[F:30][C:14]1[CH:13]=[C:12]([C:10]2[CH:9]=[N:8][N:7]([C:5]([CH3:6])([CH2:54][OH:55])[C:4]([OH:31])=[O:33])[CH:11]=2)[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([OH:29])([C:25]([F:27])([F:28])[F:26])[C:16]=2[CH:15]=1

Participants

Conditions

Temperature: 100 °C

Procedure

To a solution of an optically active form (27.9 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester and paraformaldehyde (17.0 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (170 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was filtered through celite, and the solid was washed with ethyl acetate (100 ml). To the filtrate was added 1N hydrochloric acid (400 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (26.6 g).

Workup

filtrationThe reaction mixture was filtered through celite
washthe solid was washed with ethyl acetate (100 ml)
additionTo the filtrate was added 1N hydrochloric acid (400 ml)
extractionthe mixture was extracted with ethyl acetate (100 ml)
extractionThe separated aqueous layer was extracted twice with ethyl acetate (100 ml)
washThe combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine
dry with materialdried over anhydrous sodium sulfate
concentrationconcentrated under reduced pressure
customThe obtained residue was azeotroped twice with toluene

Sources & evidence

ORD record: ord-54a21331e60847b4ba8eb1b47bbd109a
Source dataset: uspto-grants-2014_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08871934B2

Reaction notes

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