Hydroxyamine hydrochloride → methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate

HRID 2414972Notes

Reaction equation

Cl.[NH2:2][OH:3].O=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]>N1C=CC=CC=1>[OH:3][N:2]=[C:5]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([O:40][CH3:41])[CH:38]=2)[N:33]=[CH:32][C:31]=1[F:42])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[CH2:10][CH:9]1[CH2:25][C:26]([O:28][CH3:29])=[O:27]

Participants

Conditions

Temperature: 20 °C

Procedure

0.347 g of hydroxylamine hydrochloride were added, in several portions, to a mixture of 1 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl)-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate in 10-cm3 of pyridine, with stirring and under an inert atmosphere, and the resulting mixture was stirred in the region of 20° C. for 24 hours and then for 20 hours in the region of 50° C. and for 1.25 hours in the region of 62° C. After cooling in the region of 20° C., the reaction mixture was concentrated to dryness under reduced pressure (1.5 kPa) at a temperature in the region of 50° C. The evaporation residue was taken up in 70-cm3 of ethyl acetate and 40-cm3 of distilled water. The organic phase was separated after settling out, washed 3 times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatrography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume) and then dichloromethane-methanol (90/10 by volume) and collecting 10-cm3 fractions. Fractions 1 to 21 were combined and then concentrated to dryness according to the conditions described above. 0.813 g of methyl (3RS,4RS)-4-[3-hydroxyimino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetate were obtained in the form of a whitish viscous oil.

Workup

stirringthe resulting mixture was stirred in the region of 20° C. for 24 hours
waitfor 1.25 hours in the region of 62° C
concentrationthe reaction mixture was concentrated to dryness under reduced pressure (1.5 kPa) at a temperature in the region of 50° C
customThe organic phase was separated
washwashed 3 times with 40-cm3 of distilled water and 40-cm3 of a saturated sodium chloride solution
dry with materialdried over magnesium sulfate
filtrationfiltered
concentrationconcentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C
customThe evaporation residue was purified by chromatrography under an argon pressure of 50 kPa
washon a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a successive mixture of cyclohexane-ethyl acetate (60/40 by volume)
customdichloromethane-methanol (90/10 by volume) and collecting 10-cm3 fractions
concentrationconcentrated to dryness

Sources & evidence

ORD record: ord-0cee35b77514465fad90637ec2f9017b
Source dataset: uspto-grants-2004_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06815547B2

Reaction notes

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