Cyano-borohydride → (1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine

HRID 1098878Notes

Reaction equation

[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([CH3:22])=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:36]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:36])[CH3:22]

Participants

Conditions

Temperature: 140 °C

Procedure

1-{[6-Chloro-1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(4-fluorophenyl)acetone (500 mg, 1.21 mmol), ammonium acetate (934 mg, 12.11) and cyanoborohydride on polymer support (1.82 g, 3.63 mmol) were mixed in methanol (3 ml) and heated in micro at 140° C. for 10 min. The mixture was concentrated and treated with NaHCO3 and DCM. The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/heptane followed by EtOAc/methanol). The diasteromers were separated on preparative HPLC (Kromasil column, water buffered with 2 g NH4OAc/l, pH set to 5.5 with HOAc, and MeCN, 25%-75%) to give the syn-isomer (1RS,2RS)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (98a-rac-1) as first eluted isomer (assignment by 1H-NMR).

Workup

concentrationThe mixture was concentrated
additiontreated with NaHCO3 and DCM
concentrationThe organic phase was concentrated
customthe crude product was purified by flash chromatography (EtOAc/heptane followed by EtOAc/methanol)
customThe diasteromers were separated on preparative HPLC (Kromasil column, water

Sources & evidence

ORD record: ord-256b74bcdd18478c969272453f0478fe
Source dataset: uspto-grants-2012_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08143290B2

Reaction notes

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